How to Synthesize Written Information from Multiple Sources

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When you write a literature review or essay, you have to go beyond just summarizing the articles you’ve read – you need to synthesize the literature to show how it all fits together (and how your own research fits in).

Synthesizing simply means combining. Instead of summarizing the main points of each source in turn, you put together the ideas and findings of multiple sources in order to make an overall point.

At the most basic level, this involves looking for similarities and differences between your sources. Your synthesis should show the reader where the sources overlap and where they diverge.

Unsynthesized Example

Franz (2008) studied undergraduate online students. He looked at 17 females and 18 males and found that none of them liked APA. According to Franz, the evidence suggested that all students are reluctant to learn citations style. Perez (2010) also studies undergraduate students. She looked at 42 females and 50 males and found that males were significantly more inclined to use citation software ( p < .05). Findings suggest that females might graduate sooner. Goldstein (2012) looked at British undergraduates. Among a sample of 50, all females, all confident in their abilities to cite and were eager to write their dissertations.

Synthesized Example

Studies of undergraduate students reveal conflicting conclusions regarding relationships between advanced scholarly study and citation efficacy. Although Franz (2008) found that no participants enjoyed learning citation style, Goldstein (2012) determined in a larger study that all participants watched felt comfortable citing sources, suggesting that variables among participant and control group populations must be examined more closely. Although Perez (2010) expanded on Franz’s original study with a larger, more diverse sample…

Step 1: Organize your sources

After collecting the relevant literature, you’ve got a lot of information to work through, and no clear idea of how it all fits together.

Before you can start writing, you need to organize your notes in a way that allows you to see the relationships between sources.

One way to begin synthesizing the literature is to put your notes into a table. Depending on your topic and the type of literature you’re dealing with, there are a couple of different ways you can organize this.

Summary table

A summary table collates the key points of each source under consistent headings. This is a good approach if your sources tend to have a similar structure – for instance, if they’re all empirical papers.

Each row in the table lists one source, and each column identifies a specific part of the source. You can decide which headings to include based on what’s most relevant to the literature you’re dealing with.

For example, you might include columns for things like aims, methods, variables, population, sample size, and conclusion.

For each study, you briefly summarize each of these aspects. You can also include columns for your own evaluation and analysis.

summary table for synthesizing the literature

The summary table gives you a quick overview of the key points of each source. This allows you to group sources by relevant similarities, as well as noticing important differences or contradictions in their findings.

Synthesis matrix

A synthesis matrix is useful when your sources are more varied in their purpose and structure – for example, when you’re dealing with books and essays making various different arguments about a topic.

Each column in the table lists one source. Each row is labeled with a specific concept, topic or theme that recurs across all or most of the sources.

Then, for each source, you summarize the main points or arguments related to the theme.

synthesis matrix

The purposes of the table is to identify the common points that connect the sources, as well as identifying points where they diverge or disagree.

Step 2: Outline your structure

Now you should have a clear overview of the main connections and differences between the sources you’ve read. Next, you need to decide how you’ll group them together and the order in which you’ll discuss them.

For shorter papers, your outline can just identify the focus of each paragraph; for longer papers, you might want to divide it into sections with headings.

There are a few different approaches you can take to help you structure your synthesis.

If your sources cover a broad time period, and you found patterns in how researchers approached the topic over time, you can organize your discussion chronologically .

That doesn’t mean you just summarize each paper in chronological order; instead, you should group articles into time periods and identify what they have in common, as well as signalling important turning points or developments in the literature.

If the literature covers various different topics, you can organize it thematically .

That means that each paragraph or section focuses on a specific theme and explains how that theme is approached in the literature.

synthesizing the literature using themes

Source Used with Permission: The Chicago School

If you’re drawing on literature from various different fields or they use a wide variety of research methods, you can organize your sources methodologically .

That means grouping together studies based on the type of research they did and discussing the findings that emerged from each method.

If your topic involves a debate between different schools of thought, you can organize it theoretically .

That means comparing the different theories that have been developed and grouping together papers based on the position or perspective they take on the topic, as well as evaluating which arguments are most convincing.

Step 3: Write paragraphs with topic sentences

What sets a synthesis apart from a summary is that it combines various sources. The easiest way to think about this is that each paragraph should discuss a few different sources, and you should be able to condense the overall point of the paragraph into one sentence.

This is called a topic sentence , and it usually appears at the start of the paragraph. The topic sentence signals what the whole paragraph is about; every sentence in the paragraph should be clearly related to it.

A topic sentence can be a simple summary of the paragraph’s content:

“Early research on [x] focused heavily on [y].”

For an effective synthesis, you can use topic sentences to link back to the previous paragraph, highlighting a point of debate or critique:

“Several scholars have pointed out the flaws in this approach.” “While recent research has attempted to address the problem, many of these studies have methodological flaws that limit their validity.”

By using topic sentences, you can ensure that your paragraphs are coherent and clearly show the connections between the articles you are discussing.

As you write your paragraphs, avoid quoting directly from sources: use your own words to explain the commonalities and differences that you found in the literature.

Don’t try to cover every single point from every single source – the key to synthesizing is to extract the most important and relevant information and combine it to give your reader an overall picture of the state of knowledge on your topic.

Step 4: Revise, edit and proofread

Like any other piece of academic writing, synthesizing literature doesn’t happen all in one go – it involves redrafting, revising, editing and proofreading your work.

Checklist for Synthesis

  •   Do I introduce the paragraph with a clear, focused topic sentence?
  •   Do I discuss more than one source in the paragraph?
  •   Do I mention only the most relevant findings, rather than describing every part of the studies?
  •   Do I discuss the similarities or differences between the sources, rather than summarizing each source in turn?
  •   Do I put the findings or arguments of the sources in my own words?
  •   Is the paragraph organized around a single idea?
  •   Is the paragraph directly relevant to my research question or topic?
  •   Is there a logical transition from this paragraph to the next one?

Further Information

How to Synthesise: a Step-by-Step Approach

Help…I”ve Been Asked to Synthesize!

Learn how to Synthesise (combine information from sources)

How to write a Psychology Essay

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  • Synthesizing Sources | Examples & Synthesis Matrix

Synthesizing Sources | Examples & Synthesis Matrix

Published on July 4, 2022 by Eoghan Ryan . Revised on May 31, 2023.

Synthesizing sources involves combining the work of other scholars to provide new insights. It’s a way of integrating sources that helps situate your work in relation to existing research.

Synthesizing sources involves more than just summarizing . You must emphasize how each source contributes to current debates, highlighting points of (dis)agreement and putting the sources in conversation with each other.

You might synthesize sources in your literature review to give an overview of the field or throughout your research paper when you want to position your work in relation to existing research.

Table of contents

Example of synthesizing sources, how to synthesize sources, synthesis matrix, other interesting articles, frequently asked questions about synthesizing sources.

Let’s take a look at an example where sources are not properly synthesized, and then see what can be done to improve it.

This paragraph provides no context for the information and does not explain the relationships between the sources described. It also doesn’t analyze the sources or consider gaps in existing research.

Research on the barriers to second language acquisition has primarily focused on age-related difficulties. Building on Lenneberg’s (1967) theory of a critical period of language acquisition, Johnson and Newport (1988) tested Lenneberg’s idea in the context of second language acquisition. Their research seemed to confirm that young learners acquire a second language more easily than older learners. Recent research has considered other potential barriers to language acquisition. Schepens, van Hout, and van der Slik (2022) have revealed that the difficulties of learning a second language at an older age are compounded by dissimilarity between a learner’s first language and the language they aim to acquire. Further research needs to be carried out to determine whether the difficulty faced by adult monoglot speakers is also faced by adults who acquired a second language during the “critical period.”

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To synthesize sources, group them around a specific theme or point of contention.

As you read sources, ask:

  • What questions or ideas recur? Do the sources focus on the same points, or do they look at the issue from different angles?
  • How does each source relate to others? Does it confirm or challenge the findings of past research?
  • Where do the sources agree or disagree?

Once you have a clear idea of how each source positions itself, put them in conversation with each other. Analyze and interpret their points of agreement and disagreement. This displays the relationships among sources and creates a sense of coherence.

Consider both implicit and explicit (dis)agreements. Whether one source specifically refutes another or just happens to come to different conclusions without specifically engaging with it, you can mention it in your synthesis either way.

Synthesize your sources using:

  • Topic sentences to introduce the relationship between the sources
  • Signal phrases to attribute ideas to their authors
  • Transition words and phrases to link together different ideas

To more easily determine the similarities and dissimilarities among your sources, you can create a visual representation of their main ideas with a synthesis matrix . This is a tool that you can use when researching and writing your paper, not a part of the final text.

In a synthesis matrix, each column represents one source, and each row represents a common theme or idea among the sources. In the relevant rows, fill in a short summary of how the source treats each theme or topic.

This helps you to clearly see the commonalities or points of divergence among your sources. You can then synthesize these sources in your work by explaining their relationship.

If you want to know more about ChatGPT, AI tools , citation , and plagiarism , make sure to check out some of our other articles with explanations and examples.

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Synthesizing sources means comparing and contrasting the work of other scholars to provide new insights.

It involves analyzing and interpreting the points of agreement and disagreement among sources.

You might synthesize sources in your literature review to give an overview of the field of research or throughout your paper when you want to contribute something new to existing research.

A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .

It is often written as part of a thesis, dissertation , or research paper , in order to situate your work in relation to existing knowledge.

Topic sentences help keep your writing focused and guide the reader through your argument.

In an essay or paper , each paragraph should focus on a single idea. By stating the main idea in the topic sentence, you clarify what the paragraph is about for both yourself and your reader.

At college level, you must properly cite your sources in all essays , research papers , and other academic texts (except exams and in-class exercises).

Add a citation whenever you quote , paraphrase , or summarize information or ideas from a source. You should also give full source details in a bibliography or reference list at the end of your text.

The exact format of your citations depends on which citation style you are instructed to use. The most common styles are APA , MLA , and Chicago .

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When you look for areas where your sources agree or disagree and try to draw broader conclusions about your topic based on what your sources say, you are engaging in synthesis. Writing a research paper usually requires synthesizing the available sources in order to provide new insight or a different perspective into your particular topic (as opposed to simply restating what each individual source says about your research topic).

Note that synthesizing is not the same as summarizing.  

  • A summary restates the information in one or more sources without providing new insight or reaching new conclusions.
  • A synthesis draws on multiple sources to reach a broader conclusion.

There are two types of syntheses: explanatory syntheses and argumentative syntheses . Explanatory syntheses seek to bring sources together to explain a perspective and the reasoning behind it. Argumentative syntheses seek to bring sources together to make an argument. Both types of synthesis involve looking for relationships between sources and drawing conclusions.

In order to successfully synthesize your sources, you might begin by grouping your sources by topic and looking for connections. For example, if you were researching the pros and cons of encouraging healthy eating in children, you would want to separate your sources to find which ones agree with each other and which ones disagree.

After you have a good idea of what your sources are saying, you want to construct your body paragraphs in a way that acknowledges different sources and highlights where you can draw new conclusions.

As you continue synthesizing, here are a few points to remember:

  • Don’t force a relationship between sources if there isn’t one. Not all of your sources have to complement one another.
  • Do your best to highlight the relationships between sources in very clear ways.
  • Don’t ignore any outliers in your research. It’s important to take note of every perspective (even those that disagree with your broader conclusions).

Example Syntheses

Below are two examples of synthesis: one where synthesis is NOT utilized well, and one where it is.

Parents are always trying to find ways to encourage healthy eating in their children. Elena Pearl Ben-Joseph, a doctor and writer for KidsHealth , encourages parents to be role models for their children by not dieting or vocalizing concerns about their body image. The first popular diet began in 1863. William Banting named it the “Banting” diet after himself, and it consisted of eating fruits, vegetables, meat, and dry wine. Despite the fact that dieting has been around for over a hundred and fifty years, parents should not diet because it hinders children’s understanding of healthy eating.

In this sample paragraph, the paragraph begins with one idea then drastically shifts to another. Rather than comparing the sources, the author simply describes their content. This leads the paragraph to veer in an different direction at the end, and it prevents the paragraph from expressing any strong arguments or conclusions.

An example of a stronger synthesis can be found below.

Parents are always trying to find ways to encourage healthy eating in their children. Different scientists and educators have different strategies for promoting a well-rounded diet while still encouraging body positivity in children. David R. Just and Joseph Price suggest in their article “Using Incentives to Encourage Healthy Eating in Children” that children are more likely to eat fruits and vegetables if they are given a reward (855-856). Similarly, Elena Pearl Ben-Joseph, a doctor and writer for Kids Health , encourages parents to be role models for their children. She states that “parents who are always dieting or complaining about their bodies may foster these same negative feelings in their kids. Try to keep a positive approach about food” (Ben-Joseph). Martha J. Nepper and Weiwen Chai support Ben-Joseph’s suggestions in their article “Parents’ Barriers and Strategies to Promote Healthy Eating among School-age Children.” Nepper and Chai note, “Parents felt that patience, consistency, educating themselves on proper nutrition, and having more healthy foods available in the home were important strategies when developing healthy eating habits for their children.” By following some of these ideas, parents can help their children develop healthy eating habits while still maintaining body positivity.

In this example, the author puts different sources in conversation with one another. Rather than simply describing the content of the sources in order, the author uses transitions (like "similarly") and makes the relationship between the sources evident.

research paper with synthesis

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How to Write a Literature Review

  • 6. Synthesize
  • Literature Reviews: A Recap
  • Reading Journal Articles
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  • 4. Manage Your References
  • 5. Critically Analyze and Evaluate

Synthesis Visualization

Synthesis matrix example.

  • 7. Write a Literature Review


  • Synthesis Worksheet

About Synthesis

Approaches to synthesis.

You can sort the literature in various ways, for example:

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How to Begin?

Read your sources carefully and find the main idea(s) of each source

Look for similarities in your sources – which sources are talking about the same main ideas? (for example, sources that discuss the historical background on your topic)

Use the worksheet (above) or synthesis matrix (below) to get organized

This work can be messy. Don't worry if you have to go through a few iterations of the worksheet or matrix as you work on your lit review!

Four Examples of Student Writing

In the four examples below, only ONE shows a good example of synthesis: the fourth column, or  Student D . For a web accessible version, click the link below the image.

Four Examples of Student Writing; Follow the "long description" infographic link for a web accessible description.

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When combining another author’s ideas with your own, we have talked about how using the can help make sure your points are being adequately argued (if you have not read our handout on the  evidence cycle,  check it out!). Synthesis takes assertions (statements that describe your claim), evidence (facts and proof from outside sources), and commentary (your connections to why the evidence supports your claim), and blends these processes together to make a cohesive paragraph.

In other words, synthesis encompasses several aspects:

  • It is the process of integrating support from more than one source for one idea/argument while also identifying how sources are related to each other and to your main idea.
  • It is an acknowledgment of how the source material from several sources address the same question/research topic.
  • It is the identification of how important factors (assumptions, interpretations of results, theories, hypothesis, speculations, etc.) relate between separate sources.

TIP: It’s a fruit smoothie!

Think of synthesis as a fruit smoothie that you are creating in your paper. You will have unique parts and flavors in your writing that you will need to blend together to make one tasty, unified drink!

Why Synthesis is Important

  • Synthesis integrates information from multiple sources, which shows that you have done the necessary research to engage with a topic more fully.
  • Research involves incorporating many sources to understand and/or answer a research question, and discovering these connections between the sources helps you better analyze and understand the conversations surrounding your topic.
  • Successful synthesis creates links between your ideas helping your paper “flow” and connect better.
  • Synthesis prevents your papers from looking like a list of copied and pasted sources from various authors.
  • Synthesis is a higher order process in writing—this is the area where you as a writer get to shine and show your audience your reasoning.

Types of Synthesis

Demonstrates how two or more sources agree with one another.

The collaborative nature of writing tutorials has been discussed by scholars like Andrea Lunsford (1991) and Stephen North (1984). In these essays, they explore the usefulness and the complexities of collaboration between tutors and students in writing center contexts.

Demonstrates how two or more sources support a main point in different ways.

While some scholars like Berlin (1987) have primarily placed their focus on the histories of large, famous universities, other scholars like Yahner and Murdick (1991) have found value in connecting their local histories to contrast or highlight trends found in bigger-name universities.


Demonstrates how one source builds on the idea of another.

Although North’s (1984) essay is fundamental to many writing centers today, Lunsford (1991) takes his ideas a step further by identifying different writing center models and also expanding North’s ideas on how writing centers can help students become better writers.

Demonstrates how one source discusses the effects of another source’s ideas.

While Healy (2001) notes the concerns of having primarily email appointments in writing centers, he also notes that constraints like funding, resources, and time affect how online resources are formed. For writing centers, email is the most economical and practical option for those wanting to offer online services but cannot dedicate the time or money to other online tutoring methods. As a result, in Neaderheiser and Wolfe’s (2009) reveals that of all the online options available in higher education, over 91% of institutions utilize online tutoring through email, meaning these constraints significantly affect the types of services writing centers offer.

Discussing Specific Source Ideas/Arguments

To debate with clarity and precision, you may need to incorporate a quote into your statement. Using can help you to thoroughly introduce your quotes so that they fit in to your paragraph and your argument. Remember that you need to use the to bridge between your ideas and outside source material.

Berlin, J. (1987).  Rhetoric and reality: Writing instruction in American colleges, 1900-1985 . Carbondale: Southern Illinois University Press.

Boquet, E.H. (2001). “Our little secret”: A history of writing centers, pre- to open admissions. In R.W. Barnett & J.S. Blumner (Eds.),  The Allyn and Bacon guide to writing center theory and practice  (pp. 42-60). Boston: Allyn and Bacon.

Carino, P. (1995). Early writing centers: Toward a history.  The Writing Center Journal ,  15 (2), 103-15.

Healy, D. (2001). From place to space: Perceptual and administrative issues in the online writing center. In R.W. Barnett & J.S. Blumner (Eds.), T he Allyn and Bacon guide to writing center theory and practice  (pp. 541-554). Boston: Allyn and Bacon.

Lunsford, A. (1991). Collaboration, control, and the idea of the writing center.  The Writing Center Journal ,  12 (1), 310-75.

Neaderheiser, S. & Wolfe, J. (2009). Between technological endorsement and resistance: The state of online writing centers.  The Writing Center Journal .  29 (1), 49-75.

North, S. (1984). The idea of a writing center.  College English ,  45 (5), 433-446.

Yahner, W. & Murdick, W. (1991). The evolution of a writing center: 1972-1990.  Writing Center Journal ,  11 (2), 13-28.

research paper with synthesis

How to Write a Synthesis Essay: Your Guide From Start to Finish

research paper with synthesis

In the fast-paced landscape of today's information age, the average person contends with an astonishing volume of data, akin to reading around 174 newspapers daily. The sources are diverse, ranging from news articles and social media updates to scientific studies and beyond. This constant deluge of information might create a sense of being overwhelmed—a feeling of drowning in a sea of facts, opinions, and statistics. Yet, amidst this information onslaught, the skill to synthesize and extract meaning is indispensable. As we navigate this era of data saturation, the ability to sift through and comprehend this abundance is not just valuable; it's a fundamental skill for navigating the complexities of our modern world.

How to Write a Synthesis Essay: Short Description

This guide goes beyond merely helping you navigate the sea of information; it empowers you to leverage it for crafting compelling synthesis essays. We'll walk you through crucial steps and tips, revealing the secrets to successful synthesis essay writing. Uncover the format that lends structure and clarity to your work, and master the art of selecting an essay topic that not only engages but also sparks critical thinking. So, let's delve in and discover how to transform fragmented information into coherent and persuasive essays that leave a lasting impression.

What Is a Synthesis Essay: Understanding Its Nature and Purpose

According to our ' write paper for me ' experts, the synthesis essay emerges as a dynamic catalyst in the realm of composition. Beyond the act of assembling disparate facts and opinions, it's a nuanced process of weaving coherence. Envision it as constructing an intricate tapestry from scattered threads.

The purpose of writing a synthesis essay extends far beyond the mere presentation of information; it beckons a deeper intellectual dive. This genre challenges writers to extract commonalities from diverse sources—be they articles, studies, or arguments—and leverage these connections to construct a compelling and persuasive narrative.

In our era of information saturation, this essay form has become an indispensable tool for insightful minds. It not only permits exploration of how diverse ideas interconnect but also serves as a platform for articulating well-considered perspectives on intricate subjects. Whether navigating through the realms of literature, science, history, or contemporary affairs, this kind of essay becomes a showcase of analytical finesse, offering a holistic viewpoint. It transcends the role of a mere knowledge conveyor; instead, it unveils profound insights by adeptly linking diverse pieces of information.

Explanatory vs. Argumentative Synthesis Essays: Key Differences

In the domain of synthesis writing, two primary categories come to the fore: explanatory and argumentative. Grasping the distinction between these is pivotal as it defines the purpose, tone, and approach of your essay.

Explanatory :

An explanatory synthesis essay precisely lives up to its name—it explains. These essays strive to offer an unbiased and well-balanced perspective on a topic by collecting information from various sources and presenting it in a clear, organized manner. The aim here is not to adopt a stance or persuade but rather to inform and clarify. Often serving as comprehensive overviews, they break down intricate concepts, theories, or ideas for a wider audience. These essays heavily lean on factual data and expert opinions to provide a thorough picture, steering clear of personal bias or persuasion.

Argumentative :

Conversely, argumentative synthesis essays are all about persuasion. They engage in the synthesis process with the primary goal of taking a stance on a particular issue or topic. They gather information from various sources not only to present a well-rounded view but also to construct a compelling argument. Argumentative essays aim to convince the reader of a specific viewpoint, leveraging the gathered information as evidence to support their claims. These papers inherently express opinions and employ rhetorical strategies to sway the reader's perspective.

And if you're keen on knowing how to write an informative essay , we've got you covered on that, too!

Synthesis Essay Structure

Knowing how to write a synthesis essay effectively is comparable to constructing a resilient building—it relies on a strong foundation. To guide you through this process, consider the following structured approach:

Introductory Paragraph: 

  • Creating a robust synthesis essay is comparable to constructing a resilient building—it relies on a strong foundation. To guide you through this process, consider the following structured approach:
  • Start with an engaging hook or an intriguing fact to immediately capture your reader's attention. Provide contextual information about your topic and the sources you'll be synthesizing. Present a concise and clear thesis statement outlining your primary argument or viewpoint.
  • If your topic requires it, incorporate background information to help readers understand the context of the sources.

Body Paragraphs:

  • Dedicate each paragraph to a specific sub-topic or source. Begin with a clear topic sentence directly related to your thesis. Introduce the source you're synthesizing and outline its key points.
  • Support your arguments with evidence from the source, employing quotes, paraphrases, or summaries. Analyze and interpret the source, elucidating its connection to your thesis and other sources.
  • Address counterarguments if relevant, ensuring a comprehensive exploration. Transition seamlessly between paragraphs to maintain the fluidity of your essay.
  • This pivotal section serves as the nexus between your sources, revealing intersections, divergences, or complementary aspects.
  • Highlight common themes, patterns, or contradictions among your sources.
  • Leverage your analysis to construct a coherent argument or perspective.
  • If pertinent, acknowledge opposing viewpoints and counter them with well-reasoned arguments.


  • Restate your thesis and succinctly summarize the main points of your essay.
  • Emphasize the significance of your argument, elucidating its broader implications.
  • Conclude with a thought-provoking statement or a compelling call to action.


  • Include a comprehensive list of all sources used in your essay, adhering to the prescribed citation style (e.g., MLA, APA).

Choosing a Synthesis Essay Topic: A Guide to Decision-Making

Selecting essay topics marks just the starting point; the synthesis process demands a critical evaluation and connection of various sources to construct a coherent argument or perspective. Here's a systematic approach to guide you in making an informed choice when choosing synthesis essay topics:

choosing a synthesis essay topic

How to Write a Synthesis Essay: Key Steps and Tips

Much like a compare and contrast essay , the process of writing a synthesis essay demands a systematic approach to effectively integrate information from various sources into a cohesive and compelling argument. Here are essential steps and insights to assist you throughout this journey:

  • Clarify Your Purpose

Define whether you are composing an explanatory or argumentative synthesis essay, as this choice will shape your approach and tone.

  • Source Selection and Analysis

Carefully pick credible and pertinent sources that contribute to your synthesis essay topic. Maintain a balance among different source types, such as academic articles, books, and reputable websites. Critically analyze each source, identifying the main ideas, arguments, and evidence presented.

  • Formulate a Strong Thesis Statement

Develop a clear and concise thesis statement that communicates your central argument or perspective. Your synthesis essay thesis statement should serve as the guiding force for the entire essay.

  • Structure Your Essay

Organize your essay with a well-structured synthesis essay outline, typically featuring an introduction, body paragraphs, and a conclusion. Each body paragraph should center on a specific aspect of your topic, utilizing evidence from your sources to support your points.

  • Employ Effective Transition Sentences

Use transition sentences to smoothly connect paragraphs and ideas, ensuring a seamless flow in your essay.

  • Synthesize Information

Within the body paragraphs, synthesize information from your sources. Discuss how each source contributes to your thesis and identify common themes or contradictions.

  • Avoid Simple Summarization

Refuse the urge to merely summarize your sources. Instead, engage with them critically and employ them as building blocks for your argument.

  • Address Counterarguments (if applicable)

Recognize opposing viewpoints and counter them with well-reasoned arguments, showcasing a thorough understanding of the topic.

  • Craft a Resolute Conclusion

In your conclusion, restate your thesis and summarize your main points. Emphasize the significance of your argument or insights. Conclude with a thought-provoking closing statement or a compelling call to action.

  • Revise and Proofread

Review your essay for clarity, coherence, and grammar errors. Ensure your citations are accurate and consistent with the chosen citation style (e.g., MLA, APA).

  • Seek Feedback

Consider obtaining feedback from peers, instructors, or writing centers to enhance the overall quality of your essay.

  • Edit for Conciseness

Eliminate unnecessary repetition and ensure your writing is concise and direct, and don't overlook this step while learning how to write a good synthesis essay.

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Synthesis Essay Format

The structure of your synthesis paper hinges on the specific formatting style prescribed by your instructor. The most frequently employed styles encompass MLA, APA, and Chicago, each catering to distinct academic disciplines. APA takes center stage in Education, Psychology, and Science; MLA is the preferred choice for citations in Humanities, while the Chicago style finds its application in Business, History, and Fine Arts.

synthesis essay format

1. MLA (Modern Language Association):

  • Incorporates in-text citations featuring the author's last name and page number.
  • Concludes with a 'Works Cited' page at the paper's end, listing all sources alphabetically.
  • Prioritizes authorship and publication date.
  • Applied in academic essays, research papers, and literary analyses.

2. APA (American Psychological Association):

  • Utilizes in-text citations containing the author's last name and publication date within parentheses.
  • Includes a 'References' page, presenting all sources in alphabetical order.
  • Highlights the publication date and emphasizes scientific precision.
  • Adopted for research papers, scholarly articles, and empirical studies.

3. Chicago Style:

  • Provides two documentation styles: Notes-Bibliography (commonly used in humanities) and Author-Date (commonly used in social sciences).
  • Notes-Bibliography style incorporates footnotes or endnotes for citations, while the Author-Date style uses in-text citations with a reference list.
  • Suitable for a diverse array of academic writing, including research papers, theses, and historical studies.
  • Allows for flexibility in formatting and citation methods.

Synthesis Essay Example

In this section, we present two synthesis essay examples that exemplify the practical application of the synthesis process. They delve into intriguing topics and serve as practical guides for those looking to master the art of writing this kind of paper.

Synthesis Essay Example MLA

An article published by Jean Twenge clearly warns readers that the rise in the use of smartphones in the modern world is ruining teenagers. Furthermore, the author makes a sensational claim that the rise in social media and smartphone usage are creating a metaphorical earthquake, the likes of which have never been previously witnessed in the world. The author provides pieces of evidence from other studies concerning the issue, as well as personal observations—all of which support Twenge’s claim. According to Twenge, the main theory for claiming that smartphone and social media usage result in destroying a generation is that increased use of these two platforms results in mental depression and other mental problems. This paper will mainly refute the claims of the author by focusing on the issues raised by the author’s work.

Sample Synthesis Paper APA Style

Society has various aspects that signify the difference in lifestyles and behaviors amongst individuals in a community. Language is one of these essential aspects that help to identify individuals in a society. Identification of a common language will generalize a specific group of individuals possessing the same culture, even if they are from different races. In this essay, let’s examine how language defines our identity in society. Let’s also look at how two different authors have given different views about how language defines black schoolchildren in the Oakland School District.

Synthesis Essay Tips

Developing a compelling paper necessitates a reflective approach and strategic methodologies. Here are five crucial tips for writing a synthesis essay:

Thoughtful Source Selection : Opt for varied, reliable sources offering diverse perspectives on your chosen topic. Verify that your sources are recent and pertinent to the subject under consideration.

Skillful Source Integration : Steer clear of merely summarizing your sources; instead, seamlessly integrate them into your essay by analyzing, comparing, and contrasting their ideas. Demonstrate the connections between sources to construct a coherent narrative.

Maintain an Even-Handed Tone : In the process of learning how to write a synthesis essay, uphold a balanced tone in your writing. Despite personal opinions, synthesis essays demand objectivity. Present different viewpoints impartially and without bias.

Prioritize Synthesis, Not Recapitulation : Keep in mind that synthesis essays revolve around linking ideas, not solely summarizing sources. Scrutinize the relationships between sources and offer insights into how they interconnect to build a cohesive argument.

Address Counterarguments Deliberately : Similar to addressing persuasive essays topics , engage with counterarguments in a considerate and deliberate manner. Acknowledge opposing viewpoints and then elucidate why your perspective stands on firmer ground. This showcases a comprehensive understanding of the topic.

Concluding Thoughts

When creating a synthesis essay, the crucial aspect involves choosing a range of reliable sources, skillfully integrating them to form a cohesive argument, and upholding objectivity. Utilize clear transitions, carefully consider counterarguments, and prioritize analysis over mere summarization. By employing these strategies, you'll craft essays that inform, persuade, and captivate your audience!

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What Makes Synthesis Significant?

How should you conclude a synthesis essay, related articles.

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Synthesis: Home

Engaging in synthesis.

Synthesis requires you to make sense of all the relevant ideas in your sources and blend them together with your own thoughts and ideas. Watch this video to learn how to engage in synthesis in order to take research from multiple sources along with your own arguments and turn it into a research paper.

Synthesizing Your Research

Understanding your research.

1. Read through your sources carefully.

2. Identify common themes or sub-topics that keep appearing in the articles you’re reading.

4 different articles, 3 common ideas from all of them are, Beyonce, Feminism, and Popular Music.

The Research Matrix

  • Blank Research Matrix Fill out this blank matrix.
  • Blank Synthesis Matrix template (Google Docs)

The research matrix is a helpful tool you can use to synthesize your research along with your own voice. The blank research matrix above can help you organize your paper by main idea, identify connections between your sources, and add your own analysis.

Blank Matrix. Grid with columns titled by main idea, Rows are titled by sources.

Filling Out Your Matrix

1. Write your topic or research question above the matrix.

Did the US government cover up a research program on UFOs in the early 2000s and how did it do this?

2. Write your main ideas for your paper on the left side of the matrix. Helpful Tip: Choose your main ideas AFTER you have read your sources!

Martix grid, see above info

3. Write the title, author, or citation of each source in the top row of the matrix.

Matrix grid, see above info

4. Fill in the matrix boxes with a paraphrase or direct quote that represents how the source discussed that main idea. You do not need every source to address every main idea!

Example for source one, article by Art Bell, paraphrase: Funds hidden in massive DARPA Budget

5. Don't forget to nclude your own analysis of the main idea and the sources in the last column on the matrix.

Matrix grid, See above info

Identify Gaps in Your Research

1. There’s a high likelihood that you will have empty spaces on your research matrix and that’s okay! Small gaps show that there is room for your own voice to join the conversation.

Matrix Grid, See above info.

2. Large gaps in your matrix are often a sign that you need to do more research on that main idea. As a rule of thumb you should have at least two sources for each main idea in order to create a meaningful dialogue. 

Matrisx grid, see above info

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Synthesis in Research: Home

A visualization of synthesis

Pretend you are working with five sources for an essay, as represented by the five colored dots below.  

Sources not synthesized

Notice how there are no connections between the sources; the five sources are simply listed in some arbitrary order. What if you need to  synethesize  the sources, though? You can start synthesising by noting the similarities and differences between the sources and mapping them accordingly.

Sources sythensized

Perhaps you noticed that A (blue), B (yellow), and C (pink) make similar arguments, so they are grouped together. You also noticed that D (red) and B (yellow) share a similar methodology, so they are linked together. But perhaps D (red) does not make the same argument as B (yellow), A (blue), and C (pink). And E (green) is completely out there on his own! So you can now see that there are several possibilities for synthesizing these sources. 

The gray ring around these sources represents the synthesized claims that you can make. For instance, you might claim, "While multiple scholars agree that X, there is no overall consensus on this issue." Or you may claim, "Conflicting methodologies among research creates gaps in the research on X.

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A Guide to Evidence Synthesis: What is Evidence Synthesis?

  • Meet Our Team
  • Our Published Reviews and Protocols
  • What is Evidence Synthesis?
  • Types of Evidence Synthesis
  • Evidence Synthesis Across Disciplines
  • Finding and Appraising Existing Systematic Reviews
  • 0. Develop a Protocol
  • 1. Draft your Research Question
  • 2. Select Databases
  • 3. Select Grey Literature Sources
  • 4. Write a Search Strategy
  • 5. Register a Protocol
  • 6. Translate Search Strategies
  • 7. Citation Management
  • 8. Article Screening
  • 9. Risk of Bias Assessment
  • 10. Data Extraction
  • 11. Synthesize, Map, or Describe the Results
  • Evidence Synthesis Institute for Librarians
  • Open Access Evidence Synthesis Resources

What are Evidence Syntheses?

What are evidence syntheses.

According to the Royal Society, 'evidence synthesis' refers to the process of bringing together information from a range of sources and disciplines to inform debates and decisions on specific issues. They generally include a methodical and comprehensive literature synthesis focused on a well-formulated research question.  Their aim is to identify and synthesize all  of the scholarly research on a particular topic, including both published and unpublished studies. Evidence syntheses are conducted in an unbiased, reproducible way to provide evidence for practice and policy-making, as well as to identify gaps in the research. Evidence syntheses may also include a meta-analysis, a more quantitative process of synthesizing and visualizing data retrieved from various studies. 

Evidence syntheses are much more time-intensive than traditional literature reviews and require a multi-person research team. See this PredicTER tool to get a sense of a systematic review timeline (one type of evidence synthesis). Before embarking on an evidence synthesis, it's important to clearly identify your reasons for conducting one. For a list of types of evidence synthesis projects, see the next tab.

How Does a Traditional Literature Review Differ From an Evidence Synthesis?

How does a systematic review differ from a traditional literature review.

One commonly used form of evidence synthesis is a systematic review.  This table compares a traditional literature review with a systematic review.

Video: Reproducibility and transparent methods (Video 3:25)

Reporting Standards

There are some reporting standards for evidence syntheses. These can serve as guidelines for protocol and manuscript preparation and journals may require that these standards are followed for the review type that is being employed (e.g. systematic review, scoping review, etc). ​

  • PRISMA checklist Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses.
  • PRISMA-P Standards An updated version of the original PRISMA standards for protocol development.
  • PRISMA - ScR Reporting guidelines for scoping reviews and evidence maps
  • PRISMA-IPD Standards Extension of the original PRISMA standards for systematic reviews and meta-analyses of individual participant data.
  • EQUATOR Network The EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network is an international initiative that seeks to improve the reliability and value of published health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines. They provide a list of various standards for reporting in systematic reviews.

Video: Guidelines and reporting standards

PRISMA Flow Diagram

The  PRISMA  flow diagram depicts the flow of information through the different phases of an evidence synthesis. It maps the search (number of records identified), screening (number of records included and excluded), and selection (reasons for exclusion).  Many evidence syntheses include a PRISMA flow diagram in the published manuscript.

See below for resources to help you generate your own PRISMA flow diagram.

  • PRISMA Flow Diagram Tool
  • PRISMA Flow Diagram Word Template
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Writing Resources

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Learning about Synthesis Analysis

What D oes Synthesis and Analysis Mean?

Synthesis: the combination of ideas to

Synthesis, Analysis, and Evaluation

  • show commonalities or patterns

Analysis: a detailed examination

  • of elements, ideas, or the structure of something
  • can be a basis for discussion or interpretation

Synthesis and Analysis: combine and examine ideas to

  • show how commonalities, patterns, and elements fit together
  • form a unified point for a theory, discussion, or interpretation
  • develop an informed evaluation of the idea by presenting several different viewpoints and/or ideas

Key Resource: Synthesis Matrix

Synthesis Matrix

A synthesis matrix is an excellent tool to use to organize sources by theme and to be able to see the similarities and differences as well as any important patterns in the methodology and recommendations for future research. Using a synthesis matrix can assist you not only in synthesizing and analyzing,  but it can also aid you in finding a researchable problem and gaps in methodology and/or research.

Synthesis Matrix

Use the Synthesis Matrix Template attached below to organize your research by theme and look for patterns in your sources .Use the companion handout, "Types of Articles" to aid you in identifying the different article types for the sources you are using in your matrix. If you have any questions about how to use the synthesis matrix, sign up for the synthesis analysis group session to practice using them with Dr. Sara Northern!

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Royal Society of Chemistry

Nanomaterials: a review of synthesis methods, properties, recent progress, and challenges

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First published on 24th February 2021

Nanomaterials have emerged as an amazing class of materials that consists of a broad spectrum of examples with at least one dimension in the range of 1 to 100 nm. Exceptionally high surface areas can be achieved through the rational design of nanomaterials. Nanomaterials can be produced with outstanding magnetic, electrical, optical, mechanical, and catalytic properties that are substantially different from their bulk counterparts. The nanomaterial properties can be tuned as desired via precisely controlling the size, shape, synthesis conditions, and appropriate functionalization. This review discusses a brief history of nanomaterials and their use throughout history to trigger advances in nanotechnology development. In particular, we describe and define various terms relating to nanomaterials. Various nanomaterial synthesis methods, including top-down and bottom-up approaches, are discussed. The unique features of nanomaterials are highlighted throughout the review. This review describes advances in nanomaterials, specifically fullerenes, carbon nanotubes, graphene, carbon quantum dots, nanodiamonds, carbon nanohorns, nanoporous materials, core–shell nanoparticles, silicene, antimonene, MXenes, 2D MOF nanosheets, boron nitride nanosheets, layered double hydroxides, and metal-based nanomaterials. Finally, we conclude by discussing challenges and future perspectives relating to nanomaterials.

1. Introduction

The term nanometer was first used in 1914 by Richard Adolf Zsigmondy. 5 The American physicist and Nobel Prize laureate Richard Feynman introduced the specific concept of nanotechnology in 1959 in his speech during the American Physical Society's annual meeting. This is considered to be the first academic talk about nanotechnology. 5 He presented a lecture that was entitled “There's Plenty of Room at the Bottom”. During this meeting, the following concept was presented: “why can’t we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?” The vision was to develop smaller machines, down to the molecular level. 6,7 In this talk, Feynman explained that the laws of nature do not limit our ability to work at the atomic and molecular levels, but rather it is a lack of appropriate equipment and techniques that limit this. 8 Through this, the concept of modern technology was seeded. Due to this, he is often considered the father of modern nanotechnology. Norio Taniguchi might be the first person who used the term nanotechnology, in 1974. Norio Taniguchi stated: “nano-technology mainly consists of the processing of, separation, consolidation, and deformation of materials by one atom or one molecule.” 5,9 Before the 1980s, nanotechnology remained only an area for discussion, but the concept of nanotechnology was seeded in the minds of researchers with the potential for future development.

The invention of various spectroscopic techniques sped up research and innovations in the field of nanotechnology. IBM researchers developed scanning tunneling microscopy (STM) in 1982, and with STM it became feasible to attain images of single atoms on “flat” ( i.e. , not a tip) surfaces. 10 Atomic force microscopy (AFM) was invented in 1986, and it has become the most crucial scanning probe microscope technique. 11 The motivation to develop hard discs with high storage density stimulated the measurement of electrostatic and magnetic forces. This led to the development of Kelvin-probe-, electrostatic-, and magnetic-force microscopy. 12 Currently, nanotechnology is rapidly evolving and becoming part of almost every field related to materials chemistry. The field of nanotechnology is evolving every day, and now powerful characterization and synthesis tools are available for producing nanomaterials with better-controlled dimensions.

Nanotechnology is an excellent example of an emerging technology, offering engineered nanomaterials with the great potential for producing products with substantially improved performances. 13 Currently, nanomaterials find commercial roles in scratch-free paints, surface coatings, electronics, cosmetics, environmental remediation, sports equipment, sensors, and energy-storage devices. 14 This review attempts to provide information in a single platform about the basic concepts, advances, and trends relating to nanomaterials via covering the related information and discussing synthesis methods, properties, and possible opportunities relating to the broad and fascinating area of nanomaterials ( Scheme 1 ). It is not easy to cover all the literature related to nanomaterials, but important papers from history and the current literature are discussed in this review. This review provides fundamental insight for researchers, quickly capturing the advances in and properties of various classes of nanomaterials in one place.

2. Descriptions of terms associated with nanomaterials

3. approaches for the synthesis of nanomaterials, 3.1. top-down approaches.

The conditions under which arc discharge takes place play a significant role in achieving new forms of nanomaterials. The conditions under which different carbon-based nanomaterials are formed via the arc discharge method are explained in Fig. 6 . Various carbon-based nanomaterials are collected from different positions during the arc discharge method, as their growth mechanisms differ. 44 MWCNTs, high-purity polyhedral graphite particles, pyrolytic graphite, and nano-graphite particles can be collected from either anode or cathode deposits or deposits at both electrodes. 46–48 Apart from the electrodes, carbon-based nanomaterials can also be collected from the inner chamber. Different morphologies of single-wall carbon nanohorns (SWCNHs) can be obtained under different atmospheres. For example, ‘dahlia-like’ SWCNHs are produced under an ambient atmosphere, whereas ‘bud-like’ SWCNHs are generated under CO and CO 2 atmospheres. 49 The arc discharge method can be used to efficiently achieve graphene nanostructures. The conditions present during the synthesis of graphene can affect its properties. Graphene sheets prepared via a hydrogen arc discharge exfoliation method are found to be superior in terms of electrical conductivity and have good thermal stability compared to those obtained via argon arc discharge. 50

3.2. Bottom-up approaches

The hard template method is also called nano-casting. Well-designed solid materials are used as templates, and the solid template pores are filled with precursor molecules to achieve nanostructures for required applications ( Fig. 10 ). 78 The selection of the hard template is critical for developing well-ordered mesoporous materials. It is desirable that such hard templates should maintain a mesoporous structure during the precursor conversion process, and they should be easily removable without disrupting the produced nanostructure. A range of materials has been used as hard templates, not limited to carbon black, silica, carbon nanotubes, particles, colloidal crystals, and wood shells. 85 Three main steps are involved in the synthetic pathway for obtaining nanostructures via templating methods. In the first step, the appropriate original template is developed or selected. Then, a targeted precursor is filled into the template mesopores to convert them into an inorganic solid. In the final step, the original template is removed to achieve the mesoporous replica. 86 Via using mesoporous templates, unique nanostructured materials such as nanowires, nanorods, 3D nanostructured materials, nanostructured metal oxides, and many other nanoparticles can be produced. 87 From this brief discussion, it can be seen that a wide range of unique structured nanomaterials can be produced using soft and hard template methods.

4. Unique nanomaterial features

The electronic properties of semiconductors in the 1–10 nm range are controlled by quantum mechanical considerations. Thus, nanospheres with diameters in the range of 1–10 nm are known as quantum dots. The optical properties of nanomaterials such as quantum dots strongly depend upon their shape and size. 96 A photogenerated electron–hole pair has an exciton diameter on the scale of 1–10 nm. Thus, the absorption and emission of light by semiconductors could be controlled via tuning the nanoparticle size in this range. However, in the case of metals, the mean free path of electrons is ∼10–100 nm and, due to this, electronic and optical effects are expected to be observed in the range of ∼10–100 nm. The colors of aqueous solutions of metal nanoparticles can be changed via changing the aspect ratio. Aqueous solutions of Ag NPs show different colors at different aspect ratios. A red shift in the absorption band appears with an increase in the aspect ratio ( Fig. 12 ). 21

Among a range of unique properties, the following key properties can be obtained upon tuning the sizes and morphologies of nanomaterials.

4.1. Surface area

4.2. magnetism, 4.3. quantum effects, 4.4. high thermal and electrical conductivity, 4.5. excellent mechanical properties, 4.6. excellent support for catalysts, 4.7. antimicrobial activity.

Overall, these features have made nanoscale materials valuable for a wide range of applications, substantially boosting the performances of various devices and materials in a number of fields. Details of various nanomaterials, their properties, and applications in various fields will be discussed below.

5. Nanomaterials, characteristics, and applications

5.1. special carbon-based nanomaterials.

In the carbon-based nanomaterial family, fullerenes were the first symmetric material, and they provided new perspectives in the nanomaterials field. This led to the discovery of other carbon-based nanostructured materials, such as carbon nanotubes and graphene. 110 Fullerenes are present in nature and interstellar space. 111 Interestingly, fullerenes were the molecule of the year in 1991 and attracted the most research projects compared to other scientific subjects during that period. 112 Fullerenes possess several unique features that make them attractive for applications in different fields. Fullerenes display solubility to some extent in a range of solvents, and these characteristics make them unique compared to the other allotropes of carbon. 108

The chemical modification of fullerenes is an exciting subject, improving their effectiveness for applications. There are two main ways to modify fullerenes: 113 fullerene inner-space modification, and fullerene outer-surface modification.

Endohedral and exohedral doping examples are shown in Fig. 13 . 114 Fullerenes are hollow cages, and the interior acts as a robust nano-container for host target species when forming endohedral fullerene. 115 Endohedral fullerenes do not always follow the isolated pentagon rule (IPR). 116 To date, fullerene nanocages have received substantial consideration in the materials chemistry field due to their useful potential applications. Neutral and charged single atoms in free space are highly reactive and unstable. In the confined environment of fullerenes, these reactive species can be stabilized; for example, the LaC 60 + ion does not react with the NH 3 , O 2 , H 2 , or NO. Thus, reactive metals can be protected from the surrounding environment by trapping them inside fullerene cages. 117 Another emerging carbon nanomaterial is endohedral fullerene containing lithium (Li@C 60 ). 118 Lithium metal is very reactive, and extreme controlled environmental conditions are required to preserve or use it. In other words, secure structures are required for lithium storage. Li-Based endohedral fullerene shows unique solid-state properties. The encapsulation of lithium atoms in fullerene helps to protect lithium atoms from external agents. Li-Based endohedral fullerenes have the potential to open the door to nanoscale lithium batteries. 119 For the development of endohedral metallofullerenes, larger fullerenes are generally required, as they possess large cages to accommodate lanthanide and transition metal atoms more smoothly. 118 Fullerene nanocages are useful for the storage of gases. Fullerene is under consideration for hydrogen storage. 120,121

Exohedral fullerenes carry more potential for applications as outer surfaces can be more easily modified or functionalized. The exohedral doping of metals into fullerenes strongly affects the electronic properties via shifting electrons from the metal to the fullerene nanocage. 122 The practical application of fullerenes can be achieved with tailor-made fullerene derivatives via chemical functionalization. As fullerene chemistry has matured, a wide range of functionalized fullerenes has been realized through simple synthetic routes. 123 The combination of hydrogen-bonding motifs and fullerenes has allowed the modulation of 1D, 2D, and 3D fullerene-based architectures. 124 The excellent electron affinities of fullerenes have shown great potential for eliminating reactive oxygen species. The presence of excess reactive oxygen species can cause biological dysfunction or other health issues. The surfaces of fullerenes have been functionalized via mussel-inspired chemistry and Michael addition reactions for the fabrication of C 60 –PDA–GSH. The developed C 60 –PDA–GSH nanoparticles demonstrated excellent potential for scavenging reactive oxygen species. 125

Amphiphiles have great importance in industrial processes and daily life applications. Amphiphilic molecules consist of hydrophilic and hydrophobic parts, and they perform functions in water via forming two- and three-dimensional assemblies. Recently, conical fullerene amphiphiles 126 have emerged as a new class of amphiphiles, in which a nonpolar apex is supplied by fullerenes and a hydrophilic part is achieved through functionalization. The selective functionalization of the fullerene on one side helps to achieve a supramolecule due to unique interfacial behavior. The unique supramolecular structure formed via the spontaneous assembly of one-sided selectively functionalized fullerenes through strong hydrophobic interactions between the fullerene apexes and polar functionalized portions is soluble in water. Conical fullerene amphiphiles are mechanically robust. Via upholding the structural integrity, conical fullerene amphiphiles can be readily aggregated with nanomaterials and biomolecules to form multicomponent agglomerates with controllable structural features. 127 Fullerenes, after suitable surface modification, have excellent potential for use in drug delivery, but there have only been limited explorations of their drug delivery applications. 128,129 Fullerene-based nano-vesicles have been developed for the delayed release of drugs. 130 Water-soluble proteins have great potential in the field of nanomedicine. The water-soluble cationic fullerene, tetra(piperazino)[60] fullerene epoxide (TPFE), has been used for the targeted delivery of DNA and siRNA specifically to the lungs. 131 For diseases in lungs or any other organ, efficient treatment requires the targeted delivery of active agents to a targeted place in the organ. The accumulation of micrometer-sized carriers in the lung makes lung-selective delivery difficult, as this may induce embolization and inflammation in the lungs. Size-controlled blood vessel carrier vehicles have been developed using tetra(piperazino)fullerene epoxide (TPFE). TPFE and siRNA agglutinate in the bloodstream with plasma proteins and, as a result, micrometer-sized particles are formed. These particles clog the lung capillaries and release siRNA into lungs cells; after siRNA delivery, they are immediately cleared from the lungs ( Fig. 14 ). 132

The supramolecular organization of fullerene (C 60 ) is a unique approach for producing shape-controlled moieties on the nano-, micro-, and macro-scale. Nano-, micro-, and macro-scale supramolecular assemblies can be controlled via manipulating the preparation conditions to achieve unique optoelectronic properties. 133 The development of well-ordered and organized 1D, 2D, and 3D fullerene assemblies is essential for achieving advanced optical and organic-based electronic devices. 134 Fullerene-based nanostructured materials with new dimensions are being developed from zero-dimensional fullerene and tuned to achieve the desired characteristics. 1D C 60 fullerene nanowires have received substantial attention over other crystalline forms due to their excellent features of potential quantum confinement effects, low dimensionality, and large surface areas. 135

Carbon nanomaterials are also used as supports for catalysts, and the main reasons to use them are their high surface areas and electrical conductivities. Carbon supports strongly influence the properties of metal nanoparticles. In fuel cells, the carbon support strongly affects the stability, electronic conductivity, mass transport properties, and electroactive surface area of the supported catalyst. 136 In fuel cells, the degradation of some catalysts, such as platinum-based examples, and carbon is correlated and reinforced as a result of both being present. Carbon support oxidation is catalyzed by platinum and the oxidation of carbon accelerates platinum-catalyst release. Overall, this results in a loss of catalytically active surface area. 137 Fullerenes are considered suitable support materials due to their excellent electrochemical activities and stability during electrochemical reactions. 138 Due to their high stability and good conductivity, fullerenes can replace conventional carbon as catalyst support materials. Fullerenes are also used for the development of efficient solar cells. 139

Apart from the applications mentioned above, fullerenes have a broader spectrum of applications where they can be used to improve outcomes considerably. Fullerenes have the potential to be used in the development of superconductors. 140 The strong covalent bonds in fullerenes make them useful nanomaterials for improving the mechanical properties of composites. 141 The combination of fullerenes with polymers can result in good flame-retardant and thermal properties. 142 Fullerenes and their derivatives are used for the development of advanced lubricants. They are used as modifiers for greases and individual solid lubricants. 138 Fullerenes have tremendous medicinal importance due to their anticancer, antioxidant, anti-bacterial, and anti-viral activities. 104

Fullerenes are vital members of the carbon-based nanomaterial family and they certainly possess exceptional properties. This discussion further emphasizes their importance for advanced applications. However, the discovery of other carbon-based nanomaterials has put fullerenes in the shade, and the pace of their exploration has been reduced. As fullerenes are highly symmetrical molecules with unique properties, they can act as performance boosters, but more attention is needed from researchers for their practical expansion. 110

Single-walled carbon nanotubes consist of a seamless one-atom-thick graphitic layer, in which carbon atoms are connected through strong covalent bonds. 146 Double-walled carbon nanotubes consist of two single-walled carbon nanotubes. One carbon nanotube is nested in another nanotube to construct a double-walled carbon nanotube. 147 In multi-walled carbon nanotubes, multiple sheets of single-layer carbon atom are rolled up. In other words, many single-walled carbon nanotubes are nested within each other. From different types of nanotubes, it can be concluded that the nanotubes may consist of one, tens, or hundreds of concentric carbon shells, and these shells are separated from each other with a distance of ∼0.34 nm. 148 Carbon nanotubes can be synthesized via chemical vapor deposition, 149 laser ablation, 150 arc-discharge, 143 and gas-phase catalytic growth. 151

Single-walled carbon nanotubes display a diameter of 0.4 to 2 nm. The inner wall distance between double-walled carbon nanotubes was found to be in the range of 0.33 to 0.42 nm. MWCNT diameters are usually in the range of 2–100 nm, and the inner wall distance is about 0.34 nm. 147,152 However, it is essential to note that the diameters and lengths of carbon nanotubes are not well defined, and they depend on the synthesis route and many other factors. The electrical conductivities of SWCNTs and MWCNTs are about 10 2 –10 6 S cm −1 and 10 3 –10 5 S cm −1 , respectively. SWCNTs and MWCNTs also display excellent thermal conductivities of ∼6000 W m −1 K −1 and ∼2000 W m −1 K −1 , respectively. CNTs remain stable in air at temperatures higher than 600 °C. 153 These properties indicate that CNTs have obvious advantages over graphite.

Single-walled carbon nanotubes can display metallic or semiconducting behavior. Whether carbon nanotubes show metallic or semiconducting behavior depends on the diameter and helicity of the graphitic rings. 154 The rolling of graphene sheets leads to three different types of CNTs: chiral, armchair, and zigzag ( Fig. 15 ). 155

Carbon nanotubes demonstrate some amazing characteristics that make them valuable nanomaterials for possible practical applications. Theoretical and experimental studies of carbon nanotubes have revealed their extraordinary tensile properties. J. R. Xiao et al. used an analytical molecular structural mechanics model to predict SWCNT tensile strengths of 94.5 (zigzag nanotubes) and 126.2 (armchair nanotubes) GPa. 156 In another study, the Young's modulus and average tensile strength of millimeter-long multi-walled carbon nanotubes were analyzed and found to be 34.65 GPa and 0.85 GPa, respectively. 157 Carbon nanotubes possess a high aspect ratio. Due to their high tensile strength, carbon nanotubes are used to enhance the mechanical properties of composites.

Carbon nanotubes have become an important industrial material and hundreds of tonnes are produced for applications. 158 Their high tensile strength and high aspect ratio have made carbon nanotubes an ideal reinforcing agent. 159 Carbon nanotubes are lightweight in nature and are used to produce lightweight and biodegradable nanocomposite foams. 160 The structural parameters of carbon nanotubes define whether they will be semiconducting or metallic in nature. This property of carbon nanotubes is considered to be effective for their use as a central element in the design of electronic devices such as rectifying diodes, 161 single-electron transistors, 162 and field-effect transistors. 163 The chemical stability, nano-size, high electrical conductivity, and amazing structural perfection of carbon nanotubes make them suitable for electron field emitter applications. 164 The unique set of mechanical and electrochemical properties make CNTs a valuable smart candidate for use in lithium-ion batteries. 165 CNTs have the full potential to be used as a binderless free-standing electrode for active lithium-ion storage. CNT-based anodes can have reversible lithium-ion capacities exceeding 1000 mA h g −1 , and this is a substantial improvement compared with conventional graphite anodes. In short, the following factors play a role in controlling and optimizing the performances of CNT-based composites: 166 (i) the volume fraction of carbon nanotubes; (ii) the CNT orientation; (iii) the CNT matrix adhesion; (iv) the CNT aspect ratio; and (iv) the composite homogeneity.

For some applications, a proper stable aqueous dispersion of CNTs at a high concentration is pivotal to allow the system to perform its function efficiently and effectively. 167 One of the major issues associated with carbon nanotubes is their poor dispersion in aqueous media due to their hydrophobic nature. Clusters of CNTs are formed due to van der Waals attraction, π–π stacking, and hydrophobicity. The CNT clusters, due to their strong interactions, hinder solubility or dispersion in water or even organic-solvent-based systems. 168 This challenging dispersion associated with CNTs has limited their use for promising applications, such as in biomedical devices, drug delivery, cell biology, and drug delivery. 167 Carbon nanotube applications and inherent characteristics can be further tuned via suitable functionalization. The functionalization of carbon nanotubes helps scientists to manipulate the properties of carbon nanotubes and, without functionalization, some properties are not attainable. 169 The functionalization of nanotubes can be divided into two main categories: covalent functionalization and non-covalent functionalization.

The heating of CNTs under strongly acidic and oxidative conditions results in the formation of oxygen-containing functionalities. These functional groups, such as carboxylic acid, react further with other functional groups, such as amines or alcohols, to produce amide or ester linkages on the carbon nanotubes. 172 One of the main issues preventing the utilization of CNTs for biomedical applications is their toxicity. The cytotoxicity of pristine carbon nanotubes can be reduced via introducing carbonyl, –COOH, and –OH functional groups. Apart from functionalization through oxidized CNTs, the direct functionalization of CNTs is also possible. However, direct functionalization requires more reactive species to directly react with the CNTs, such as free radicals. Addition reactions to CNTs can cause a transformation from sp 2 hybridization to sp 3 hybridization at the point of addition. At the point where functionalization has taken place, the local bond geometry is changed from trigonal planar to tetrahedral geometry. Some addition reactions to the sidewalls of CNTs are shown in Fig. 16 . 155

It is important to discuss how the covalent functionalization of carbon nanotubes comes at the price of the degradation of the carbon sp 2 network. This substantially affects the electronic, thermal, and optoelectronic properties of the carbon nanotubes. 169 Efforts are being made to introduce a new method of covalent functionalization that can keep the π network of CNTs intact. Antonio Setaro et al. introduced a new [2+1] cycloaddition reaction for the non-destructive, covalent, gram-scale functionalization of single-walled carbon nanotubes. The reaction rebuilds the extended π-network, and the carbon nanotubes retained their outstanding quantum optoelectronic properties ( Fig. 17 ). 173

Polymers are frequently combined with CNTs to enhance their dispersion capabilities. Polymers interact with CNTs through CH–π and π–π interactions. 174 Hexanes and cycloalkanes are poor CNT solvents but the good solubility or dispersion of CNTs in these solvents is required for surface coating applications. Poly(dimethylsiloxane) (PDMS) macromer-grafted polymers have been prepared using PDMS macromers and pyrene-containing monomers that strongly adsorb on CNTs, thus improved the solubility of CNTs in chloroform and hexane. 176 The use of head–tail surfactants is another attractive way to achieve a fine dispersion of CNTs in an aqueous medium. In head–tail surfactants, the tail is hydrophobic and interacts with the CNT sidewalls, and the hydrophilic head groups interact with the aqueous environment to provide a fine dispersion. 177

For electrical applications, non-covalently functionalized CNTs are more preferred because the electrical properties of the CNTs are not compromised. CNTs have been non-covalently functionalized with a variety of biomolecules for the fabrication of electrochemical biosensors. 175 Non-covalently functionalized SWCNTs are used for energy applications. Single-walled carbon nanotubes (SWCNTs) have been non-covalently functionalized with 3d transition metal( II ) phthalocyanines, lowering the potential of the oxygen evolution reaction by approximately 120 mV compared with unmodified SWCNTs. 178 The toxicity of pristine CNTs toward living organisms can be lessened via using surfactant-functionalized CNTs. 170 However, in some cases, during polymer non-covalent functionalization, the polymer may wrap CNT bundles and make it difficult to separate the CNTs from each other. Polymers can develop into insulating wrapping that affects the CNT conductivity.

In the literature, several graphene-related materials have been reported, such as graphene oxide and reduced graphene oxide. 187 Among graphenoids, graphene oxide is a more reported and explored graphene-related material as a precursor for chemically modified graphene. The synthetic route to graphene oxide is straightforward, and it is synthesized from inexpensive graphite powder that is readily available. 188 Graphene oxide has many oxygen-containing functional groups, such as epoxy, hydroxyl, carboxyl, and carbonyl groups. The basal plane of graphene oxide is generally decorated with epoxide and hydroxyl groups, whereas the edges presumably contain carboxyl- and carbonyl-based functional groups. 189 The presence of active functional groups in graphene oxide allows its further functionalization with different polymers, small organic compounds, or other nanomaterials to realize several applications. 190

Graphene oxide, due to its oxygen functionality, is insulating in nature and displays poor electrochemical performance. The presence of oxygen functionalities in graphene oxide breaks the conjugated structure and localizes the π-electron network, resulting in poor carrier mobility and carrier concentration. 196 Its electrochemical performance is improved substantially after removing the oxygen-containing functional groups. 197 These functional groups can be removed or reduced via thermal, electrochemical, and chemical means. The product obtained after removing or reducing oxygen moieties is called reduced graphene oxide. The properties of reduced graphene oxide depend upon the effective removal of oxygen moieties from graphene oxide. The process used to remove oxygen-containing functionalities from graphene oxide will determine the extent to which reduced the properties of graphene oxide resemble pristine graphene. 198

Reduced graphene oxide is extensively used to improve the performances of various electrochemical devices. 199 It is essential to mention that even after reducing graphene oxide, some residual sp 3 carbon bonded to oxygen still exists, which somehow disturbs the movement of charge through the delocalized electronic cloud of the sp 2 carbon network. 200 Apart from this, the electrochemical activity of reduced graphene oxide is substantially high enough to manufacture electrochemical devices with improved performances. Recently, the demand for super-performance electrochemical devices has increased to overcome modern challenges relating to electronics and energy-storage devices. 201 Graphene-based materials are considered to be excellent electrode materials, and they can be proved to be revolutionary for use in energy-storage devices such as supercapacitors (SC) and batteries. Graphene-based electrodes improve the performances of existing batteries (lithium-ion batteries) and they are considered useful for developing next-generation batteries such as sodium-ion batteries, lithium–O 2 batteries, and lithium–sulfur batteries ( Fig. 18 ). Being flat in nature, each carbon atom of graphene is available, and ions can easily access the surface due to low diffusion resistance, which provides high electrochemical activity. 202

Graphene and its derivatives are extensively used for the development of electrochemical sensors. 203 The surfaces of bare electrodes are usually not able to sense analytes at trace levels and they cannot differentiate between analytes that have close electrooxidation properties due to their poor surface kinetics. The addition of graphene layers to the surfaces of electrodes can substantially improve the electrocatalytic activity and surface sensitivity towards analytes. 204 Graphene has definite advantages over other materials that are used as electrode materials for sensor applications. Graphene has a substantially high surface-to-volume ratio and atomic thickness, making it extremely sensitive to any changes in its local environment. This is an essential factor in developing advanced sensing tools, as all the carbon atoms are available to interact with target species.

Consequently, graphene exhibits higher sensitivity than its counterparts such as CNTs and silicon nanowires. 205 Graphene has two main advantages over CNTs for the development of electrochemical sensors. First, graphene is mostly produced from graphite, which is a cost-effective route, and second, graphene does not contain metallic impurities like CNTs can. Graphene offers many other advantages when developing sensors and biosensors, such as biocompatibility and π–π stacking interactions with biomolecules. 206 Graphene-based materials are ideal for the construction of nanostructured sensors and biosensors.

The mechanical properties of graphene are used to fabricate highly desired stretchable and flexible sensors. 207 Graphene can be utilized to develop transparent electrodes with excellent optical transmittance. It displays good piezoresistive sensitivity. Researchers are making efforts to replace conventional brittle indium tin oxide (ITO) electrodes with flexible graphene electrodes in optoelectronic devices such as liquid-crystal displays and organic light-emitting diodes. 208 For human–machine interfaces, transparent and flexible tactile sensors with high sensitivity have become essential. Graphene film (GF) and PET have been applied to develop transparent tactile sensors that exhibit outstanding cycling stability, fast response times, and excellent sensitivity ( Fig. 19 ). 209 Similarly, graphene is applied for the fabrication of pressure sensors. 210 Overall, graphene is an excellent material for developing transparent and flexible devices. 211,212

The use of graphene-based materials is an effective way to deal with a broad spectrum of pollutants. 213 There are many ways to deal with environmental pollution; among these, adsorption is an effective and cost-effective method. 214,215 Graphene-based adsorbents are found to be useful in the removal of organic, 216 inorganic, and gaseous contaminants. Graphene-based materials have some obvious advantages over CNT-based adsorbents. For example, graphene sheets offer two basal planes for contaminant adsorption, enhancing their effectiveness as an adsorbent. 192 GO contains several oxygen functional groups that impart hydrophilic features. Due to appropriate hydrophilicity, GO-based adsorbents can efficiently operate in water to remove contaminants. Moreover, graphene-oxide-based materials can be functionalized further through reactive moieties with various organic molecules to enhance their adsorption capacities. 217

In short, extensive research must continue in order to develop graphene-based materials with high performance and bring them to the market. Massive focus on graphene research is also justified due to the extraordinary features described in extensive theoretical and experimental research works.

Nanodiamonds possess a core–shell-like structure and display rich surface chemistry, and numerous functional groups are present on their surface. Several functional groups, such as amide, aldehyde, ketone, carboxylic acid, alkene, hydroperoxide, nitroso, carbonate ester, and alcohol groups, are present on nanodiamond surfaces, assisting in their further functionalization for desired applications ( Fig. 20 ). 226

Furthermore, nanodiamond surfaces can be homogenized with a single type of functional group according to the application requirements. 227 The use of nanodiamond particles as a reinforcing material in polymer composites has attracted great attention for improving the performance of polymer composite materials. The superior mechanical properties and rich surface chemistry of nanodiamonds have made them a superior material for tuning and reinforcing polymer composites. Nanodiamonds might operate via changing the interphase properties and forming a robust covalent interface with the matrix. 228 Nanodiamond (ND)-reinforced polymer composites have shown superior thermal stabilities, mechanical properties, and thermal conductivities. Nanodiamonds have shown great potential for energy storage applications. 229 Nanodiamonds and their composites are also used in sensor fabrication, environmental remediation, and wastewater treatment. 230,231 Their stable fluorescence and long fluorescence lifetimes have made nanodiamonds useful for imaging and cancer treatment. For biomedical applications, the rational engineering of nanodiamond particle surfaces has played a crucial role in the carrying of bioactive substances, target ligands, and nucleic acids, resisting their aggregation. 232,233 Nanodiamonds have a great future in nanotechnology due to their amazing surface chemistry and unique characteristics.

Carbon quantum dots can be synthesized through several chemical routes. 241–245 Some methodologies for synthesizing carbon dots are described in Fig. 21 . 246–248 Carbon itself is a black material and displays low solubility in water. In contrast, carbon quantum dots are attractive due to their excellent solubility in water. They contain a plethora of oxygen-containing functional groups on their surface, such as carboxylic acids. These functional moieties allow for further functionalization with biological, inorganic, polymeric, and organic species.

Carbon quantum dots are also called carbon nano-lights due to their strong luminescence. 248 In particular, carbon quantum dots offer enhanced chemiluminescence, 249,250 fluorescent emission, 251 two-photon luminescence under near-infrared pulsed-laser excitation, 252 and tunable excitation-dependent fluorescence. 253 The luminescence characteristics of carbon quantum dots have been used to develop highly sensitive and selective sensors. In most cases, a simple principle is involved in sensing with luminescent carbon quantum dots: their photoluminescence intensity changes upon the addition of an analyte. 254 Based on this principle, several efficient sensors have been developed using carbon quantum dots. 255–257 They can be used as sensitive and selective tools for sensing explosives such as TNT. Recognition molecules on the surfaces of carbon quantum dots can help to sense targeted analytes. Amino-group-functionalized carbon quantum dot fluorescence is quenched in the presence of TNT through a photo-induced electron-transfer effect between TNT and primary amino groups. This quenching phenomenon can help to sense the target analyte ( Fig. 22 ). 258 Chiral carbon quantum dots (cCQDs) can exhibit an enantioselective response. The PL responses of cCQDs were evaluated toward 17 amino acids and it was found that the PL intensity of the cCQDs was only substantially enhanced in the presence of L -Lys ( Fig. 22 ). 254

Carbon quantum dots have received significant interest in the fields of biological imaging and nanomedicine ( Fig. 23 ). 239 Direct images of RNA and DNA are essential for understanding cell anatomy. Due to the limitations of current imaging probes, tracking the dynamics of these biological macromolecules is not an easy job. Recently, membrane-penetrating carbon quantum dots have been developed for the imaging of nucleic acids in live organisms. 259 It is important to note that most of the carbon quantum dots utilized to attain cell imaging under UV excitation emit blue radiation. Some biological tissue also emits blue light, specifically that involving carbohydrates, and this interferes with cell imaging carried out with blue-emitting CQDs. This seriously hinders their potential in the field of biomedical imaging. Due to this reason, researchers are focusing on tuning CQDs in a way that their emission peak is red-shifted to avoid interference. 260 Carbon quantum dots with yellow and green fluorescence have been reported for bioimaging purposes. 261,262 The suitable doping of carbon quantum dots can red-shift the emission to enhance the bioimaging effectiveness. 263 Doped carbon quantum dots are capable of biological imaging and display advanced capabilities for scavenging reactive oxygen species. 264

Carbon quantum dots demonstrate photo-induced electron transfer properties 265 that make them valuable for photocatalytic, light-energy conversion, and other related applications. 266 Carbon quantum dots enhance the activities of other photocatalysts to which they are attached. Carbon quantum dots, along with photocatalysts, provide better charge separation and suppress the regeneration of photogenerated electron–hole pairs. Moreover, the proper implantation of carbon quantum dots into photocatalysts can broaden the photo-absorption region. Implanted carbon quantum dots form micro-regional heterostructures that facilitate photo-electron transport. 267 The implantation of carbon quantum dots into g-C 3 N 4 can substantially enhance charge transfer and separation efficiencies, prevent photoexcited carrier recombination, narrow the bandgap, and red shift the absorption edge. 268 The intrinsic catalytic activity of polymeric carbon nitride is improved as a result of the nano-frame heterojunctions formed with the help of CQDs. 269

Carbon quantum dots offer many advantages over conventional semiconductor-based QDs and, thus, they have attracted considerable researcher attention. 244 Due to their remarkable features, they have shown importance in recent years in the fields of light-emitting diodes, nanomedicine, solar cells, sensors, catalysis, and bioimaging. 236

The production of carbon nanohorns has some obvious advantages over carbon nanotubes, such as the ability for toxic-metal-catalyst-free synthesis and large-scale production at room temperature. Carbon nanotube synthesis involves metal particles, and harsh conditions, such as the use of strong acids, are required to remove metallic catalysts. This process introduces many defects into CNT structures and may cause a loss of carbon material. 270 Carbon nanohorns possess a wide diameter compared to CNTs. CNHs possess good absorption capabilities and their interiors are also available after partial oxidation, which provides direct access to their internal parts. Heat treatment under acidic or oxidative conditions facilitates the facile introduction of holes into carbon nanohorns. Holes in graphene sheets of single-walled carbon nanohorns can be produced with O 2 gas at high temperatures. A large quantity of material can be stored inside CNH tubes. 274 The surface area of CNHs is substantially enhanced upon opening the horns to make their interiors accessible. 275 Carbon nanohorns have great potential for energy storage, 275 electrochemiluminescence, 276 adsorption, 277 catalyst support, 278 electrochemical sensing, 279 and drug delivery system 273 uses. CNHs as catalyst supports can provide a homogeneous dispersion of Pt nanoparticles ( Fig. 25 ). The current density of Pt supported on single-walled carbon nanohorns is double compared to a fuel cell made from Pt supported on carbon black. 280 Thus, carbon nanohorns provide a better uniform dispersion that facilitates a high surface area and better catalyst performance.

5.2. Nanoporous materials

In nanoporous materials, the size distributions, volumes, and shapes of the pores directly affect the performances of porous materials for particular applications. It has become a hot area of research to develop materials with precisely controlled pores and arrangements. Recent research has focused more on the precise control of the shapes, sizes, and volumes of pores to produce nanoporous materials with high performance. Several state-of-the-art reviews are present in the literature that focus explicitly on the synthesis, properties, advances, and applications of nanoporous materials. 85,287–289 Based on the materials used, nanoporous materials can be divided into three main groups: inorganic nanoporous materials; carbonaceous nanoporous materials; and organic polymeric nanoporous materials.

Inorganic nanoporous materials include porous silicas, clays, porous metal oxides, and zeolites. The generation of pores in the material can introduce striking features into the material that are absent in non-porous materials. Nanoporous materials offer rich surface compositions with versatile characteristics. Nanoporous materials exhibit high surface-to-volume ratios. Their outstanding features and nanoporous framework structures have made these materials valuable in the fields of environmental remediation, adsorption, catalysis, sensing, energy conversion, purification, and medicine. 284,290

Porous silica is a crucial member of the inorganic nanoporous family. Over the decades, it has generated significant research interest for use in fuel cells, chemical engineering, ceramics, and biomedicine. It is essential to note that specific morphologies and pore size diameters are required for each application, and these can be achieved via tuning during the synthesis process. Nanoporous silica offers two functional surfaces: one is the cylindrical pore surfaces, and the second is the exterior surfaces of the nanoporous silica particles. The surfaces of nanoporous silica can be easily functionalized for the desired applications. The nanoporous silica surface is heavily covered with many silanol groups that act as reactive sites for functionalization ( Fig. 26 ). 291,292 For biomedical applications, mesoporous silica has emerged as a new generation of inorganic platform materials compared to other integrated nanostructured materials. Several factors make it a unique material for biomedical applications: 293,294 (a) its ordered porous structure; (b) its tunable particle size; (c) its large pore volume and surface area; (d) its biocompatibility; (e) its biodegradation, biodistribution, and excretion properties; and (f) its two functional surfaces. For instance, ordered MCM-48 nanoporous silica was used for the delivery of the poorly soluble drug indomethacin. It has been found that surface modification can control drug release. 295 Mesoporous silica-based materials have emerged as excellent materials for use in sustained drug delivery systems (SDDSs), immediate drug delivery systems (IDDSs), targeted drug delivery systems (TDDSs), and stimuli-responsive controlled drug delivery systems (CDDSs). The drug release rate from mesoporous silica can also be controlled via introducing appropriate polymers or functional groups, such as CN, SH, NH 2 , and Cl. Researchers are currently focusing on developing MSN-based (MSN = mesoporous silica nanoparticle) multifunctional drug delivery systems that can release antitumor drugs on demand in a targeted fashion via minimizing the premature release of the drug ( Fig. 27 ). 296

Hierarchically nanoporous zeolites are a vital member of the nanoporous material family. They are crystalline aluminosilicate minerals whose structures comprise uniform, regular arrays of nanopores with molecular dimensions. The microporous structures of zeolites contain pores that are usually below 1 nm in diameter. In zeolites, the micropores are uniform in shape and size, and these pores can effectively discriminate between molecules based on shape and size. 297 Currently, based on crystallography, more than 200 zeolites have been classified. 298 Zeolites have been proved to be useful materials in the field of host–guest chemistry. In solid catalysis, about 40% of the entire solid catalyst field is taken up by zeolites in chemical industry. The excellent catalysis success of zeolites is based on their framework stability, shape-selective porosity, solid acidity, and ion-exchange capacity. Oxygen tetrahedrally coordinates with the Al atoms in most zeolite crystalline silicate frameworks, resulting in charge mismatch between the oxide framework and Al. Extra-framework Na + ions compensate for this charge mismatch. The Na + ions are exchangeable for other cations such as H + and K + . 298 The zeolite crystalline networks are remarkable in that they provide high mechanical and hydrothermal stabilities. The most crucial task facing the zeolite community is to find new structures with desired functions and apply them more effectively for different applications.

Apart from these inorganic porous materials, several other metal- and metal-oxide-based nanoporous materials have been introduced that are more prominent for use in electrode material, catalyst, photodegradation, energy storage, and energy conversion applications. 299–302 Nanoporous metal-based materials are famous due to the nanosized crystalline walls, interconnected porous networks, and numerous surface metal sites that provide them with unique physical/chemical properties compared with their bulk counterparts and other nanostructured materials. 303 For example, nanoporous WO 3 films were developed via tuning the anodization conditions for photoelectrochemical water oxidation. It has been observed that the morphology of the film strongly affected the photoelectrochemical performance. 304 Nanoporous alumina is also a unique material in the inorganic nanoporous family due to several aspects. Nanoporous alumina can be prepared in a controlled fashion with any size and shape in polyprotic aqueous media via the anodic oxidation of the aluminum surface. The parallel arrangement of pores on alumina can easily be controlled from 5 nm to 300 nm, and alumina is stable in the range of 1000 °C. The anodizing time plays a significant role in controlling the pore length. Nanoporous alumina membranes offer various unique properties, such as pores of variable widths/lengths, temperature stability, and optical transparency. Nanoporous alumina pores can be filled with magnetically and optically active elements to produce the desired applications at the nanoscale level. Photoluminescent alumina membranes can be produced via introducing cadmium sulfide, gallium nitride, and siloxenes inside nanoporous alumina using appropriate precursors. 305 Porous alumina also acts as an efficient support and template for the designing of other nanomaterials. Palladium nanowires, 306 high aspect ratio cobalt nanowires, 307 and highly aligned Cu nanowires 308 were developed using porous alumina as a template. Ni–Pd as a catalyst was supported on porous alumina for hydrogenation and oxidation reactions. 309 Nanoporous anodic alumina is also considered to be an efficient material for the development of biosensors due to the ease of fabrication, tunable properties, optical/electrochemical properties, and excellent stability in aqueous environments. 310

Nanoporous carbon-based materials are a hot topic in the field of materials chemistry. Nanoporous carbon materials have become ubiquitous choices in the environmental, energy, catalysis, and sensing fields due to their unique morphologies, large pore volumes, controlled porous structures, mechanical, thermal, and chemical stabilities, and high specific surface areas ( Fig. 28A ). 311 Nanoporous materials are found to be useful in the treatment of water. The separation of spilled oil and organic pollutants from water has emerged as a significant challenge. 312–314 The design of materials that can allow the efficient separation of organic, dye, and metal contaminants from water has become a leading environmental research area. 315,316 Nanoporous carbon can be derived from different natural and synthetic sources. 317–319 Nanoporous carbon foam can be derived from natural sources, such as flour, pectin, and agar, via table-salt-assisted pyrolysis. The agar-derived nanoporous carbon foam showed high absorption capacities, a maximum of 202 times its own weight, for oil and organic solvents. Air filtration paper developed from carbon nanoporous materials and non-woven fabrics has shown a filtration efficiency of greater than 99% ( Fig. 28B ). 320 Nanoporous carbon can also be produced from other porous frameworks, such as metal–organic frameworks. MOF- and COF-based materials are promising precursors for nanoporous carbon-based materials. The direct carbonization of amino-functionalized aluminum terephthalate metal–organic frameworks has produced nitrogen-doped nanoporous carbon that shows an adequate removal capacity of 98.5% for methyl orange under the optimum conditions. 321 Fe 3 O 4 /nanoporous carbon was also produced with Fe salts as a magnetic precursor and MOF-5 as a carbon precursor for removing the organic dye methylene blue (MB) from aqueous solutions. 322 The mesoporous carbon removal efficiency could be further enhanced via modifying or functionalizing the surface with various materials. Unmodified mesoporous carbon has shown a mercury removal efficiency of 54.5%. This efficiency can be substantially improved to 81.6% and 94% upon modification with the anionic surfactant sodium dodecyl sulfate and cationic surfactant cetyltrimethyl ammonium bromide (CTAB), respectively. 323

Ordered nanoporous carbon, CNTs, and fullerenes are extensively applied for energy and environmental applications. The complicated synthesis routes required for fullerenes and CNTs have slowed down the full exploitation of their potential for highly demanding applications. In comparison, the synthesis of highly ordered nanoporous carbon is facile, and the properties of ordered nanoporous carbon are also appealing for energy and environmental applications. 311 CO 2 is a greenhouse gas, and its sustainable conversion into value-added products has become the subject of extensive research. A nitrogen-doped nanoporous-carbon/carbon-nanotube composite membrane is a high-performance gas-diffusion electrode applied for the electrocatalytic conversion of CO 2 into formate. A faradaic efficiency of 81% was found for the production of formate. 324 Nanoporous carbon materials modified with the non-precious elements P, S, N, and B have emerged as efficient electrode materials for use in the oxygen evolution reaction (OER), hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), batteries, and fuel cells. 311,325–327

Nanoporous polymers, including nanoporous coordination polymers and crystalline nanoporous polymers, have emerged as impressive nanoporous materials. 328 Nanoporous polymers have many applications, and these materials are extensively being evaluated for gas separation and gas storage. The great interest in these applications arises from the presence of pores providing an exceptionally high Brunauer–Emmett–Teller (BET) surface area. Recently, new classes of metal organic framework and covalent organic framework porous materials have been reported that have shown exceptionally high and unprecedented surface areas. For instance, in 2010, a MOF was reported with a surface area of 6143 m 2 g −1 ; 329 in 2012, a MOF was reported with a surface area greater than 7000 m 2 g −1 ; 330 and in 2018, a MOF (DUT-60) was reported with a record surface area of 7836 m 2 g −1 . 331 Mesoporous DUT-60 has also shown a high free volume of 90.3% with a density of 0.187 g cm −3 . 331

Due to their exceptionally high surface areas and porous networks, these MOFs and COFs are ideal for gas storage. Air separation and post-combustion CO 2 capture have become integral parts of mainstream industries related to the energy sector in order to avoid substantial economic penalties. Due to the inefficiencies of available technology and the critical importance of this area, earnest efforts are being made to design gas-selective porous materials for the selective adsorption of desired gases. Nanoporous MOF- and COF-based materials can significantly capture CO 2 and help reach zero or minimum CO 2 emission levels. For instance, nanoporous fluorinated metal–organic frameworks have shown the selective adsorption of CO 2 over H 2 and CH 4 . 332 Hasmukh A. Patel et al. developed N 2 -phobic nanoporous covalent organic polymers for the selective adsorption of CO 2 over N 2 . The azo groups in the framework rejected N 2 , leading to CO 2 selectivity. 333 Nanoporous polymers that are superhydrophobic in nature can also be used for volatile organic compounds and organic contaminants. 334 Nanoporous polymers, due to the presence of a porous network, have been considered as highly suitable materials for catalyst supports. Furthermore, organocatalytic functional groups can be introduced pre-synthetically and post-synthetically into solid catalysts. 335

Nanoporous polymeric materials are amazingly heading towards being extremely lightweight with exceptionally high surface areas. These high surface areas and the fine-tuning of the nanopores has made these nanoporous materials, specifically MOFs and zeolites, ideal support materials for encapsulating ultrasmall metal nanoparticles inside void spaces to produce nanocatalysts with exceptionally high efficiencies. 336 In the coming years, more exponential growth of nanoporous materials is expected in the energy, targeted drug delivery, catalysis, and water treatment fields.

5.3. Ultrathin two-dimensional nanomaterials beyond graphene

However, from a material synthesis standpoint, a graphite-like layered form of Si does not exist in nature and there is no conventional exfoliation process that can generate 2D silicene, although single-walled 351 and multi-walled 352 silicon nanotubes and even monolayers of silicon have been synthesized via exfoliation methods. 353 Forming honeycomb Si nanostructures on substrates like Ag(001) and Ag(110) via molecular beam deposition, so-called “epitaxial growth”, was then proposed as a method for the architectural design of silicene sheets. 354–356 The successful synthesis of a silicene monolayer was first achieved on Ag(111) and ZrB 2 (0001) substrates in 2012; 357,358 later, various demonstrations were made using Ir(111), ZrB 2 (001), ZrC(111), and MoS 2 surfaces as the silicene growth substrates. 359–361 Despite various extensive studies to date involving the “epitaxial growth” of silicene on different substrates and investigations of the electronic properties, 357,362–364 the limited nanometer size, difficulties relating to substrate removal, and air stability issues have substantially impeded the practical applications of silicene. Bearing in mind all these known difficulties, Akinwande and co-workers recently reported a growth–transfer–fabrication process for novel silicene-based field-effect transistor development that involved silicene-encapsulated delamination with native electrodes. 365 An etch-back approach was used to define source/drain contacts in Ag film. Without causing any damage to the silicene, a novel potassium-iodide-based iodine-containing solution was used to etch Ag, avoiding rapid oxidation, unlike other commonly used Ag etchants. The results demonstrated that this was the first proof-of-concept study confirming the Dirac-like ambipolar charge transport predictions made about silicene devices. Comparative studies with a graphene system, the low residual carrier density, and the high gate modulation suggested the opening of a small bandgap in the experimental devices, proving that silicene can be considered a viable 2D nanomaterial beyond graphene.

Nonetheless, the synthesis of silicene on a large-scale is greatly limited, as “epitaxial growth” is the only promising method for obtaining high-quality silicene, and this presents an enduring challenge in relation to silicene research and development. Xu and co-workers recently introduced liquid oxidation and the exfoliation of CaSi 2 as a means for the first scalable preparation of high-quality silicene nanosheets. 366 This new synthetic strategy successfully induced the exfoliation of stacked silicene layers via the mild oxidation of the (Si 2 n ) 2 n layers in CaSi 2 into neutral Si 2 n layers without damage to the pristine silicene structure ( Fig. 29 ). The selective oxidation of pristine CaSi 2 into free-standing silicene sheets without any damage to the original Si framework was carried out via exfoliation in the presence of I 2 in acetonitrile solvent. Furthermore, the obtained silicene sheets yielded ultrathin monolayers or layers with few-layer thickness and exhibited excellent crystallinity. This 2D silicene nanosheet material was extensively explored as a novel anode, which was unlike previously developed silicon-based anodes for lithium-ion batteries. It displayed a theoretical capacity of 721 mA h g −1 at 0.1 A g −1 and superior cycling stability of 1800 cycles. Overall, during the last decade, silicene has been widely accepted as an ideal 2D material with many fascinating properties, suggesting great promise for a future beyond graphene.

Like other 2D materials, MXenes exhibit crystal geometry with a hexagonal close-packed structure based on the equivalent MAX-phase precursor, and the close-packed structure is formed from M atoms with X atoms occupying octahedral sites. 371 According to the formula, there are three representative structures of MXenes: M 2 XT x , M 3 X2T x , and M 4 X3T x . In these combinations, X atoms are formed with n layers, whereas M atoms have n + 1 layers ( Fig. 30 ). 372 Apart from graphene, MXenes are considered the most dynamic developing material, and they have incredible innovation potential amongst typical 2D nanomaterials because of their remarkable properties, such as hydrophilicity, conductivity, considerable adsorption abilities, and catalytic activity. These vital properties of MXenes suggest their use for various potential applications, including in the photocatalysis, electrocatalysis, 373,374 energy, 375 membrane-based separation, 376,377 and biological therapy 378 fields. In this section, we focus on describing new developments relating to MXenes that are utilized for electrocatalytic and energy storage applications, competing as alternatives to graphene materials.

Interestingly, due to the presence of abundant terminal groups, mainly –O, –OH, and –F, and their modifying nature, MXenes can exhibit outstanding hydrophilic properties and high conductivity and charge carrier mobility, making them a very attractive material for various electrocatalytic applications, such as the hydrogen evolution reaction, oxygen evolution reaction, oxygen reduction reaction, nitrogen reduction reaction, and CO 2 reduction reaction. To further increase their electrocatalytic activities, recent works involving MXenes have included incorporation with CNTs, 379 g-C 3 N 4 , 380 FeNi-LDH, 381 NiFeCo-LDH, 382 and metal–organic frameworks. 383

Cho and co-workers designed and developed MXene–TiO 2 2D nanosheets via the surface oxidation of MXene with defect-free control. These MXene–TiO 2 2D nanosheets were successfully implemented in nano-floating-gate transistor memory (NFGTM) providing a floating gate ( i.e. , multilayer MXene) and tunneling dielectric ( i.e. , the TiO 2 layer). A process of oxidation in water further represented a cost-effective and environmentally benign method, as depicted in Fig. 31 . The MXene NFGTM with an optimal oxidation process displayed exceptional nonvolatile memory features, having a great memory window, high programming/erasing current ratio, long term retention, and high durability. 384

There have been some exciting reports on 2D materials from the pnictogen family, particularly phosphorene. Recently, more attention has also been given to the remaining group 15 elements, 390 with the novel 2D materials arsenene, antimonene, and bismuthene being obtained from the key elements arsenic, antimony, and bismuth, respectively. It is reported that 2D monolayers of group 15 elements, including phosphorene allotropes, have five distinct honeycomb (α, β, γ, δ, and ε) and four distinct non-honeycomb (ζ, η, θ, and ι) structures, as depicted in Fig. 32 . Dissimilar crystal orientations were found for single-layered As, Sb, and Bi. Zeng and co-workers also reported comprehensive density functional theory (DFT) computations that proved the energetic stability and broad-range application of these materials in 2D semiconductors. 391 Previously, following theoretical predictions, Wu and co-workers successfully demonstrated that α-phosphorene showed lowest energy configurations in both honeycomb and non-honeycomb nanosheets. 392 In contrast, Zeng and co-workers proved that the buckled forms of 2D sheets of As, Sb, and Bi allotropes are the most stable structures, particularly their β phases. 391

Among monolayer group 15 family materials, 2D sheets of arsenic (As) and antimony (Sb) have gained considerable attention from researchers. 393,394 Studies have shown that As and Sb exhibit better stability than black phosphorus; they are highly stable at room temperature and less reactive to air, likely inhibiting the oxidization process. 395–398 Nevertheless, it has been demonstrated that the oxidation process is perhaps favorable for fine-tuning the electronic properties; increases in the indirect band gaps ranging from 0 to a maximum of 2.49 eV are found in free-standing arsenene and antimonene semiconductors. 399–403 Simultaneously, arsenene and antimonene can also be transformed into semiconductors with direct band gaps. These two 2D nanosheets can be used to design mechanical sensors, moving beyond common electronic and optoelectronic applications. These two extraordinary 2D nanosheets have been studied for their structural–property relationships via first-principles methods. 403–405

Continuing the characterization and structural property studies of arsenene carried out by Kamal 404 et al. and Zhang 403 et al. , Anurag Srivastava and co-workers analyzed applications of arsenene to explore the possibility of improving sensor devices that can be utilized to detect ammonia (NH 3 ) and nitrogen dioxide (NO 2 ) molecules. 406,407 They investigated the affinities of NH 3 and NO 2 molecules for pristine arsenene sheets, examining the binding energies, bonding distances, density distributions, and current–voltage features. The results showed that arsenene 2D sheets are highly durable, with significant electronic charge transfer. They also considered germanium-doped arsenene and characterized the 2D lattice based on molecular affinity relationships with respect to the dopant.

However, the incorporation of any dopants into 2D nanomaterials not only results in experimental difficulty but it also lowers the stability of 2D materials. 408 Recently, Dameng Liu and co-workers reported the electronic structures, focusing on band structures, band offsets, and intrinsic defect properties, of few-layer arsenic and antimony. 409 The spontaneous oxide passivation layer that is formed naturally on pristine antimonene provides excellent stability. 410 Very recently, Stefan Wolff and co-workers conducted DFT calculations on various single or few-layer antimony oxide structures to describe the stoichiometry and bonding type. Interestingly, the samples exhibited various structural stabilities and electronic properties with a wide range of direct and indirect band gaps. Showing band gaps between 2.0 and 4.9 eV, these 2D layers of antimonene exhibited the potential to be used as insulators or semiconductors. 411 The same group also analyzed Raman spectra and discussed identifying the predicted antimonene oxide structures experimentally. The enduring task of exploring the utility of antimonene has boosted recent research interest in 2D nanomaterials due to the broad range of potential applications, such as their use in electrochemical sensors, 412,413 stable organic solar cells, 414 and supercapacitors 415 to name a few.

The 2D MOF nanosheets are also evaluated for the development of high-performance power-storage devices. For example, Li et al. 427 recently reported two novel Mn-2D MOFs and Ni-2D MOFs as anode materials for rechargeable lithium batteries. The Mn-based ultrathin metal–organic-framework nanosheets, due to thinner nanosheets, a higher specific surface area, and smaller metal ion radius, had structural advantages over Ni-based ultrathin metal–organic-framework nanosheets. Due to these features, the Mn-based ultrathin metal–organic-framework nanosheets displayed a high reversible capacity of 1187 mA h g −1 at 100 mA g −1 for 100 cycles and a rate capability of 701 mA h g −1 even at 2 A g −1 .

The expensive metal oxides utilized in the catalytic process can be replaced in due course by 2D-MOF-based nanosheets with exposed metal sites that impart an adjustable pore structure, ultrathin thickness, a high surface-to-volume atom ratio, and high design flexibility. As a result, 2D-MOFs have extensively been explored for various electrocatalytic applications, including the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and carbon dioxide reduction reaction (CO 2 RR). For example, Marinescu et al. 428 combined cobalt dithiolene species with benzenehexathiol (BHT) and yielded 2D-MOFs capable of acting as electrocatalysts for the HER in water ( Fig. 34 ). In the presence of 2D-MOF sheets, a high current density of 41 mA cm −2 , at −0.8 V vs. SHE and a pH value of 1.3, is observed. Similarly, Feng et al. 429 also developed single-layer Ni-based 2D-MOF sheets that are highly effective for electrocatalytic hydrogen evolution. Later, Patra et al. 430 reported similar 2D sheets from covalent organic frameworks (2D-COFs) as metal-free catalysts for HER applications. 2D-MOFs are also being explored as active catalysts for the OER process. For example, Xu et al. 431 reported the preparation of 2D Co-MOF sheets using polyvinylpyrrolidone as a surfactant under mild solvothermal conditions. These novel 2D Co-MOFs displayed ultrathin nanosheets with many surface-based metal active sites, improving the overall OER performance.

Interestingly, experimental electrochemical measurement data showed that Co-MOF sheets offer a low overpotential ( i.e. , 263 mV at 10 mA cm −2 ). Similarly, Wang et al. 432 also reported that double-metal 2D-sheets (2D NiFe MOFs) consisting of a very ultrathin structure with a thickness of ∼10 nm further offer a low overpotential of 260 mV at 10 mA cm −2 . In other reports, Zhang et al. 433 successfully performed the OER process with ultrathin 2D-MOF sheets prepared via electrochemical and chemical exfoliation strategies.

Recent work on the catalytic activity of 2D-MOFs has also been reported in relation to the ORR and CO 2 RR because of their layered crystal structures and high-volume modifiable porous structures. For example, Dincă et al. 434 demonstrated that ultrathin layered conductive sheets of the 2D-MOF Ni 3 (HITP) 2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene) could actively be utilized as a catalyst in an alkaline medium for the ORR process. These 2D-MOF sheets show high stability while retaining 88% of the initial current density over 8 h at 0.77 V vs. RHE. In another report, through fabricating Co x Zn 2− x (bim) 4 2D-sheets as precursors, Zhao et al. 435 successfully synthesized cobalt nanodots (Co-NDs) with bimetallic Co x Zn 2− x (bim) 4 nanosheets encapsulating few-layer graphene (Co@FLG). For the CO 2 RR, a cobalt–porphyrin-containing 2D-MOF was achieved for the selective electrochemical reduction of CO 2 to CO with enhanced stability by Peidong Yang and co-workers. 436 The results further proved that these thin-film catalysts have the highest selectivity for CO ( i.e. , 76%) at −0.7 V vs. RHE with the little-to-no substantial decrease in activity over 7 h at −0.7 V vs. RHE, and 16 mL of CO was produced. Besides, like many other porous materials, 2D-MOFs were also shown to be a supporting platform for catalytic nanoparticles because of their high specific surface areas and favorable porosity distributions. To this end, an example can be noted from Wang et al. 437 reporting that fine porous MOF-5 nanosheets can be utilized to immobilize Pd nanoparticles.

5.4. Metal-based nanostructured materials

As discussed, catalysis is one of the main uses of metal-based nanostructured materials. A continuous increase in the demand for energy, the rapid depletion of conventional energy reservoirs, and rising concerns over the emission of CO 2 have increased the challenges and urgency in the energy field. 460 Metal-based nanostructured materials are extensively being explored to produce alternative clean and renewable energy sources. A range of metal-based nanomaterials has been evaluated and is under consideration for developing robust electrodes that can be effectively applied to water splitting, batteries, and solar cells.

High energy demands have led to more pressure to improve the performances of existing highly demanded lithium-ion batteries. Researchers have focused on improving their lifetimes, sizes, and safety. 462 Nanostructured metal-oxide-based materials are promising electrode materials for use in high-performance charge-storage devices. A metal-based nanostructured electrode is evaluated as both the anode and cathode to overcome the challenges of conventional electrodes. 463 In a conventional LIB, LiCoO 2 was used as the cathode material. Controlled morphology plays a crucial role in determining the performance of a material. Powder composed of spherical particles of LiNi 0.8 Co 0.2 O 2 showed a higher tap density compared to irregular particles and the material substantially improved the power density of secondary lithium batteries. 464 Hierarchical nanostructures of metal-based oxides (such as 3D hierarchical ZnCo 2 O 4 nanostructures) have emerged as a new trend for the development of high-capacity electrodes for lithium-ion batteries. 465 Since their commercialization by Sony in the early 1990s, LIBs have achieved tremendous success in bringing portable electronic devices to the market. However, their sustainable development on the grid-scale is hampered due to limited Li resources in nature, and this is causing a continuous increase in cost. 466 Sodium-ion batteries are in the spotlight to replace powerful lithium-ion batteries due to the widespread availability of sodium and its lower cost compared with lithium. 467 It is essential to note that, in terms of energy densities for SIBs, it is difficult to bypass LIBs because of the low standard electrochemical potential and higher weight of Na. SIBs could be proved to be ideal for those applications where cost is a critical factor compared to energy density. 466

SIBs also operate similarly to LIBs, based on an intercalation mechanism. SIBs also consist of cathode and anode electrodes separated through an electrolyte. During the charging process, sodium ions are extracted from the cathode and inserted into the anode via the electrolyte. In the discharging process, the electrons leave the anode through an external circuit to reach the cathode, providing electricity to the load, whereas Na + moves to the cathode during this process. The radius of Na + (1.02 Å) is greater than that of Li + (0.76 Å), making it challenging to intercalate into electrode materials. 468 Thus, appropriate electrode materials are required in which fast Na-ion insertion and extraction is possible. However, SIBs are suffering from a lack of appropriate electrode materials. It is important to develop electrode materials that have enough interstitial space within their crystallographic structures and better electrochemical performance. Among the various proposed electrode materials, Na x MO 2 layered transition-metal oxides (M = V, Fe, Cu, Co, Ni, Cr, Mn, and their combinations) are considered to be promising electrode materials for SIBs. Layered metal oxides are considered to be promising electrode materials due to their facile scalable synthesis, simple structures, appropriate operating potentials, and high capacities. 469,470 Large volume expansion and poor kinetics during the charge–discharge process can severely affect the cyclability and performance of SIBs. One of the effective strategies to deal with the mechanical stress triggered by large volume changes is the design of hollow or porous structures. In response, three-dimensional network-based Sb 2 O 3 @Sb composite anode materials can help to relieve the volume-change-related stress through their uniform porous networks and provide better transportation channels for Na + . 471

The large volume expansion of electrodes can also be buffered via designing 2D metal-oxide materials with large interlayer spacing. The ultrathin nanosheets provide high reversible capacity with enhanced cycling stability and contribute to providing reaction sites for electrons/ions, decreasing the diffusion distance, providing effective diffusion channels, and facilitating fast charge/discharge for sodium and lithium. 2D SnO nanosheet anodes were evaluated for SIBs. The capacity and cyclic stability improved, as the number of atomic SnO layers is decreased in the sheets. 472 Sb is a promising anode material, but during the sodiation/desodiation processes, huge volume expansion of 390% is observed, which hinders its practical use. Nanostructured Sb in the form of nanorod arrays with large interval spacing displays the great capacity to accommodate volume changes during cycling. 473 A comparison of various nanostructured metal-based electrodes for various charge storage purposes is shown in Table 3 . Overall, well-structured metal or metal-based oxide nanomaterials have the capacity to resolve current issues relating to charge storage devices.

Recently, an immense focus of research has been to produce H 2 fuel via water-splitting to replace conventional fossil fuels. This will help to eliminate emissions from the use of carbonaceous species. 484 Electrochemical method are considered simple water splitting approaches, as these methods only require an applied voltage and water as inputs to produce hydrogen fuel. 485 The coupling of solar irradiation to electrochemical water splitting has enhanced the performance and reduced the process cost. Due to these reasons, this has become a hot area of research. 486 During water electrolysis, H 2 is produced through the hydrogen evolution reaction at the cathode and O 2 is produced through the oxygen evolution reaction at the anode. However, water splitting is not so straightforward, and it requires an efficient catalyst that can facilitate the splitting of water. Metal- and metal-oxide-based catalysts are extensively being explored for water splitting. For the HER reaction, Pt-based catalysts are found to be suitable, whereas for OER reactions, Ir-/Ru-based compounds are found to be benchmark catalysts. Scarcity and high cost have limited the widespread use of these metals. The barrier of noble-metal cost can be mitigated through developing noble-metal nanostructured surfaces that produce more active sites or via depositing monolayers of noble metals on low-cost materials. The alloying of noble metals with other metals has enhanced site-specific activity. 484 At present, more focus is being placed on developing noble-metal-free catalysts for water splitting. 485 Usually, an efficient electrocatalyst is characterized by: 487 a low overpotential; high stability; low production costs; and high electrocatalytic activity.

The nano-structuring of catalysts is an effective tool to boost their surface areas. The electrolysis of water occurs at the surface of a catalyst, and nanostructured catalysts provide more active sites and the better diffusion of ions and electrolytes. 484 Non-noble metals that are under observation for the development of HER electrocatalysts include nickel (Ni), tungsten (W), iron (Fe), molybdenum (Mo), cobalt (Co), and copper (Cu). 487 For instance, a noble metal-free catalyst, carbon-decorated Co 3 O 4 nanoarrays on carbon paper, required a small overpotential of 370 mV to reach a current density of 10 mA cm −2 . It can maintain a current density of 100 mA cm −2 for 413.8 h and 86.8 h under alkaline and acidic conditions, respectively. 488

Metal-based semiconductor materials play a crucial role in a range of applications. For photoelectrochemical water splitting, the semiconductor material plays a central role in the solar-to-hydrogen conversion efficiency. Some critical features are prerequisites when it comes to selecting the right semiconductor material for the photoelectrochemical splitting of water: 489 an extraordinary capacity to absorb visible light; an appropriate bandgap; suitable valence and conduction band positions; commercial feasibility; and chemical stability.

For an ideal semiconductor for water splitting, the valence band and conduction band edge positions must straddle the oxidation and the reduction potentials of water. Metal oxides have received significant attention among semiconductors due to their wide band gap distributions, remarkable photo-electrochemical stabilities, and favorable band edge positions. 490 Semiconductor-based photoelectrodes become excited upon light irradiation, and electrons from the valence band move to the unoccupied conduction band. Some of the generated electrons at the cathode surface reduce protons to hydrogen gas, whereas holes at the photoanode produce oxygen gas via water splitting. 490 As a result, various nanostructured metal oxides can be used as photoelectrode materials, such as WO 3 , 491 Cu 2 O, 492 TiO 2 , 493 ZnO, 494 SnO 2 , 495 BiVO 4 , 496 and α-Fe 2 O 3 , 490 for the efficient splitting of water. As discussed, the nano-structuring of semiconductors can significantly impact the electrode photoelectrochemical performance during water splitting.

Metal-based nanomaterials have been used for the development of sensitive sensors. These metal-based sensors can replace the complex and expensive instruments that are conventionally used for the sensing of analytes. Metal-oxide-based sensors have the interesting characteristics of low detection limits, low cost, high sensitivity, and facile operation. 497 Mostly, semiconducting metal-oxide-based sensors are used for the sensing of toxic, flammable, and exhaust gases. Semiconductor metal oxides with a size in the range of 1–100 nm have been significantly investigated as gas sensors due to their size-dependent properties. The geometry and size of a nanomaterial can considerably affect the hole and electron movement in semiconductors. 498 The surface-to-volume ratio and surface area are substantially enhanced at the nanoscale level, and this is amazingly beneficial for sensing. Chemiresistive semiconducting metal oxides are potential candidates for gas sensing due to the following features: 499 rapid response times; fast recovery times; low cost; simple electronic interfaces; user-friendliness and low maintenance; and abilities to sense a wide range of gases.

Electrode materials decorated with metal- or metal-oxide-based nanostructured materials have shown better responses and selectivity for determining various analytes over conventional electrode materials. The nano-sized metal structures act as an electrocatalyst and electronic wires to provide rapid electron transfer between the transducers and analyte molecules. 500 The electrochemical redox reaction of H 2 O 2 can be improved via the thermally controlled anchoring of Pt NPs on the electrode surface. 501

Currently, researchers are not just concentrating on the development of randomly shaped nanomaterials; instead, they are very focused on and interested in the rational design of materials with controlled nano-architectures for boosting their performances for specific applications. As a result, extensive research has been carried out to develop metal-based materials with controlled dimensions to achieve better catalytic responses. Particle morphology is a crucial factor in the performance of nanomaterials for specific applications. Laifa Shen et al. rationally designed an electrode architecture via growing mesoporous NiCo 2 O 4 nanowire arrays on carbon textiles, which boosted the electrode performance ( Fig. 37 ). 474

The same materials with different morphologies can produce different outcomes. For instance, MnO 2 nanoflowers have provided high initial sodium-ion storage capacity compared with MnO 2 nanorods. 481 Radha Narayanan and Mostafa A. El-Sayed have analyzed various nanoscale morphologies of Pt, such as tetrahedral, cubic, and near-spherical nanoparticles. The highest rate constant is observed with tetrahedral nanoparticles and the lowest rate constant was observed with cubic nanoparticles, whereas spherical nanoparticles exhibited an intermediate rate constant during catalysis. 502 Xiaowei Xie et al. found that Co 3 O 4 nanorods show high activity compared to conventional Co 3 O 4 nanoparticles for the low-temperature oxidation of CO. 503 The catalytic activity of metal-based nanomaterials is strongly affected by their shape. 504 Shape-defined mesoporous materials (TiO 2 ) have shown superior photoanode activities ( Fig. 38 ). 505 As a result, in the literature, several nanostructured morphologies of metal-based materials, such as nanotubes, 506,507 nanorods, 508,509 nanoflowers, 510 nanosheets, 511 nanowires, 512 nanocubes, 513 nanospheres, 514,515 nanocages, 516 and nanoboxes, 517 have been reported for a range of applications.

Hollow nanostructures have surfaced as an amazing class of nanostructured material, and they have received significant attention from researchers. Hollow nanostructures have the unique features of: 518,519 low density; abundant inner void spaces; large surface areas; and the ability to act as nanoscale containers with high loading capacity, nanoreactors, and nanocarriers.

Various metal-based hollow nanostructures, such as hollow SnO 2 , 520 hollow palladium nanocrystals, 521 Co–Mn mixed oxide double-shell hollow spheres, 521 hollow Cu 2 O nanocages, 522 three-dimensional hollow SnO 2 @TiO 2 spheres, 523 hollow ZnO/Co 3 O 4 nano-heterostructure, 524 triple-shell hollow α-Fe 2 O 3 , 525 and hierarchical hollow Mn-doped Ni(OH) 2 nanostructures, 526 have been developed for various applications. The presence of nanoscale hollow interiors and functional shells imparts them with great potential for gas sensing, catalysis, biomedicine, energy storage, and conversion. 519

From this discussion, it can be concluded that metal-based nanostructured materials have great potential compared to their bulk counterparts. The conversion of materials to the nanoscale is not enough to achieve high performance with better selectivity. Now, research is switching from conventional nanomaterials to more advanced and smartly designed nanomaterials. In modern research, nanomaterials are being designed with better-controlled morphologies and regulated features.

5.5. Core–shell nanoparticles

A spherical nanoparticle core–shell nanostructure is a practical way to introduce multiple functionalities on the nanoscopic length scale. 528 The properties arising from the core or shell can be different, and these properties can be tuned via controlling the ratio of the constituent materials. The shape, size, and composition play a critical role in tuning the core–shell nanoparticle properties. 529 The shell material can help to improve the chemical and thermal stabilities of the core material. The core–shell design has become effective where an inexpensive material cannot be used directly due to its instability or easily oxidizable nature. The core can consist of an easily oxidizable inexpensive metal, whereas the shell might consist of noble metals, oxides, polymers, or silica. 530 For instance, magnetic nanoparticles when prepared can be sensitive toward air, acids, and bases. Magnetic nanoparticles can be protected via coating with organic or inorganic shells. 528

Core–shell metal nanoparticles are an emerging nanostructured material with great potential in the fields of energy and catalysis. 531 The first report of core–shell nanoparticles (2007) for supercapacitor applications consisted of a polyaniline/multi-walled-carbon-nanotube composite (PANI/MWNTs). 532 Metal-based core–shell structured nanoparticles have shown enhanced catalytic performance due to their shape-controlled properties. 533 Ming-Yu Kuo et al. developed Au@Cu 2 O core–shell particles with controllable shell thicknesses that acted as a dual-functional catalyst. The shell thickness of Cu 2 O increased with an increasing concentration of Cu 2+ precursor. The thicknesses of the shells of Au@Cu 2 O-1.5 (12.2 ± 1.7 nm), Au@Cu 2 O-2 (13.2 ± 1.8 nm), Au@Cu 2 O-3 (18.2 ± 2.2 nm), and Au@Cu 2 O-4 (20.8 ± 2.5 nm) due to various concentrations are shown in Fig. 40 . 534 A NiO@SiO 2 core–shell catalyst provided a higher yield of acrylic acid from acetylene hydroxycarbonylation. 535 Core–shell architecture can be used to prevent active metal nanoparticles from oxidation during operation. For instance, a plasmonic photocatalyst was developed that consisted of silver nanoparticles embedded in titanium dioxide. The direct contact of Ag with TiO 2 could lead to its oxidization; this is prevented via developing core–shell architecture in which Ag is used as the core and SiO 2 is used as a shell to protect it. 536 Another excellent option is to replace an expensive core with a non-noble metal to reduce the core–shell cost while using a thin layer of a noble metal that consumes a small amount of metal as the shell. This will ensure the prolonged stability of the catalyst during operation. 533 Overall, core–shell morphologies provide better catalytic activity due to the synergistic effect of the metallic core–shell components. 152

Among the several classes of nanomaterials, core–shell nanoparticles are found to be more promising for different biomedical applications. For instance, magnetic nanoparticles are considered to be useful for biomedical applications due to the following reasons: (a) aggregation is prevented due to superparamagnetism; (b) delivery and separation can be controlled using an external magnetic field; (c) they can be appropriately dispersed; and (d) there is the possibility of functionalization. A range of magnetic nanoparticles is available, such as NiO, Ni, Co, and Mn 3 O 4 . The most famous example is iron oxide, but uncoated iron oxides are unstable under physiological conditions. This may result in controlled drug delivery failure due to improper ligand surface binding and the promotion of the formation of harmful free radicals. Therefore, the formation of shells around magnetic nanoparticles has tremendous significance for biomedical applications. 537 One of the approaches is to use gold shells on magnetic nanoparticles. Au NPs are also called surface plasmons and they substantially enhanced the absorption of light in the visible and near-infrared regions. Thus, coating magnetic nanoparticles with a Au shell can result in a core–shell nanostructure that displays both optical and magnetic functionality in combination. 529

Numerous biocompatible core–shell nanoparticles are being developed for photothermal therapy, as core–shell materials are found to be useful for photothermal therapy. Hui Wang et al. have developed bifunctional core–shell nanoparticles for dual-modal imaging-guided photothermal therapy. The core–shell nanoparticles consist of a magnetic ∼9.1 nm core of Fe 3 O 4 covered by an approximately 3.4 nm fluorescent carbon shell. The Fe 3 O 4 core leads to superparamagnetic behavior, whereas the carbon shell provides near-infrared (NIR) fluorescence properties. The bifunctional nanoparticles have shown dual-modal imaging capacity both in vivo and in vitro . The iron oxide–carbon core–shell nanoparticles absorbed and converted near-infrared light to heat, facilitating photothermal therapy. 538 Au-Based core–shell structures are also being prepared for photothermal therapy. Bulk gold is biocompatible, but Au NPs can accumulate in the spleen and liver, causing severe toxicity. Koo Chul Kwon et al. have developed Au-NP-based core–shell structures that did not result in any gross or histological lesions in the major organs of mice, which revealed that this is a potent and safe agent for photothermal cancer therapy. The core–shell nanoparticles consisted of proteinticle/gold (PGCS-NP) and were developed via proteinticle surface engineering. PGCS-NP was injected intravenously into mice with tumors, and the injected core–shell nanoparticles successfully reached the EGFR-expressing tumor cells. The tumor size was significantly reduced upon exposure to near-infrared laser irradiation ( Fig. 41 ). No accumulation of Au NPs was observed in the mice organs, which indicated that PGCS-NP disassembled into many tiny gold dots, which were easily excreted by the kidneys and liver without causing any toxicity. 539 In another example, multifunctional Au@graphene oxide nanocolloid core@shell nanoparticles were developed, in which the core and shell consisted of gold and a graphene oxide nanocolloid, respectively. The developed core–shell structure showed multifunctional properties, allowing Raman bioimaging and photothermal/photodynamic therapy with low toxicity. 540 Apart from this, numerous other core–shell nanoparticles, such as polydopamine–mesoporous silica core–shell nanoparticles, 541 AuPd@PVP core–shell nanoparticles, 542 Au@Cu 2− x S core–shell nanoparticles, 543 bismuth sulfide@mesoporous silica core–shell nanoparticles, 544 and Ag@S-nitrosothiol core–shell nanoparticles, have been used for photothermal therapy. 545

Due to their unique features and the combination of properties from the shell and core, these core–shell nanoparticles have received considerable interest in many fields, ranging from materials chemistry to the biomedical field. For electrochemical reactions, the core–shell structure conductivity can be enhanced via conducting polymers, carbon materials, and metals. Core–shell nanoparticles as electrode materials showed better performance compared to single components. Most of the core materials are prepared via hydrothermal methods, and shells can be prepared via hydrothermal or electrodeposition methods. 546 Even though significant progress has been made relating to the synthesis methods of core–shell materials, a major challenge is the high-quality production of core–shell materials in more effective ways for required applications, specifically biomedical applications.

6. Challenges and future perspectives

(a) The presence of defects in nanomaterials can affect their performance and their inherent characteristics can be compromised. For instance, carbon nanotubes are one of the strongest materials that are known. However, impurities, discontinuous tube lengths, defects, and random orientations can substantially impair the tensile strength of carbon nanotubes. 547

(b) The synthesis of nanomaterials through cost-effective routes is another major challenge. High-quality nanomaterials are generally produced using sophisticated instrumentation and harsh conditions, limiting their large-scale production. This issue is more critical for the synthesis of 2D nanomaterials. Most of the methods that have been adopted for large-scale production are low cost, and these methods generally produce materials with defects that are of poor quality. The controlled synthesis of nanomaterials is still a challenging job. For example, a crucial challenge associated with carbon nanotube synthesis is to achieve chiral selectivity, conductivity, and precisely controlled diameters. 548,549 Obtaining structurally pure nanomaterials is the only way to achieve the theoretically calculated characteristics described in the literature. More focused efforts are required to develop new synthesis methods that overcome the challenges associated with conventional methods.

(c) The agglomeration of particles at the nanoscale level is an inherent issue that substantially damages performance in relevant fields. Most nanomaterials start to agglomerate when they encounter each other. The process of agglomeration may be due to physical entanglement, electrostatic interactions, or high surface energy. 550 CNTs undergo van der Waals interactions and form bundles, making it difficult to align or properly disperse them in polymer matrices. 159 Similarly, graphene agglomeration is triggered by the basal planes of graphene sheets due to π–π interactions and van der Waals forces. Due to severe agglomeration, the high surface areas and other unique graphene features are compromised. These challenges hinder the practical application of high-throughput electrode materials or composite materials for various applications. 551

(d) The efficiency of nanomaterials can be tuned via developing 3D architectures. 3D architectures have been tried with several nanomaterials, such as graphene, to improve their inherent features. 3D architectures of 2D graphene have provided high specific surface areas and fast mass and electron transport kinetics. This has become possible due to the combination of the exceptional intrinsic properties of graphene and 3D porous structures. 194,552 The combination of graphene and CNT assemblies into 3-D architectures has emerged as the most investigated nanotechnology research area. Porous architectures of other nanomaterials can be developed to enhance their catalysis performance through providing nanomaterial interior availability.

(e) 2D ultrathin materials are an outstanding class of nanomaterial with promising theoretical properties; however, very little experimental evaluation of these materials has been done, apart from the case of graphene. The synthesis and stability of 2D ultrathin materials are some of the major challenges associated with them. In the future, more focus is anticipated to be placed on their synthesis and practical utilization.

(f) Nanomaterial utilization in industry is being increased, and there is also demand for nanoscale material production at higher rates. Moreover, nanotechnology research has vast horizons; the exploration of new nanomaterials with fascinating features will continue and, in the future, more areas will be discovered. One of the significant concerns relating to nanomaterials that cannot be overlooked is their toxicity, which is still poorly understood, and this is a serious concern relating to their environmental, domestic, and industrial use. The extent to which nanoparticle-based materials can contribute to cellular toxicity is unclear. 553 There is a need for the scientific community to put efforts into reducing the knowledge gap between the rapid development of nanomaterials and their possible in vivo toxicity. A proper and systematic understanding of the interaction of nanomaterials with cells, tissues, and proteins is critical for the safe design and commercialization of nanotechnology. 14

The future of advanced technology is linked with advancements in the field of nanotechnology. The dream of clean energy production is becoming possible with the advancement of nanomaterial-based engineering strategies. These materials have shown promising results, leading to new generations of hydrogen fuel cells and solar cells, acting as efficient catalysts for water splitting, and showing excellent capacity for hydrogen storage. Nanomaterials have a great future in the field of nanomedicine. Nanocarriers can be used for the delivery of therapeutic molecules.

7. Conclusions

Conflicts of interest, acknowledgements.

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  • Published: 19 February 2024

‘It depends’: what 86 systematic reviews tell us about what strategies to use to support the use of research in clinical practice

  • Annette Boaz   ORCID: 1 ,
  • Juan Baeza 2 ,
  • Alec Fraser   ORCID: 2 &
  • Erik Persson 3  

Implementation Science volume  19 , Article number:  15 ( 2024 ) Cite this article

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The gap between research findings and clinical practice is well documented and a range of strategies have been developed to support the implementation of research into clinical practice. The objective of this study was to update and extend two previous reviews of systematic reviews of strategies designed to implement research evidence into clinical practice.

We developed a comprehensive systematic literature search strategy based on the terms used in the previous reviews to identify studies that looked explicitly at interventions designed to turn research evidence into practice. The search was performed in June 2022 in four electronic databases: Medline, Embase, Cochrane and Epistemonikos. We searched from January 2010 up to June 2022 and applied no language restrictions. Two independent reviewers appraised the quality of included studies using a quality assessment checklist. To reduce the risk of bias, papers were excluded following discussion between all members of the team. Data were synthesised using descriptive and narrative techniques to identify themes and patterns linked to intervention strategies, targeted behaviours, study settings and study outcomes.

We identified 32 reviews conducted between 2010 and 2022. The reviews are mainly of multi-faceted interventions ( n  = 20) although there are reviews focusing on single strategies (ICT, educational, reminders, local opinion leaders, audit and feedback, social media and toolkits). The majority of reviews report strategies achieving small impacts (normally on processes of care). There is much less evidence that these strategies have shifted patient outcomes. Furthermore, a lot of nuance lies behind these headline findings, and this is increasingly commented upon in the reviews themselves.

Combined with the two previous reviews, 86 systematic reviews of strategies to increase the implementation of research into clinical practice have been identified. We need to shift the emphasis away from isolating individual and multi-faceted interventions to better understanding and building more situated, relational and organisational capability to support the use of research in clinical practice. This will involve drawing on a wider range of research perspectives (including social science) in primary studies and diversifying the types of synthesis undertaken to include approaches such as realist synthesis which facilitate exploration of the context in which strategies are employed.

Peer Review reports

Contribution to the literature

Considerable time and money is invested in implementing and evaluating strategies to increase the implementation of research into clinical practice.

The growing body of evidence is not providing the anticipated clear lessons to support improved implementation.

Instead what is needed is better understanding and building more situated, relational and organisational capability to support the use of research in clinical practice.

This would involve a more central role in implementation science for a wider range of perspectives, especially from the social, economic, political and behavioural sciences and for greater use of different types of synthesis, such as realist synthesis.


The gap between research findings and clinical practice is well documented and a range of interventions has been developed to increase the implementation of research into clinical practice [ 1 , 2 ]. In recent years researchers have worked to improve the consistency in the ways in which these interventions (often called strategies) are described to support their evaluation. One notable development has been the emergence of Implementation Science as a field focusing explicitly on “the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice” ([ 3 ] p. 1). The work of implementation science focuses on closing, or at least narrowing, the gap between research and practice. One contribution has been to map existing interventions, identifying 73 discreet strategies to support research implementation [ 4 ] which have been grouped into 9 clusters [ 5 ]. The authors note that they have not considered the evidence of effectiveness of the individual strategies and that a next step is to understand better which strategies perform best in which combinations and for what purposes [ 4 ]. Other authors have noted that there is also scope to learn more from other related fields of study such as policy implementation [ 6 ] and to draw on methods designed to support the evaluation of complex interventions [ 7 ].

The increase in activity designed to support the implementation of research into practice and improvements in reporting provided the impetus for an update of a review of systematic reviews of the effectiveness of interventions designed to support the use of research in clinical practice [ 8 ] which was itself an update of the review conducted by Grimshaw and colleagues in 2001. The 2001 review [ 9 ] identified 41 reviews considering a range of strategies including educational interventions, audit and feedback, computerised decision support to financial incentives and combined interventions. The authors concluded that all the interventions had the potential to promote the uptake of evidence in practice, although no one intervention seemed to be more effective than the others in all settings. They concluded that combined interventions were more likely to be effective than single interventions. The 2011 review identified a further 13 systematic reviews containing 313 discrete primary studies. Consistent with the previous review, four main strategy types were identified: audit and feedback; computerised decision support; opinion leaders; and multi-faceted interventions (MFIs). Nine of the reviews reported on MFIs. The review highlighted the small effects of single interventions such as audit and feedback, computerised decision support and opinion leaders. MFIs claimed an improvement in effectiveness over single interventions, although effect sizes remained small to moderate and this improvement in effectiveness relating to MFIs has been questioned in a subsequent review [ 10 ]. In updating the review, we anticipated a larger pool of reviews and an opportunity to consolidate learning from more recent systematic reviews of interventions.

This review updates and extends our previous review of systematic reviews of interventions designed to implement research evidence into clinical practice. To identify potentially relevant peer-reviewed research papers, we developed a comprehensive systematic literature search strategy based on the terms used in the Grimshaw et al. [ 9 ] and Boaz, Baeza and Fraser [ 8 ] overview articles. To ensure optimal retrieval, our search strategy was refined with support from an expert university librarian, considering the ongoing improvements in the development of search filters for systematic reviews since our first review [ 11 ]. We also wanted to include technology-related terms (e.g. apps, algorithms, machine learning, artificial intelligence) to find studies that explored interventions based on the use of technological innovations as mechanistic tools for increasing the use of evidence into practice (see Additional file 1 : Appendix A for full search strategy).

The search was performed in June 2022 in the following electronic databases: Medline, Embase, Cochrane and Epistemonikos. We searched for articles published since the 2011 review. We searched from January 2010 up to June 2022 and applied no language restrictions. Reference lists of relevant papers were also examined.

We uploaded the results using EPPI-Reviewer, a web-based tool that facilitated semi-automation of the screening process and removal of duplicate studies. We made particular use of a priority screening function to reduce screening workload and avoid ‘data deluge’ [ 12 ]. Through machine learning, one reviewer screened a smaller number of records ( n  = 1200) to train the software to predict whether a given record was more likely to be relevant or irrelevant, thus pulling the relevant studies towards the beginning of the screening process. This automation did not replace manual work but helped the reviewer to identify eligible studies more quickly. During the selection process, we included studies that looked explicitly at interventions designed to turn research evidence into practice. Studies were included if they met the following pre-determined inclusion criteria:

The study was a systematic review

Search terms were included

Focused on the implementation of research evidence into practice

The methodological quality of the included studies was assessed as part of the review

Study populations included healthcare providers and patients. The EPOC taxonomy [ 13 ] was used to categorise the strategies. The EPOC taxonomy has four domains: delivery arrangements, financial arrangements, governance arrangements and implementation strategies. The implementation strategies domain includes 20 strategies targeted at healthcare workers. Numerous EPOC strategies were assessed in the review including educational strategies, local opinion leaders, reminders, ICT-focused approaches and audit and feedback. Some strategies that did not fit easily within the EPOC categories were also included. These were social media strategies and toolkits, and multi-faceted interventions (MFIs) (see Table  2 ). Some systematic reviews included comparisons of different interventions while other reviews compared one type of intervention against a control group. Outcomes related to improvements in health care processes or patient well-being. Numerous individual study types (RCT, CCT, BA, ITS) were included within the systematic reviews.

We excluded papers that:

Focused on changing patient rather than provider behaviour

Had no demonstrable outcomes

Made unclear or no reference to research evidence

The last of these criteria was sometimes difficult to judge, and there was considerable discussion amongst the research team as to whether the link between research evidence and practice was sufficiently explicit in the interventions analysed. As we discussed in the previous review [ 8 ] in the field of healthcare, the principle of evidence-based practice is widely acknowledged and tools to change behaviour such as guidelines are often seen to be an implicit codification of evidence, despite the fact that this is not always the case.

Reviewers employed a two-stage process to select papers for inclusion. First, all titles and abstracts were screened by one reviewer to determine whether the study met the inclusion criteria. Two papers [ 14 , 15 ] were identified that fell just before the 2010 cut-off. As they were not identified in the searches for the first review [ 8 ] they were included and progressed to assessment. Each paper was rated as include, exclude or maybe. The full texts of 111 relevant papers were assessed independently by at least two authors. To reduce the risk of bias, papers were excluded following discussion between all members of the team. 32 papers met the inclusion criteria and proceeded to data extraction. The study selection procedure is documented in a PRISMA literature flow diagram (see Fig.  1 ). We were able to include French, Spanish and Portuguese papers in the selection reflecting the language skills in the study team, but none of the papers identified met the inclusion criteria. Other non- English language papers were excluded.

figure 1

PRISMA flow diagram. Source: authors

One reviewer extracted data on strategy type, number of included studies, local, target population, effectiveness and scope of impact from the included studies. Two reviewers then independently read each paper and noted key findings and broad themes of interest which were then discussed amongst the wider authorial team. Two independent reviewers appraised the quality of included studies using a Quality Assessment Checklist based on Oxman and Guyatt [ 16 ] and Francke et al. [ 17 ]. Each study was rated a quality score ranging from 1 (extensive flaws) to 7 (minimal flaws) (see Additional file 2 : Appendix B). All disagreements were resolved through discussion. Studies were not excluded in this updated overview based on methodological quality as we aimed to reflect the full extent of current research into this topic.

The extracted data were synthesised using descriptive and narrative techniques to identify themes and patterns in the data linked to intervention strategies, targeted behaviours, study settings and study outcomes.

Thirty-two studies were included in the systematic review. Table 1. provides a detailed overview of the included systematic reviews comprising reference, strategy type, quality score, number of included studies, local, target population, effectiveness and scope of impact (see Table  1. at the end of the manuscript). Overall, the quality of the studies was high. Twenty-three studies scored 7, six studies scored 6, one study scored 5, one study scored 4 and one study scored 3. The primary focus of the review was on reviews of effectiveness studies, but a small number of reviews did include data from a wider range of methods including qualitative studies which added to the analysis in the papers [ 18 , 19 , 20 , 21 ]. The majority of reviews report strategies achieving small impacts (normally on processes of care). There is much less evidence that these strategies have shifted patient outcomes. In this section, we discuss the different EPOC-defined implementation strategies in turn. Interestingly, we found only two ‘new’ approaches in this review that did not fit into the existing EPOC approaches. These are a review focused on the use of social media and a review considering toolkits. In addition to single interventions, we also discuss multi-faceted interventions. These were the most common intervention approach overall. A summary is provided in Table  2 .

Educational strategies

The overview identified three systematic reviews focusing on educational strategies. Grudniewicz et al. [ 22 ] explored the effectiveness of printed educational materials on primary care physician knowledge, behaviour and patient outcomes and concluded they were not effective in any of these aspects. Koota, Kääriäinen and Melender [ 23 ] focused on educational interventions promoting evidence-based practice among emergency room/accident and emergency nurses and found that interventions involving face-to-face contact led to significant or highly significant effects on patient benefits and emergency nurses’ knowledge, skills and behaviour. Interventions using written self-directed learning materials also led to significant improvements in nurses’ knowledge of evidence-based practice. Although the quality of the studies was high, the review primarily included small studies with low response rates, and many of them relied on self-assessed outcomes; consequently, the strength of the evidence for these outcomes is modest. Wu et al. [ 20 ] questioned if educational interventions aimed at nurses to support the implementation of evidence-based practice improve patient outcomes. Although based on evaluation projects and qualitative data, their results also suggest that positive changes on patient outcomes can be made following the implementation of specific evidence-based approaches (or projects). The differing positive outcomes for educational strategies aimed at nurses might indicate that the target audience is important.

Local opinion leaders

Flodgren et al. [ 24 ] was the only systemic review focusing solely on opinion leaders. The review found that local opinion leaders alone, or in combination with other interventions, can be effective in promoting evidence‐based practice, but this varies both within and between studies and the effect on patient outcomes is uncertain. The review found that, overall, any intervention involving opinion leaders probably improves healthcare professionals’ compliance with evidence-based practice but varies within and across studies. However, how opinion leaders had an impact could not be determined because of insufficient details were provided, illustrating that reporting specific details in published studies is important if diffusion of effective methods of increasing evidence-based practice is to be spread across a system. The usefulness of this review is questionable because it cannot provide evidence of what is an effective opinion leader, whether teams of opinion leaders or a single opinion leader are most effective, or the most effective methods used by opinion leaders.

Pantoja et al. [ 26 ] was the only systemic review focusing solely on manually generated reminders delivered on paper included in the overview. The review explored how these affected professional practice and patient outcomes. The review concluded that manually generated reminders delivered on paper as a single intervention probably led to small to moderate increases in adherence to clinical recommendations, and they could be used as a single quality improvement intervention. However, the authors indicated that this intervention would make little or no difference to patient outcomes. The authors state that such a low-tech intervention may be useful in low- and middle-income countries where paper records are more likely to be the norm.

ICT-focused approaches

The three ICT-focused reviews [ 14 , 27 , 28 ] showed mixed results. Jamal, McKenzie and Clark [ 14 ] explored the impact of health information technology on the quality of medical and health care. They examined the impact of electronic health record, computerised provider order-entry, or decision support system. This showed a positive improvement in adherence to evidence-based guidelines but not to patient outcomes. The number of studies included in the review was low and so a conclusive recommendation could not be reached based on this review. Similarly, Brown et al. [ 28 ] found that technology-enabled knowledge translation interventions may improve knowledge of health professionals, but all eight studies raised concerns of bias. The De Angelis et al. [ 27 ] review was more promising, reporting that ICT can be a good way of disseminating clinical practice guidelines but conclude that it is unclear which type of ICT method is the most effective.

Audit and feedback

Sykes, McAnuff and Kolehmainen [ 29 ] examined whether audit and feedback were effective in dementia care and concluded that it remains unclear which ingredients of audit and feedback are successful as the reviewed papers illustrated large variations in the effectiveness of interventions using audit and feedback.

Non-EPOC listed strategies: social media, toolkits

There were two new (non-EPOC listed) intervention types identified in this review compared to the 2011 review — fewer than anticipated. We categorised a third — ‘care bundles’ [ 36 ] as a multi-faceted intervention due to its description in practice and a fourth — ‘Technology Enhanced Knowledge Transfer’ [ 28 ] was classified as an ICT-focused approach. The first new strategy was identified in Bhatt et al.’s [ 30 ] systematic review of the use of social media for the dissemination of clinical practice guidelines. They reported that the use of social media resulted in a significant improvement in knowledge and compliance with evidence-based guidelines compared with more traditional methods. They noted that a wide selection of different healthcare professionals and patients engaged with this type of social media and its global reach may be significant for low- and middle-income countries. This review was also noteworthy for developing a simple stepwise method for using social media for the dissemination of clinical practice guidelines. However, it is debatable whether social media can be classified as an intervention or just a different way of delivering an intervention. For example, the review discussed involving opinion leaders and patient advocates through social media. However, this was a small review that included only five studies, so further research in this new area is needed. Yamada et al. [ 31 ] draw on 39 studies to explore the application of toolkits, 18 of which had toolkits embedded within larger KT interventions, and 21 of which evaluated toolkits as standalone interventions. The individual component strategies of the toolkits were highly variable though the authors suggest that they align most closely with educational strategies. The authors conclude that toolkits as either standalone strategies or as part of MFIs hold some promise for facilitating evidence use in practice but caution that the quality of many of the primary studies included is considered weak limiting these findings.

Multi-faceted interventions

The majority of the systematic reviews ( n  = 20) reported on more than one intervention type. Some of these systematic reviews focus exclusively on multi-faceted interventions, whilst others compare different single or combined interventions aimed at achieving similar outcomes in particular settings. While these two approaches are often described in a similar way, they are actually quite distinct from each other as the former report how multiple strategies may be strategically combined in pursuance of an agreed goal, whilst the latter report how different strategies may be incidentally used in sometimes contrasting settings in the pursuance of similar goals. Ariyo et al. [ 35 ] helpfully summarise five key elements often found in effective MFI strategies in LMICs — but which may also be transferrable to HICs. First, effective MFIs encourage a multi-disciplinary approach acknowledging the roles played by different professional groups to collectively incorporate evidence-informed practice. Second, they utilise leadership drawing on a wide set of clinical and non-clinical actors including managers and even government officials. Third, multiple types of educational practices are utilised — including input from patients as stakeholders in some cases. Fourth, protocols, checklists and bundles are used — most effectively when local ownership is encouraged. Finally, most MFIs included an emphasis on monitoring and evaluation [ 35 ]. In contrast, other studies offer little information about the nature of the different MFI components of included studies which makes it difficult to extrapolate much learning from them in relation to why or how MFIs might affect practice (e.g. [ 28 , 38 ]). Ultimately, context matters, which some review authors argue makes it difficult to say with real certainty whether single or MFI strategies are superior (e.g. [ 21 , 27 ]). Taking all the systematic reviews together we may conclude that MFIs appear to be more likely to generate positive results than single interventions (e.g. [ 34 , 45 ]) though other reviews should make us cautious (e.g. [ 32 , 43 ]).

While multi-faceted interventions still seem to be more effective than single-strategy interventions, there were important distinctions between how the results of reviews of MFIs are interpreted in this review as compared to the previous reviews [ 8 , 9 ], reflecting greater nuance and debate in the literature. This was particularly noticeable where the effectiveness of MFIs was compared to single strategies, reflecting developments widely discussed in previous studies [ 10 ]. We found that most systematic reviews are bounded by their clinical, professional, spatial, system, or setting criteria and often seek to draw out implications for the implementation of evidence in their areas of specific interest (such as nursing or acute care). Frequently this means combining all relevant studies to explore the respective foci of each systematic review. Therefore, most reviews we categorised as MFIs actually include highly variable numbers and combinations of intervention strategies and highly heterogeneous original study designs. This makes statistical analyses of the type used by Squires et al. [ 10 ] on the three reviews in their paper not possible. Further, it also makes extrapolating findings and commenting on broad themes complex and difficult. This may suggest that future research should shift its focus from merely examining ‘what works’ to ‘what works where and what works for whom’ — perhaps pointing to the value of realist approaches to these complex review topics [ 48 , 49 ] and other more theory-informed approaches [ 50 ].

Some reviews have a relatively small number of studies (i.e. fewer than 10) and the authors are often understandably reluctant to engage with wider debates about the implications of their findings. Other larger studies do engage in deeper discussions about internal comparisons of findings across included studies and also contextualise these in wider debates. Some of the most informative studies (e.g. [ 35 , 40 ]) move beyond EPOC categories and contextualise MFIs within wider systems thinking and implementation theory. This distinction between MFIs and single interventions can actually be very useful as it offers lessons about the contexts in which individual interventions might have bounded effectiveness (i.e. educational interventions for individual change). Taken as a whole, this may also then help in terms of how and when to conjoin single interventions into effective MFIs.

In the two previous reviews, a consistent finding was that MFIs were more effective than single interventions [ 8 , 9 ]. However, like Squires et al. [ 10 ] this overview is more equivocal on this important issue. There are four points which may help account for the differences in findings in this regard. Firstly, the diversity of the systematic reviews in terms of clinical topic or setting is an important factor. Secondly, there is heterogeneity of the studies within the included systematic reviews themselves. Thirdly, there is a lack of consistency with regards to the definition and strategies included within of MFIs. Finally, there are epistemological differences across the papers and the reviews. This means that the results that are presented depend on the methods used to measure, report, and synthesise them. For instance, some reviews highlight that education strategies can be useful to improve provider understanding — but without wider organisational or system-level change, they may struggle to deliver sustained transformation [ 19 , 44 ].

It is also worth highlighting the importance of the theory of change underlying the different interventions. Where authors of the systematic reviews draw on theory, there is space to discuss/explain findings. We note a distinction between theoretical and atheoretical systematic review discussion sections. Atheoretical reviews tend to present acontextual findings (for instance, one study found very positive results for one intervention, and this gets highlighted in the abstract) whilst theoretically informed reviews attempt to contextualise and explain patterns within the included studies. Theory-informed systematic reviews seem more likely to offer more profound and useful insights (see [ 19 , 35 , 40 , 43 , 45 ]). We find that the most insightful systematic reviews of MFIs engage in theoretical generalisation — they attempt to go beyond the data of individual studies and discuss the wider implications of the findings of the studies within their reviews drawing on implementation theory. At the same time, they highlight the active role of context and the wider relational and system-wide issues linked to implementation. It is these types of investigations that can help providers further develop evidence-based practice.

This overview has identified a small, but insightful set of papers that interrogate and help theorise why, how, for whom, and in which circumstances it might be the case that MFIs are superior (see [ 19 , 35 , 40 ] once more). At the level of this overview — and in most of the systematic reviews included — it appears to be the case that MFIs struggle with the question of attribution. In addition, there are other important elements that are often unmeasured, or unreported (e.g. costs of the intervention — see [ 40 ]). Finally, the stronger systematic reviews [ 19 , 35 , 40 , 43 , 45 ] engage with systems issues, human agency and context [ 18 ] in a way that was not evident in the systematic reviews identified in the previous reviews [ 8 , 9 ]. The earlier reviews lacked any theory of change that might explain why MFIs might be more effective than single ones — whereas now some systematic reviews do this, which enables them to conclude that sometimes single interventions can still be more effective.

As Nilsen et al. ([ 6 ] p. 7) note ‘Study findings concerning the effectiveness of various approaches are continuously synthesized and assembled in systematic reviews’. We may have gone as far as we can in understanding the implementation of evidence through systematic reviews of single and multi-faceted interventions and the next step would be to conduct more research exploring the complex and situated nature of evidence used in clinical practice and by particular professional groups. This would further build on the nuanced discussion and conclusion sections in a subset of the papers we reviewed. This might also support the field to move away from isolating individual implementation strategies [ 6 ] to explore the complex processes involving a range of actors with differing capacities [ 51 ] working in diverse organisational cultures. Taxonomies of implementation strategies do not fully account for the complex process of implementation, which involves a range of different actors with different capacities and skills across multiple system levels. There is plenty of work to build on, particularly in the social sciences, which currently sits at the margins of debates about evidence implementation (see for example, Normalisation Process Theory [ 52 ]).

There are several changes that we have identified in this overview of systematic reviews in comparison to the review we published in 2011 [ 8 ]. A consistent and welcome finding is that the overall quality of the systematic reviews themselves appears to have improved between the two reviews, although this is not reflected upon in the papers. This is exhibited through better, clearer reporting mechanisms in relation to the mechanics of the reviews, alongside a greater attention to, and deeper description of, how potential biases in included papers are discussed. Additionally, there is an increased, but still limited, inclusion of original studies conducted in low- and middle-income countries as opposed to just high-income countries. Importantly, we found that many of these systematic reviews are attuned to, and comment upon the contextual distinctions of pursuing evidence-informed interventions in health care settings in different economic settings. Furthermore, systematic reviews included in this updated article cover a wider set of clinical specialities (both within and beyond hospital settings) and have a focus on a wider set of healthcare professions — discussing both similarities, differences and inter-professional challenges faced therein, compared to the earlier reviews. These wider ranges of studies highlight that a particular intervention or group of interventions may work well for one professional group but be ineffective for another. This diversity of study settings allows us to consider the important role context (in its many forms) plays on implementing evidence into practice. Examining the complex and varied context of health care will help us address what Nilsen et al. ([ 6 ] p. 1) described as, ‘society’s health problems [that] require research-based knowledge acted on by healthcare practitioners together with implementation of political measures from governmental agencies’. This will help us shift implementation science to move, ‘beyond a success or failure perspective towards improved analysis of variables that could explain the impact of the implementation process’ ([ 6 ] p. 2).

This review brings together 32 papers considering individual and multi-faceted interventions designed to support the use of evidence in clinical practice. The majority of reviews report strategies achieving small impacts (normally on processes of care). There is much less evidence that these strategies have shifted patient outcomes. Combined with the two previous reviews, 86 systematic reviews of strategies to increase the implementation of research into clinical practice have been conducted. As a whole, this substantial body of knowledge struggles to tell us more about the use of individual and MFIs than: ‘it depends’. To really move forwards in addressing the gap between research evidence and practice, we may need to shift the emphasis away from isolating individual and multi-faceted interventions to better understanding and building more situated, relational and organisational capability to support the use of research in clinical practice. This will involve drawing on a wider range of perspectives, especially from the social, economic, political and behavioural sciences in primary studies and diversifying the types of synthesis undertaken to include approaches such as realist synthesis which facilitate exploration of the context in which strategies are employed. Harvey et al. [ 53 ] suggest that when context is likely to be critical to implementation success there are a range of primary research approaches (participatory research, realist evaluation, developmental evaluation, ethnography, quality/ rapid cycle improvement) that are likely to be appropriate and insightful. While these approaches often form part of implementation studies in the form of process evaluations, they are usually relatively small scale in relation to implementation research as a whole. As a result, the findings often do not make it into the subsequent systematic reviews. This review provides further evidence that we need to bring qualitative approaches in from the periphery to play a central role in many implementation studies and subsequent evidence syntheses. It would be helpful for systematic reviews, at the very least, to include more detail about the interventions and their implementation in terms of how and why they worked.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.


Before and after study

Controlled clinical trial

Effective Practice and Organisation of Care

High-income countries

Information and Communications Technology

Interrupted time series

Knowledge translation

Low- and middle-income countries

Randomised controlled trial

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The authors would like to thank Professor Kathryn Oliver for her support in the planning the review, Professor Steve Hanney for reading and commenting on the final manuscript and the staff at LSHTM library for their support in planning and conducting the literature search.

This study was supported by LSHTM’s Research England QR strategic priorities funding allocation and the National Institute for Health and Care Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust. Grant number NIHR200152. The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or Research England.

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Indole synthesis: a review and proposed classification

Douglass f. taber.

a Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA

Pavan K. Tirunahari

b Accel Synthesis, Inc., Garnet Valley, PA 19060, USA

1. Introduction

The indole alkaloids, ranging from lysergic acid to vincristine, have long inspired organic synthesis chemists. Interest in developing new methods for indole synthesis has burgeoned over the past few years. These new methods have been fragmented across the literature of organic chemistry. In this review, we present a framework for the classification of all indole syntheses.

As we approach the classification of routes for the preparation of indoles, we are mindful that the subject has occupied the minds of organic chemists for more than a century. There have been many reviews of indole synthesis. 1 We were also aware that much more could be said than we have written. We have only briefly covered the conversion of indolines into indoles, and the reduction of oxindoles to indoles. We have not covered the extensive literature on the modification of existing indoles. Throughout, our interest has been to be illustrative, not exhaustively inclusive. It is apparent, however, that every indole synthesis must fit one or the other of the nine strategic approaches adumbrated here. The web of scientific citations unites and organizes the world-wide research effort. It is our intention that the system put forward here for classifying indole syntheses will be universally understood. As authors conceive of new approaches to the indole nucleus, they will be able to classify their approach, and so readily discover both the history and the current state of the art with that strategy for indole construction. In addition to avoiding duplication, it is also our hope that efforts will then be directed toward the very real challenges that remain to be overcome. It is noteworthy that, in the most recent year we have covered, 2009, significant new contributions were reported for each of these nine strategies. We have highlighted these at the end of each section.

There are four bonds in the five-membered indole ring. In classifying methods for synthesis ( Fig. 1 ), we have focused on the last bond formed. We have also differentiated, in distinguishing Type 1 versus Type 2 and Type 3 versus Type 4, between forming a bond to a functionalized aromatic carbon, and forming a bond to an aromatic carbon occupied only by an H. Type 5 has as the last step C–N bond formation, while with Type 6 the last step is C–C bond formation. In Type 7, the benzene ring has been derived from an existing cyclohexane, and in Type 8, the benzene ring has been built onto an existing pyrrole. Finally, in Type 9, both rings have been constructed.

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The nine types of indole synthesis.

There are several name reactions associated with indole synthesis. We have tried to note these in context, and to group examples of a particular name reaction together. For convenience, the ‘name reaction’ indole syntheses mentioned in this review are:

  • Bartoli indole synthesis—Type 1
  • Bischler indole synthesis—Type 5
  • Fischer indole synthesis—Type 1
  • Hemetsberger indole synthesis—Type 3
  • Julia indole synthesis—Type 5
  • Larock indole synthesis—Type 5
  • Leimgruber–Batcho indole synthesis—Type 5
  • Madelung indole synthesis—Type 6
  • Nenitzescu indole synthesis—Type 7
  • Reissert indole synthesis—Type 5
  • Sundberg indole synthesis—Type 5

While it might be sufficient to merely label the nine strategies 1–9, for ease of recollection we have also associated each strategy with the name of an early or well-known practitioner. The division of strategies is strictly operational. Thus, the Fischer indole synthesis is classified as Type 1, Ar–H to C2, since that is the way it is carried out, even though the last bond formed, as the reaction proceeds, is in fact N to C1.

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Type 1 synthesis ( Scheme 1 - ​ -17) 17 ) involves aromatic C–H functionalization. Although C–H activation is thought of as a modern topic, the venerable Fischer indole synthesis (still under active development, Schemes 1 - ​ -3) 3 ) falls under this heading. Paul R. Brodfuehrer and Shaopeng Wang of Bristol-Myers Squibb described 2 the convenient ( Scheme 1 ) reaction of an aryl hydrazine 1 with dihydropyran 2 to give the 3-hydroxypropylindole 3 . Stephen L. Buchwald of MIT developed 3 an elegant ( Scheme 2 ) amination of aryl iodides to give Boc-protected aryl hydrazines, such as 4 . Acid-mediated condensation of 4 with the ketone 5 delivered the indole 6 . The condensation of 4 and 5 proceeded with high regioselectivity. Norio Takamura of Musashino University, Tokyo presented 4 a complementary approach ( Scheme 3 ), the addition of an aryllithium 8 to an α-diazo ester 7 , followed by acid-mediated cyclization. The ester of 9 is easily manipulated, and can also be removed altogether. Several other useful variations on the Fischer indole synthesis have been reported. 5 - 7

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Indoles can also be formed by acid-mediated cyclization of aldehydes. Richard J. Sundberg of the University of Virginia described 8 the preparation from 10 ( Scheme 4 ) and cyclization of acetals, such as 11 to give the indole 12 . The Bischler indole synthesis 9a,b is a variation on this approach. Chan Sik Cho and Sang Chul Shim of Kyungpook National University, Taegu devised 9c a route to indoles ( Scheme 5 ) based on Ru-mediated addition of an aniline 13 to an epoxide 14 . An interesting oxidatione–reduction cascade led to the 2-alkyl indole 15 , probably via a Bischler-like tautomerization.

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Other transition-metal-mediated protocols for indole synthesis have been developed. In a variant on the Bartoli indole synthesis, Kenneth M. Nicholas of the University of Oklahoma reported 10 the Ru-catalyzed reductive coupling of a nitrosoaromatic, such as 16 ( Scheme 6 ) with an alkyne 17 to give the indole 18 . Akio Saito and Yuji Hanzawa of Showa Pharmaceutical University described 11 the Rh-catalyzed cyclization of 19 ( Scheme 7 ) to 20 . The reaction was thought to proceed via the allene 21 .

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Several other Type 1 indole syntheses have been described. In the examples cited so far, only one regioisomeric aryl H could be substituted. In an ortho -metalation approach, Francis Johnson of SUNY Stony Brook showed 12 that ( Scheme 8 ) the anion from cyclization of 22 could be alkyated with an electrophile, such as 23 to give the indole 24 . Darrell Watson and D.R. Dillin at the University of Mary Hardin-Baylor reported 13 a photochemical route ( Scheme 9 ) to indoles. Irradiation of 25 in an oxygen atmosphere led to 26 . When the photolysis was carried out under nitrogen, the product was 27 . Frank Glorius of the Universität Münster devised 14 a related catalytic oxidation of enamines, such as 28 ( Scheme 10 ) to the indole 29 . Just recently, Yan-Guang Wang of Zhejian University, Hangzhou described 15 the coupling ( Scheme 11 ) of a wide range of anilides, such as 30 with ethyl diazoacetate 31 to give the indole 32 .

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Indoles, such as 35 ( Scheme 12 ) can also be prepared from oxindoles, such as 34 , prepared from 33 . Wendell Wierenga, then at Upjohn, optimized 16 both the Gassman synthesis of oxindoles from anilines, and the subsequent reduction. This is a net Type 1 synthesis.

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Samir Z. Zard of Ecole Polytechnique described 17 the cyclization ( Scheme 13 ) of allyl anilines, such as 36 to the indoline 38 using 37 . As indolines can be converted into indoles by oxidation 18 or by base-mediated elimination of an N -sulfonyl group 19 this is also a net Type 1 indole synthesis.

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In 2009, four interesting new examples of Type 1 indole synthesis were described. It had been thought that the cyclization of an acetal ( Scheme 4 ) to the indole would only work with electron-rich aromatic rings. Dali Yin of the Institute of Materia Medica, Beijing 20 observed that 39 ( Scheme 14 ), readily prepared by sequential displacement on the corresponding difluorodintrobenzene, smoothly cyclized to 40 .

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Following up on the work of Glorius ( Scheme 10 ), Ning Jiao of Peking University found 21 that, under oxidizing conditions, an aniline derivative, such as 41 ( Scheme 15 ) could be condensed with the diester 42 to give the indole 43 . Note that the cyclization proceeded with high regioselectivity. The product was easily hydrolyzed and decarboxylated to give the 2,3-unsubstituted indole.

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Akio Saito and Yuji Hanazawa of Showa Pharmaceutical University published 22 a full account of the Rh-mediated cyclization of propargylaniline derivatives, such as 44 ( Scheme 16 ) that they developed. This reaction is apparently proceeding via rearrangement to an intermediate o -allenylaniline, that then cyclizes to the product, 45 .

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Erik J. Sorensen of Princeton University uncovered 23 a route to indoles ( Scheme 17 ) based on an interrupted Ugi reaction, the combination of 46 and tert -butyl isocyanide to give the aminoindole 48 . The acid 47 was particularly effective at mediating this reaction.

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In a landmark paper in 1977, Miwako Mori, working with Yoshio Ban at Hokkaido University, reported 24 the first intramolecular Heck cyclization, converting the 2-bromoaniline derivative 49 ( Scheme 18 ) into the N -acetyl indole 50 with a Pd catalyst. In 1980, Louis S. Hegedus at Colorado State University showed 25 that iodides were superior to bromides for the cyclization, and that free amines, such as 51 ( Scheme 19 ) were compatible with the reaction conditions, forming 52 .

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This approach has been extended in several directions. John E. Macor at Pfizer found 26 that cyclization of the dibromide 53 to 54 ( Scheme 20 ) was more efficient than cyclization of the corresponding monobromide. Note that the potentially labile allylic carbamate survived the Pd reaction conditions. Haruhiko Fuwa and Makoto Sasaki of Tohoku University devised 27 the conversion of the N -acetyl aniline 55 ( Scheme 21 ) into the enol phosphonate 56 . Consecutive Suzuki coupling followed by Heck cyclization delivered the indole 57 .

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Morten Jørgensen of H. Lundbeck A/S, Denmark took advantage 28 of the more facile oxidative addition of aryl iodides compared to aryl bromides to accomplish sequential N-arylation and Heck cyclization, converting 58 ( Scheme 22 ) into the indole 59 . Lutz Ackermann of the Ludwigs-Maxmilian-Universität München effected 29 regioselective Ti-mediated hydroamination of the alkyne 61 ( Scheme 23 ) with the aniline 60 . Pd-mediated cyclization of the nucleophilic enamine so formed gave the indole 62 .

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Indoles can also be prepared by free radical cyclization. Athelstan L. J. Beckwith of the University of Adelaide cleverly employed 30 the nitroxide 64 ( Scheme 24 ) to effect first reduction, to facilitate loss of N 2 from the diazonium salt 63 , then radical cyclization, then radical-radical coupling with the nitroxide, followed by loss of the amine to give the indole aldehyde 65 . Richard P. Hsung, now at the University of Wisconsin, demonstrated 31 that a more conventional reductive cyclization of the allenylaniline 66 to form 67 ( Scheme 25 ) was also effective.

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Lanny S. Liebeskind of Emory University showed 32 that ortho -bromo allyl anilines, such as 68 ( Scheme 26 ) could, on transmetalation, be induced to cyclize to the indoline anion. The anion could be trapped with a variety of electrophiles. The product indoline was readily oxidized to the indole 69 . Professor Buchwald generated 33 from 70 ( Scheme 27 ) a zirconocene benzyne complex that inserted into the pendent alkene. Iodination delivered the indoline 71 , that via elimination and bromination was carried on to the indole 72 .

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Brian M. Stoltz of Caltech added 34 the anion derived from 74 ( Scheme 28 ) to the benzyne derived from 73 to give the indoline 75 . The authors did not oxidize 75 to the corresponding indole, but this should be straightforward.

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As described 35 by Brigitte Jamart-Grégoire of the Université de Nancy, a benzynewas also the intermediate in the cyclization of the anion derived from 76 ( Scheme 29 ) to the indole 77 . Daniel Solé of the Universitat de Barcelona effected 36 the conceptual alternative, the Pd-mediated arylation of the anion derived from 78 ( Scheme 30 ). Depending on the reaction conditions, the dominant product could be either the indoline, or the indole 79 .

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Among the several Type 2 indole syntheses reported in 2009, two were particularly interesting. Sandro Cacchi of the Università degli Studi ‘La Sapienza’, Roma, prepared 37 the enaminone 80 ( Scheme 31 ) by condensation of the iodoaniline with the acetylenic ketone. On exposure to a Cu catalyst, 80 cyclized to the indole 81 .

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Luc Neuville and JZhu of CNRS Gif-sur-Yvette assembled 38 ( Scheme 32 ) the amide 82 by a four-component coupling. With the proper choice of ligand, 82 could be cyclized to 83 . The conversion of an oxindole into the indole is described in the preceding section.

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The lead Type 3 approach is the Hemetsberger 39 indole synthesis, as, for instance, employed 40 by John K. MacLeod of Australia National University in his synthesis ( Scheme 33 ) of cis -trikentrin A. The aldehyde 84 was homologated to the azido ester 85 , that was then heated to convert it into the indole 86 .

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The thermal conversion of azido styrenes, such as 85 into the indole had been shown 39 to proceed by way of the azirine. We therefore developed 41 a general method for the conversion of an α-aryl ketone, such as 87 ( Scheme 34 ) into the azirine 88 . Thermolysis of the azirine gave the indole 89 . Subsequently, Koichi Narasaka of the University of Tokyo demonstrated 42 that Rh trifluoroacetate catalyzed the conversion of azirines, such as 88 into indoles at room temperature. Tom G. Driver of the University of Illinois, Chicago later found 43 that the same catalyst converted azido styrenes, such as 85 ( Scheme 33 ) into the indole, also at room temperature.

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Kang Zhao of Tianjin University established 44 that PIFA oxidation of an enamine, such as 92 ( Scheme 35 ), prepared from 90 and 91 , offered a convenient route to the N -aryl indole 93 . This cyclization may likely also be proceeding by way of the intermediate azirine.

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H. Person of the Université de Rennes found 45 that exposure of a β-nitro styrene 94 ( Scheme 36 ) to an isonitrile 95 led to the N -hydroxy indole 96 . Glen A. Russell of Iowa State University reported 46 a related reductive cyclization of a β-nitro styrene with triethyl phosphite.

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The coupling of a phenol 97 ( Scheme 37 ) with a diazonium salt 98 is a well-known process. Masato Satomura of Fuji Photo Film Co. discovered 47 that exposure of the adduct 99 to mild acid led to cyclization to the indole 100 . The N–N bond was readily cleaved by Raney nickel to give the free amine.

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The cyclic heptadepsipeptide HUN-7293 contains the N -methoxy tryptophan 104 ( Scheme 38 ). To prepare 104 , Dale L. Boger of Scripps/La Jolla took advantage 48 of the Kikugawa oxindole synthesis to convert 101 into 102 . Reduction followed by acid-catalyzed condensation with the enamide 103 then delivered 104 .

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In 2009, Vy M. Dong of the University of Toronto found 49 that CO could serve ( Scheme 39 ) as the reductant for the cyclization of a β-nitro styrene 105 to the indole 106 . Jin-Quan Yu, also of Scripps/La Jolla, developed 50 an oxidant that enabled the Pd-mediated cyclization of 107 ( Scheme 40 ) to the indole 108 .

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The development of transition-metal-mediated aryl halide amination opened the way to Type 4 indole synthesis. In 1998, Stephen L. Buchwald of MIT reported 51 that on exposure to benzylamine in the presence of a Pd catalyst, the dibromide 109 ( Scheme 41 ) smoothly cyclized to the indoline 110 . Ammonium formate in the presence of Pd/C converted 110 into the indole 111 .

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In the course of a synthesis of the duocarmycins, Tohru Fukuyama of the University of Tokyo employed 52 a similar approach, cyclizing 112 ( Scheme 42 ) to 113 . By that time, the Cu catalysts for aryl halide amination had been developed.

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José Barluenga of the University of Oviedo took advantage 53 of the greater reactivity of an aryl bromide compared to the chloride as he developed the convergent coupling of 114 ( Scheme 43 ) with 115 to give the indole 116 . For this coupling, a Pd catalyst was required.

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Alexander V. Karchava of Moscow State University devised 54 a route to indoles from ortho -bromophenylacetic acid esters, such as 117 ( Scheme 44 ). Formylation followed by condensation with an amine 118 set the stage for the Cu-mediated intramolecular amination to give the indole 119 .

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Phenols, under photolysis, can activate meta -substituted halides for nucleophilic displacement. Nien-chu C. Yang of the University of Chicago devised 55 an indoline synthesis based on this effect, irradiating 120 ( Scheme 45 ) to give 121 .

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Similarly, nitro groups can activate para -substituted halides for nucleophilic displacement. Douglas C. Neckers of Bowling Green State University observed 56 that exposure to a primary amine converted the thiadiazole 123 ( Scheme 46 ), prepared from 122 , into the indole-2-thiol 124 . The reaction is thought to be proceeding by way of the alkyne thiol.

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In 2009, Qian Cai and Ke Ding of the Institute of Biological Chemistry, Guangzhou described 57 ( Scheme 47 ) the CuI-mediated condensation of the isocyano ester 126 with o -halo aromatic ketones and aldehydes, such as 125 to give directly the corresponding indole 127 . Stuart L. Schreiber of Harvard University took 58 a related approach, cyclizing 128 ( Scheme 48 ), prepared via the corresponding aziridine, to the indole 129 .

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In 1969, Richard J. Sundberg of the University of Virginia reported 59 that ortho -azido styrenes, such as 130 ( Scheme 49 ) were converted on thermolysis into the corresponding indole 131 . He later found 60 that heating ortho -nitro styrenes, such as 132 ( Scheme 50 ) with P(OEt) 3 also delivered the indole. Aryl migration dominated over alkyl migration, leading to 133 . Recently, Tom G. Driver of the University of Illinois, Chicago showed 61 that the azide version of the Sundberg indole synthesis could be carried out at lower temperature with a Rh catalyst.

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Benzylic methyl groups are acidic enough to be deprotonated, especially when there is an ortho -nitro group. This is the basis for the Reissert indole synthesis 62 ( 134 to 135 , Scheme 51 ) and the Leimgruber–Batcho indole synthesis 63 ( 136 to 138 , Scheme 52 ).

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Amos B. Smith III of the University of Pennsylvania took advantage 64 of the acidity of 139 ( Scheme 53 ). Double deprotonation followed by condensation with 140 delivered the indole 141 .

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Donal F. O’Shea of University College Dublin demonstrated 65 that an alkyllithium first deprotonated 142 ( Scheme 54 ), and then added to the pendent alkene. Benzonitrile 143 was added to the resulting carbanion to give the indole 144 .

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It is clear that any synthetic route to ortho -amino or ortho -nitro α-aryl ketones or aldehydes can be used to prepare indoles. Joseph F. Bunnett of the University of California, Santa Cruz observed 66 that, under S RN 1 conditions, acetone enolate displaced the bromide of 145 ( Scheme 55 ), leading to the indole 146 . Viresh H. Rawal of the University of Chicago arylated 67 the silyl enol ether 147 ( Scheme 56 ) with an ortho -nitrophenyl iodinium salt (NPIF) to give, after reduction, the indole 148 . M. Mahmoun Hossain of the University of Wisconsin, Milwaukee inserted 68 ethyl diazoacetate into the aldehyde 149 ( Scheme 57 ), converting it, via reduction, into the indole 150 .

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As demonstrated 69 by Ken-ichi Fujita and Ryohei Yamaguchi of Kyoto University, in situ oxidation of the alcohol 151 ( Scheme 58 ) led to the indole 152 . With added 2-propanol, an alcohol with an ortho -nitro group was also converted into the indole.

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Hironao Sajiki and Kosaku Hirota of Gifu Pharmaceutical University showed 70 that reduction of an ortho -amino nitrile, such as 153 ( Scheme 59 ) delivered the indole 154 , presumably by trapping of the intermediate imine. It may well be that an ortho -nitro substituent would work as well, but such a transformation was not included in this report.

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K. C. Nicolaou of Scripps/La Jolla prepared 71 the enone 155 ( Scheme 60 ) from the intermediate in the Bischler indole synthesis. Reduction of 155 gave an intermediate that reacted with mild nucleophiles, such as the allylsilane 156 to give the indole 157 .

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In 1986, Sylvestre A. Julia of the Ecole Normale Supérieure, Paris reported 72 that sulfinamides, such as 159 ( Scheme 61 ), readily prepared from the aniline 158 , were converted by heating into the indole 161 via 160 . It is striking that the Julia indole synthesis has been little used since it was reported.

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The preparation of indoles from ortho -haloanilines by condensation with an alkyne goes back at least to 1963, when C. E. Castro of the University of California, Riverside, observed 73 ( Scheme 62 ) that coupling of 162 with 163 led not to the diaryl alkyne, but to the indole 164 .

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In 1985, Edward C. Taylor of Princeton University and Alexander McKillop of the University of East Anglia showed 74 that Pd was effective at cyclizing ortho -alkynylanilines to the corresponding indole. This led to the 1989 report 75 by J. K. Stille of Colorado State University that the two-step coupling described by Castro ( Scheme 62 ) could be carried out at much lower temperature using Pd catalysis. With this precedent, in 1991 Richard C. Larock of Iowa State University disclosed 76 that, using Pd catalysis ( Scheme 63 ), internal alkynes, such as 166 could be condensed with an ortho -iodoaniline 165 under Pd catalysis to give the 2,3-disubstituted indole 167 with high regiocontrol. One of the advantages of the Larock indole synthesis is the malleability of the 2-silyl substituent on the product indole.

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More recently, (the late) Keith Fagnou of the University of Ottawa demonstrated 77 that Rh catalysis could effect ortho functionalization of acetanilides, such as 168 ( Scheme 64 ). Subsequent coupling with internal alkynes, such as 169 led to the indole 170 with high regiocontrol.

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Several other flexible routes to indoles have been developed. Mark Lautens of the University of Toronto established 78 that ortho dihaloalkylidene anilines, such as 171 ( Scheme 65 ) could be condensed with alkyl, alkenyl or aryl boranes or boronic acids to give the 2-substituted indole, in this case 172 . Kentaro Okuma of Fukuoka University found 79 that the sulfonium salt 174 ( Scheme 66 ) effected cyclization of an ortho alkenyl aniline, such as 173 to the indole 175 . Jeffrey N. Johnston, now at Vanderbilt University, effected 80 free radical reductive cyclization of halides, such as 176 ( Scheme 67 ), to give the indole 177 .

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Toyohiko Aoyama of Nagoya City University reacted 81 ortho -acylanilines, such as 178 ( Scheme 68 ) with lithio TMS diazomethane 179 to give an alkylidene carbene, that inserted into the adjacent NH to give the indole 180 . Bartolo Gabriele of the Università della Calabria added 82 acetylides, such as 182 ( Scheme 69 ) to ortho -acylanilines, such as 181 to give alkynyl alcohols, that underwent carbonylative cyclization with Pd catalysis to give the indole 183 .

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In 2009, Hideo Nagashima of Kyushu University reported 83 that an o -nitrophenyl acetonitrile 184 could indeed ( Scheme 70 ) be reductively cyclized to the indole 185 . Yanxing Jia of Peking University prepared 84 188 , a key intermediate in the synthesis of (−)- cis -clavicipitic acid, by selective condensation of the aldehyde 187 ( Scheme 71 ) with the iodoaniline 186 .

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Sandro Cacchi of the Università ‘La Sapienza’, Rome, extended 85 the Gabriele approach, cyclizing ( Scheme 72 ) the propargylic carbonate 189 to 190 . This transformation may be proceeding by way of the intermediate allene. Two related approaches to indole synthesis 86 , 87 also appeared.

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Tao Pei of Merck Rahway developed 88 a powerful new approach to substituted indoles, based on the addition ( Scheme 73 ) of an organometallic to a chloro ketone 191 . The conversion into 192 proceeded by 1,2-migration of the arene with nucleophilic displacement of chloride.

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The Madelung indole synthesis, as exemplified by the cyclization ( Scheme 74 ) of 193 to 194 , was originally carried out at elevated temperature with bases, such as NaNH 2 . Willam J. Houlihan of Sandoz, Inc. (now Novartis) showed 89 that, with BuLi, the cyclization of 193 to 194 was facile below room temperature. D. N. Reinhoudt of the University of Twente found 90 that phenylacetonitriles, such as 195 ( Scheme 75 ) could be cyclized under even milder conditions, to form 196 .

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George A. Kraus of Iowa State University described 91 a conceptually related cyclization ( Scheme 76 ). Condensation of an aldehyde 198 with the aniline 197 gave the imine, that on exposure to strong base gave the indole 199 . Gary A. Sulikowski, now at Vanderbilt University, showed 92 that cyclization of the carbene derived from 200 ( Scheme 77 ) proceeded to give 201 with high regiocontrol.

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Bond formation in the opposite direction has also been developed. William D. Jones reported 93 that a Ru complex catalyzed the conversion of the isonitrile 202 ( Scheme 78 ) into the indole 203 . This reaction may be proceeding by way of the Ru vinylidene complex.

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Charles D. Jones of Lilly described 94 an anionic cyclization in this direction, converting 204 ( Scheme 79 ) into 205 . Yoshinori Nakamura of the Tanabe Seiyaku Co. contributed 95 the Rh-mediated coupling of the diazophosphonate 207 ( Scheme 80 ) to an ortho -acylaniline, such as 206 , to give, after cyclization, the indole 208 . Note that, in the cyclization of 209 ( Scheme 81 ) developed 96 by RodneyW. Stevens of Pfizer Nagoya, re-aromatization to the indole 210 was achieved by elimination of arenesulfinate.

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In 1994, Tohru Fukuyama, now at the University of Tokyo, disclosed 97a the cascade radical cyclization of the isonitrile 211 ( Scheme 82 ) to the indole 212 . Later, he applied 97b a variant of this cyclization in the total synthesis of a complex indole alkaloid. Jon D. Rainier, now at the University of Utah, has explored 97c related radical cyclizations.

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Alois Fürstner of the Max-Planck-Institute Mülheim developed 98a, b a reductive coupling of acyl anilides, such as 213 to give 214 ( Scheme 83 ). In the presence of a silyl chloride, the reaction was catalytic in Ti. Bruce C. Lu of Boehringer Ingelheim employed 98c this reductive coupling in a combinatorial route to indoles.

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In 2009, Professor Doyle reported 99 an alternative ( Scheme 84 ) diazo-based approach to indoles, Lewis acid-mediated cyclization of 215 to 216 .

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Churl Min Seong of the Korea Research Institute of Chemical Technology described 100 the facile cyclization ( Scheme 85 ) of an o -cyano N -benzyl aniline 217 to the indole 218 . Andrew D. Hamilton employed 101 a related protocol ( Scheme 86 ), the cyclization of 219 to 220 .

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Type 7 includes all routes to indoles from cycloalkane derivatives. The earliest such approach is the Nenitzescu indole synthesis, exemplified ( Scheme 87 ) in a modern manifestation 102 by Daniel M. Ketcha of Wright State University and Lawrence J. Wilson of Procter & Gamble. The combination of the benzoquinone 221 with the resin-bound enamine 222 gave, after release from the resin, the indole 223 .

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Michael A. Kerr of the University of Western Ontario developed 103 ( Scheme 88 ) a complementary protocol for the conversion of a benzoquinone into the indole. Diels–Alder cycloaddition of the imine 224 to the diene 225 gave the adduct 226 . Protection followed by oxidative cleavage and condensation delivered the indole 227 .

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Fused pyrroles, such as 231 ( Scheme 89 ) and 235 ( Scheme 90 ) are readily aromatized. Brian L. Pagenkopf of the University of Western Ontario established 104 a pyrrole synthesis from cyclohexanone, by cyclopropanation of the enol ether 228 followed by condensation with the nitrile 230 . The aromatization of 231 to 232 was accomplished by heating with Pd/C in mesitylene.

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Teruhiko Ishikawa and Seiki Saito of Okayama University condensed 105 ( Scheme 90 ) cyclohexane-1,3-dione 233 with the nitroalkene 234 , leading after exchange with benzylamine to the pyrrole 235 . Aromatization gave the 4-oxygenated indole 236 . Chihiro Kibiyashi of the Tokyo College of Pharmacy reported 106 a related approach to 4-oxygenated indoles.

Michel Pfau of ESPCI Paris devised 107 an intriguing protocol for indole construction, starting with the benzyl imine of the monoprotected cyclohexane-1,4-dione 237 ( Scheme 91 ). Metalation of the imine followed by condensation with maleic anhydride 238 , with methanol workup, delivered the lactam 239 . Exposure of 239 to POCl 3 effected aromatization to the 5-methoxyindole 240 .

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In 2009, Yong-Qiang Tu of Lanzhou University described 108 the ring expansion ( Scheme 92 ) of 241 to 242 . The aromatization of 242 to the indole should be facile. Tsutomu Inokuchi of Okayama University showed 109 that reduction ( Scheme 93 ) of the Michael adduct 243 followed by aromatization delivered the indole 244 .

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Type 8 indole syntheses include all those that proceed by way of the preformed N -containing five-membered ring. In 1986, Albert M. van Leusen of Groningen University established 110 a route to highly substituted indoles, based on the condensation of isonitriles, such as 245 ( Scheme 94 ) with unsaturated ketones, such as 246 to give the 2,3-bisalkenylpyrrole 247 . Heating followed by aromatization with DDQ completed the synthesis of the indole 248 .

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Hiroyuki Ishibashi of Kyoto Pharmaceutical University demonstrated 111 ( Scheme 95 ) a route to 4-substituted indoles from pyrrole itself. Condensation of 249 with the chlorosulfide followed by saponification and intramolecular Friedel–Crafts acylation delivered the versatile intermediate 250 . Oxidation gave the indole 251 . The addition of nucleophiles to 250 followed by dehydration gave the 4-alkylindole (not illustrated).

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Pedro Mancini of the Universidad Nacional de Litoral showed 112 that nitropyrroles, such as 252 ( Scheme 96 ) were effective Diels–Alder dienophiles. Regiocontrol was poor with isoprene, whereas addition to the more activated diene 253 proceeded to give the 5-hydroxyindole 254 with complete regiocontrol.

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Edwin Vedejs of the University of Michigan optimized 113 the acetic anhydride-mediated cyclization of the Stobbe condensation product 255 ( Scheme 97 ) to the indole 256 . Although this cyclization had been reported earlier, Vedejs found that the conditions originally described also delivered substantial quantities of an indolizidine by-product.

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Masanobu Hidai of the University of Tokyo developed 114 the Pd-catalyzed cyclocarbonylation of the allylic acetate 257 ( Scheme 98 ) to the 4-acetoxyindole 258 . It seems likely that a more highly substituted version of 257 would cyclize with equal facility.

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Alan R. Katrizky of the University of Florida devised 115 an approach to indoles with more highly substituted benzene rings. Addition of the benzotriazolyl anion 259 ( Scheme 99 ) to an enone, such as 260 followed by acid-catalyzed dehydrative cyclization delivered the indole 261 .

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Naoki Asao of Tohoku University found 116 that AuBr 3 was an effective catalyst for the cyclocondensation ( Scheme 100 ) of 262 with 263 to give the indole 264 . F. Dean Toste of the University of California, Berkeley uncovered 117 a related Au-catalyzed cyclization leading to indoles.

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In 2009, Chi-Meng Che of the University of Hong Kong 118 described ( Scheme 101 ) the Pt-mediated intramolecular hydroamination of the alkyne 265 . Condensation of the cyclic enamine 266 so prepared with a β-diketone 267 proceeded with high regioselectivity to give the indoline 268 . For the aromatization of a similar N -benzyl indoline, see Scheme 41 .

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The least developed approach to indoles is Type 9, the simultaneous construction of both rings of the indole. This route was pioneered in 1986 119 by Ken Kanematsu of Kyushu University. Homologation of 269 ( Scheme 102 ) to the allene led to the intramolecular Diels–Alder cyclization product, that was readily aromatized to the indole 270 .

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Three related approaches have been put forward since that time. Michael J. Martinelli, then at Lilly, established 120 that acetic anhydride-mediated decarboxylation of 271 ( Scheme 103 ) led to a 1,3-dipole, that added in an intramolecular fashion to the alkyne, delivering the dihydro indole 272 . In a complementary approach, A. Stephen K. Hashmi of Ruprecht-Karls-Universität Heidelberg found 121 that with catalytic AuBr 3 , 273 ( Scheme 104 ) cyclized efficiently to 274 . As outlined earlier in this review, both 272 and 274 would be readily aromatized to the corresponding indoles.

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In 2009, Peter Wipf of the University of Pittsburgh described 122 the intramolecular Diels—Alder cyclization ( Scheme 105 ) of the allylic alcohol 275 . Microwave heating led directly to the doubly aromatized product 276 .

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11. Conclusions

In this review, we have tried to be inclusive, but certainly not comprehensive. We hope that the scheme outlined here for the classification of synthetic routes to indoles will be useful to future practitioners of the art, and will stimulate new thinking in the field.


The authors thank Professor Gordon W. Gribble for his advice and encouragement. PKT thanks Randy W. Jackson for his understanding and support.


Douglass F. Taber was born in 1948 in Berkeley, California. He earned a B.S. in Chemistry with Honors from Stanford University in 1970, and a Ph.D. in Organic Chemistry from Columbia University in 1974 (G. Stork). After a postdoctoral year at the University of Wisconsin (B.M. Trost), Taber accepted a faculty position at Vanderbilt University. He moved to the University of Delaware of Delaware in 1982, where he is currently Professor of Chemistry. Taber is the author of more than 200 research papers on organic synthesis and organometallic chemistry. He is also the author of the weekly Organic Highlights published at

Pavan K. Tirunahari was born inWarangal, A.P, India in 1968. He received his Bachelor of Science and Master of Science degrees from Osmania University, Hyderabad. He then joined the group of Dr. B. G. Hazra at National Chemical Laboratory, Pune, Maharastra. He received his Ph.D degree in Organic Chemistry from the University of Pune. He did his postdoctoral studies in the group of Professor James. P. Morken at the University of North Carolina. Currently he is working at Accel Synthesis, Inc., Garnet Valley, PA. His research interests include process research, synthetic methodologies, medicinal chemistry, and pharmacology.

References and notes

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Video generation models as world simulators.

We explore large-scale training of generative models on video data. Specifically, we train text-conditional diffusion models jointly on videos and images of variable durations, resolutions and aspect ratios. We leverage a transformer architecture that operates on spacetime patches of video and image latent codes. Our largest model, Sora, is capable of generating a minute of high fidelity video. Our results suggest that scaling video generation models is a promising path towards building general purpose simulators of the physical world.

More resources

  • View Sora overview

This technical report focuses on (1) our method for turning visual data of all types into a unified representation that enables large-scale training of generative models, and (2) qualitative evaluation of Sora’s capabilities and limitations. Model and implementation details are not included in this report.

Much prior work has studied generative modeling of video data using a variety of methods, including recurrent networks, [^1] [^2] [^3] generative adversarial networks, [^4] [^5] [^6] [^7] autoregressive transformers, [^8] [^9] and diffusion models. [^10] [^11] [^12] These works often focus on a narrow category of visual data, on shorter videos, or on videos of a fixed size. Sora is a generalist model of visual data—it can generate videos and images spanning diverse durations, aspect ratios and resolutions, up to a full minute of high definition video.

Turning visual data into patches

We take inspiration from large language models which acquire generalist capabilities by training on internet-scale data. [^13] [^14] The success of the LLM paradigm is enabled in part by the use of tokens that elegantly unify diverse modalities of text—code, math and various natural languages. In this work, we consider how generative models of visual data can inherit such benefits. Whereas LLMs have text tokens, Sora has visual patches . Patches have previously been shown to be an effective representation for models of visual data. [^15] [^16] [^17] [^18] We find that patches are a highly-scalable and effective representation for training generative models on diverse types of videos and images.

Figure Patches

At a high level, we turn videos into patches by first compressing videos into a lower-dimensional latent space, [^19] and subsequently decomposing the representation into spacetime patches.

Video compression network

We train a network that reduces the dimensionality of visual data. [^20] This network takes raw video as input and outputs a latent representation that is compressed both temporally and spatially. Sora is trained on and subsequently generates videos within this compressed latent space. We also train a corresponding decoder model that maps generated latents back to pixel space.

Spacetime latent patches

Given a compressed input video, we extract a sequence of spacetime patches which act as transformer tokens. This scheme works for images too since images are just videos with a single frame. Our patch-based representation enables Sora to train on videos and images of variable resolutions, durations and aspect ratios. At inference time, we can control the size of generated videos by arranging randomly-initialized patches in an appropriately-sized grid.

Scaling transformers for video generation

Sora is a diffusion model [^21] [^22] [^23] [^24] [^25] ; given input noisy patches (and conditioning information like text prompts), it’s trained to predict the original “clean” patches. Importantly, Sora is a diffusion transformer . [^26] Transformers have demonstrated remarkable scaling properties across a variety of domains, including language modeling, [^13] [^14] computer vision, [^15] [^16] [^17] [^18] and image generation. [^27] [^28] [^29]

Figure Diffusion

In this work, we find that diffusion transformers scale effectively as video models as well. Below, we show a comparison of video samples with fixed seeds and inputs as training progresses. Sample quality improves markedly as training compute increases.

Variable durations, resolutions, aspect ratios

Past approaches to image and video generation typically resize, crop or trim videos to a standard size—e.g., 4 second videos at 256x256 resolution. We find that instead training on data at its native size provides several benefits.

Sampling flexibility

Sora can sample widescreen 1920x1080p videos, vertical 1080x1920 videos and everything inbetween. This lets Sora create content for different devices directly at their native aspect ratios. It also lets us quickly prototype content at lower sizes before generating at full resolution—all with the same model.

Improved framing and composition

We empirically find that training on videos at their native aspect ratios improves composition and framing. We compare Sora against a version of our model that crops all training videos to be square, which is common practice when training generative models. The model trained on square crops (left) sometimes generates videos where the subject is only partially in view. In comparison, videos from Sora (right) have improved framing.

Language understanding

Training text-to-video generation systems requires a large amount of videos with corresponding text captions. We apply the re-captioning technique introduced in DALL·E 3 [^30] to videos. We first train a highly descriptive captioner model and then use it to produce text captions for all videos in our training set. We find that training on highly descriptive video captions improves text fidelity as well as the overall quality of videos.

Similar to DALL·E 3, we also leverage GPT to turn short user prompts into longer detailed captions that are sent to the video model. This enables Sora to generate high quality videos that accurately follow user prompts.

Prompting with images and videos

All of the results above and in our landing page show text-to-video samples. But Sora can also be prompted with other inputs, such as pre-existing images or video. This capability enables Sora to perform a wide range of image and video editing tasks—creating perfectly looping video, animating static images, extending videos forwards or backwards in time, etc.

Animating DALL·E images

Sora is capable of generating videos provided an image and prompt as input. Below we show example videos generated based on DALL·E 2 [^31] and DALL·E 3 [^30] images.

research paper with synthesis

Extending generated videos

Sora is also capable of extending videos, either forward or backward in time. Below are four videos that were all extended backward in time starting from a segment of a generated video. As a result, each of the four videos starts different from the others, yet all four videos lead to the same ending.

We can use this method to extend a video both forward and backward to produce a seamless infinite loop.

Video-to-video editing

Diffusion models have enabled a plethora of methods for editing images and videos from text prompts. Below we apply one of these methods, SDEdit, [^32] to Sora. This technique enables Sora to transform  the styles and environments of input videos zero-shot.

Connecting videos

We can also use Sora to gradually interpolate between two input videos, creating seamless transitions between videos with entirely different subjects and scene compositions. In the examples below, the videos in the center interpolate between the corresponding videos on the left and right.

Image generation capabilities

Sora is also capable of generating images. We do this by arranging patches of Gaussian noise in a spatial grid with a temporal extent of one frame. The model can generate images of variable sizes—up to 2048x2048 resolution.

research paper with synthesis

Emerging simulation capabilities

We find that video models exhibit a number of interesting emergent capabilities when trained at scale. These capabilities enable Sora to simulate some aspects of people, animals and environments from the physical world. These properties emerge without any explicit inductive biases for 3D, objects, etc.—they are purely phenomena of scale.

3D consistency. Sora can generate videos with dynamic camera motion. As the camera shifts and rotates, people and scene elements move consistently through three-dimensional space.

Long-range coherence and object permanence. A significant challenge for video generation systems has been maintaining temporal consistency when sampling long videos. We find that Sora is often, though not always, able to effectively model both short- and long-range dependencies. For example, our model can persist people, animals and objects even when they are occluded or leave the frame. Likewise, it can generate multiple shots of the same character in a single sample, maintaining their appearance throughout the video.

Interacting with the world. Sora can sometimes simulate actions that affect the state of the world in simple ways. For example, a painter can leave new strokes along a canvas that persist over time, or a man can eat a burger and leave bite marks.

Simulating digital worlds. Sora is also able to simulate artificial processes–one example is video games. Sora can simultaneously control the player in Minecraft with a basic policy while also rendering the world and its dynamics in high fidelity. These capabilities can be elicited zero-shot by prompting Sora with captions mentioning “Minecraft.”

These capabilities suggest that continued scaling of video models is a promising path towards the development of highly-capable simulators of the physical and digital world, and the objects, animals and people that live within them.

Sora currently exhibits numerous limitations as a simulator. For example, it does not accurately model the physics of many basic interactions, like glass shattering. Other interactions, like eating food, do not always yield correct changes in object state. We enumerate other common failure modes of the model—such as incoherencies that develop in long duration samples or spontaneous appearances of objects—in our landing page .

We believe the capabilities Sora has today demonstrate that continued scaling of video models is a promising path towards the development of capable simulators of the physical and digital world, and the objects, animals and people that live within them.

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Title: snap video: scaled spatiotemporal transformers for text-to-video synthesis.

Abstract: Contemporary models for generating images show remarkable quality and versatility. Swayed by these advantages, the research community repurposes them to generate videos. Since video content is highly redundant, we argue that naively bringing advances of image models to the video generation domain reduces motion fidelity, visual quality and impairs scalability. In this work, we build Snap Video, a video-first model that systematically addresses these challenges. To do that, we first extend the EDM framework to take into account spatially and temporally redundant pixels and naturally support video generation. Second, we show that a U-Net - a workhorse behind image generation - scales poorly when generating videos, requiring significant computational overhead. Hence, we propose a new transformer-based architecture that trains 3.31 times faster than U-Nets (and is ~4.5 faster at inference). This allows us to efficiently train a text-to-video model with billions of parameters for the first time, reach state-of-the-art results on a number of benchmarks, and generate videos with substantially higher quality, temporal consistency, and motion complexity. The user studies showed that our model was favored by a large margin over the most recent methods. See our website at this https URL .

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    Written by MasterClass Last updated: Aug 19, 2021 • 4 min read The writing process for composing a good synthesis essay requires curiosity, research, and original thought to argue a certain point or explore an idea.

  5. What Synthesis Methodology Should I Use? A Review and Analysis of

    Research synthesis, a research process in its own right ... Data type: CIS utilizes data from quantitative and qualitative empirical studies, conceptual and theoretical papers, reviews and commentaries. Research question: It is neither possible nor desirable to specify a precise review question in advance. Rather the process is highly iterative ...

  6. PDF Synthesizing Source Ideas for Your Research Paper

    "Synthesis: the combining of the constituent elements of separate material or abstract entities into a single or unified entity; the process of combining objects or ideas into a complex whole."1*...

  7. Understanding the Impacts of Research Synthesis

    1. Introduction. Research or scientific synthesis is the integration and assessment of knowledge and research findings pertinent to a particular issue with the aim of increasing the generality and applicability of, and access to, those findings (Hampton & Parker 2011, Magliocca et al., 2014, Baron et al. 2017).Synthesis of existing research and case studies can also generate new knowledge.

  8. PDF 1. Planning a Synthesis Paper

    The term "synthesis" means to combine separate elements to form a whole. Writing teachers often use this term when they assign students to write a literature review or other paper that requires the use of a variety of sources.

  9. Research Guides: How to Write a Literature Review: 6. Synthesize

    6. Synthesize - How to Write a Literature Review - Research Guides at University of Oregon Libraries How to Write a Literature Review A self-guided tutorial that walks you through the process of conducting a Literature Review. Synthesize This is the point where you sort articles by themes or categories in preparation for writing your lit review.

  10. Synthesizing Research

    Synthesis prevents your papers from looking like a list of copied and pasted sources from various authors. Synthesis is a higher order process in writing—this is the area where you as a writer get to shine and show your audience your reasoning. Types of Synthesis Similarity Demonstrates how two or more sources agree with one another. Example:

  11. How to Write a Synthesis Essay: The Ultimate Handbook

    According to our ' write paper for me ' experts, the synthesis essay emerges as a dynamic catalyst in the realm of composition. Beyond the act of assembling disparate facts and opinions, it's a nuanced process of weaving coherence. Envision it as constructing an intricate tapestry from scattered threads.

  12. Qualitative research synthesis: An appreciative and critical

    Qualitative research synthesis is a diverse set of methods for combining the data or the results of multiple studies on a topic to generate new knowledge, theory and applications. Use of qualitative research synthesis is rapidly expanding across disciplines.

  13. Synthesis

    By synthesizing research, you are showing that you can combine current information in your field of study and add a new interpretation or analysis of those sources. What steps do I need to take to reach synthesis? To effectively synthesize the literature, you must first critically read the research on your topic.

  14. Home

    1. Write your topic or research question above the matrix. 2. Write your main ideas for your paper on the left side of the matrix. Helpful Tip: Choose your main ideas AFTER you have read your sources! 3. Write the title, author, or citation of each source in the top row of the matrix. 4.

  15. How to Write a Synthesis Essay, WIth Examples

    Matt Ellis Updated on December 27, 2023 Students Synthesis essays are common assignments in both high school and university, but that doesn't mean they're easy or that everyone knows how to write them. In this guide, we discuss everything you need to know in order to write one yourself.

  16. Synthesis in Research: Home

    Synthesis is a form of analysis related to comparison and contrast, classification and division. On a basic level, synthesis involves bringing together two or more sources, looking for themes in each. In synthesis, you search for the links between various materials in order to make your point. Most advanced academic writing relies heavily on ...

  17. Qualitative Evidence Synthesis: Where Are We at?

    Framework synthesis offers a highly structure approach to QES by using an apriori framework, into which the findings from the primary qualitative research are extracted and synthesized (Booth et al., 2016); in this way it is distinct from the other two methods described in this paper.

  18. A Guide to Evidence Synthesis: What is Evidence Synthesis?

    They generally include a methodical and comprehensive literature synthesis focused on a well-formulated research question. Their aim is to identify and synthesize all of the scholarly research on a particular topic, including both published and unpublished studies.

  19. LibGuides: Writing Resources: Synthesis and Analysis

    What Does Synthesis and Analysis Mean? Synthesis: the combination of ideas to form a theory, system, larger idea, point or outcome show commonalities or patterns Analysis: a detailed examination of elements, ideas, or the structure of something can be a basis for discussion or interpretation Synthesis and Analysis: combine and examine ideas to

  20. Synthesis Paper

    Student Resources. Synthesis Paper. Synthesis, or synthesizing, is a mode of writing that groups various sources together in a way that makes the relationships between the sources clear. Usually, these sources revolve around the same subject.

  21. Nanomaterials: a review of synthesis methods, properties, recent

    In comparison, the synthesis of highly ordered nanoporous carbon is facile, and the properties of ordered nanoporous carbon are also appealing for energy and environmental applications. 311 CO 2 is a greenhouse gas, and its sustainable conversion into value-added products has become the subject of extensive research.

  22. Teaching grad students the important skill of text synthesis (opinion)

    Synthesis, also called intertextual integration, is an essential skill that Ph.D. students should have for composing graduate program milestones—such as literature reviews, prelim exam papers, theses and dissertations—allowing novice scholars to develop a deep understanding of research in their fields and to build confidence as emergent ...

  23. Trends and Opportunities in Organic Synthesis: Global State of Research

    Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three ...

  24. 'It depends': what 86 systematic reviews tell us about what strategies

    The gap between research findings and clinical practice is well documented and a range of interventions has been developed to increase the implementation of research into clinical practice [1, 2].In recent years researchers have worked to improve the consistency in the ways in which these interventions (often called strategies) are described to support their evaluation.

  25. Indole synthesis: a review and proposed classification

    After a postdoctoral year at the University of Wisconsin (B.M. Trost), Taber accepted a faculty position at Vanderbilt University. He moved to the University of Delaware of Delaware in 1982, where he is currently Professor of Chemistry. Taber is the author of more than 200 research papers on organic synthesis and organometallic chemistry.

  26. Natural Product Synthesis in the 21st Century: Beyond the Mountain Top

    Research into natural products emerged from humanity's curiosity about the nature of matter and its role in the materia medica of diverse civilizations. Plants and fungi, in particular, supplied materials that altered behavior, perception, and well-being profoundly. Many active principles remain well-known today: strychnine, morphine, psilocybin, ephedrine. The potential to circumvent the ...

  27. Major quality regulation network of flavonoid synthesis governing the

    New Phytologist is an international phytology journal owned by the New Phytologist Foundation publishing original research in plant science and its applications. Summary Black wolfberry (Lycium ruthenicum Murr.) contains various bioactive metabolites represented by flavonoids, which are quite different among production regions.

  28. Video generation models as world simulators

    We explore large-scale training of generative models on video data. Specifically, we train text-conditional diffusion models jointly on videos and images of variable durations, resolutions and aspect ratios. We leverage a transformer architecture that operates on spacetime patches of video and image latent codes. Our largest model, Sora, is capable of generating a minute of high fidelity video ...

  29. Snap Video: Scaled Spatiotemporal Transformers for Text-to-Video Synthesis

    Contemporary models for generating images show remarkable quality and versatility. Swayed by these advantages, the research community repurposes them to generate videos. Since video content is highly redundant, we argue that naively bringing advances of image models to the video generation domain reduces motion fidelity, visual quality and impairs scalability. In this work, we build Snap Video ...