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Overview
It is well-established that organic synthetic processes have been at the core of the chemical industry for hundreds of years, in the production of organic compounds with a wide range of applications. However, we are becoming increasingly aware of the hazardous substances used and generated by these chemical processes. The field of organic synthesis has undergone profound changes to switch to equally efficient, but more sustainable processes that avoid the extensive use of toxic and hazardous reagents and solvents, harsh reaction conditions and expensive and sophisticated catalysts.
Explaining methods for carrying out chemical syntheses without the use of catalysts, this book shows how avoiding catalysts during synthesis can mean less use of toxic chemicals, environmentally damaging chemicals or endangered elements and lower costs. It is an important reference for chemists involved in organic synthesis, as well as for green chemists.
Product Details
| ISBN-13: | 9781788013185 |
|---|---|
| Publisher: | Royal Society of Chemistry |
| Publication date: | 11/06/2017 |
| Series: | ISSN |
| Sold by: | Barnes & Noble |
| Format: | eBook |
| Pages: | 392 |
| File size: | 11 MB |
| Note: | This product may take a few minutes to download. |
Read an Excerpt
CHAPTER 1
Catalyst-free Organic Synthesis: An Introduction
1.1 Introduction
The terminology 'organic synthesis' is used in a broad sense to refer to constructions of organic molecules by chemical means that follow certain distinct synthetic protocols designed for those purposes. These organic synthetic processes have been at the core of the chemical industry for hundreds of years in the production of numerous organic compounds of varying skeletons finding immense applications such as fine chemicals, medicinal and pharmaceutical agents, dyes and pigments, polymeric substances, food additives, petrochemicals, agrochemicals, and many more. Over the past two centuries, synthetic organic chemistry has seen a tremendous all-round development, and the credit obviously goes to the synthetic chemists at large!
However, with the advent of the 'Green Chemistry Concept', the central theme of an organic synthetic process has now encountered a 'complete rethinking' or a 'new look' that not only considers the desired product(s) in optimum yield but also gives pertinent emphasis to the greenness and sustainability of the process! Hence, the overall outcome of an organic synthesis, i.e. the productivity, cost, safety, wastes, hazards, energy, and all other green chemistry parameters along with environmental-concerns, is largely dependent on the generality and effectiveness of its synthetic protocol. And encouraged with this motivation, the field of organic synthesis has already gained notable developments in recent years in designing equally efficient processes blended with the flavors of eco-friendliness and sustainability that avoid the extensive use of toxic and hazardous reagents and solvents, harsh reaction conditions, and expensive and sophisticated catalysts. 'Green Chemistry', thus, offers a broad platform encompassing a series of considerations in the design of efficient, eco-friendly and sustainable processes with parameters such as product yields, atom efficiency, E-factor, energy consumption, cost-effectiveness, number of reaction steps, availability of starting materials and their consumption (extent of use of bio-renewable resources), man-power (automation), and reactor usage (e.g. flow versus batch reactions). Innovative green chemical techniques, if they can be applied as alternatives to traditional synthetic processes to generate old and new chemicals of industrial importance, would be highly beneficial to mankind.
Implementation of green chemistry in designing alternative synthetic protocols for value-added products or compounds is really a great challenge to today's organic chemists and the young researchers! The fundamental challenge for developing a sustainable chemical enterprise will be finding creative ways to minimize human exposure to, and the environmental impact of, harmful chemicals while enhancing scientific progress. The task not only involves the replacement of such kinds of reagents and/or catalysts, but also makes use of eco-friendly alternative ways in an innovative fashion that can promote the desired chemistries. As a result, microwave (MW) irradiation, ultrasound (US) irradiation, and ball-milling have been gaining extensive uses in organic synthesis over the recent years, and these alternative sources of energy are now known as 'green tools'. A completely different outlook based on careful selection of reaction conditions is the cornerstone of this advanced scenario of modern organic synthesis.
Advanced organic synthesis is dedicated now to design improved and novel alternative protocols that aim to avoid the use of catalysts or to replace expensive and toxic catalysts with cheap and eco-friendly homogeneous and/ or magnetically recoverable heterogeneous catalysts; to avoid hazardous solvents or to use water and other benign solvents such aqueous ethanol, glycerol or polyethylene glycol (PEG), ionic-liquids (ILs), supercritical carbon dioxide, and deep-eutectic mixtures (DEM); to minimize side-reactions and wastes leading to target products in high yields (to attain high atom efficiency and lower E-factor); to set reaction conditions at ambient temperature and pressure to minimize energy consumption or to apply microwaves, ultrasound and ball-milling as other alternatives green tools. A significant amount of advancement toward such green chemistries has already been made, and concerted efforts are ongoing among synthetic chemists to attain more – this is, indeed, a new-born branch of chemical sciences that is growing rapidly. The present book is designed with the aim to offer recent cutting-edge advances in developing organic synthetic protocols under catalyst-free conditions.
1.2 Catalyst-free Organic Synthesis – A Step Forward
When we think of a chemical reaction, it is very much synonymous of thinking about a catalyst as well! The role of catalysts, both homogeneous and heterogeneous, in organic synthesis is obvious, and thus they find huge applications and uses. Catalysts usually promote faster chemical reactions and, for some reactions, the desired selectivities (regioselectivity or chemoselectivity) can be obtained using specific selective sites of them. Conventional catalysts/additives are usually associated with much costs, toxicity, and non-reusability, thereby generating wastes. From the green chemistry perspectives, considerable efforts have been made to improve overall suitability of catalytic substances from suitable modifications and/or innovation of new kinds of catalysts with multiple benefits. However, the most fruitful way-out would be to go for designing an organic reaction protocol without the aid of a catalyst, if feasible! With this unique and challenging view, the last decade has seen the dedicated attempts of chemists becoming successful in this venture with notable advancement. Catalyst-free synthetic processes have many-folds of benefits so as to get rid of toxicity and wastes associated with using these catalysts. Hence, designing of catalyst-free synthetic processes is a step forward toward safe, cost-effective, waste-free, simple, and sustainable environment!
To design a chemical process that would be at the same time facile, efficient and high-yielding without the use of any catalyst/additive is really challenging! And for this purpose, one must carefully select reaction conditions and starting materials. It is often observed that appropriately selected starting materials can undergo self-catalysis in suitable solvents (preferably in aqueous or aqueous ethanolic medium) in many situations and/or the solvents can also impart catalytic benefits to certain reaction processes from their unique inherent properties. Reactions can also be promoted by simple conventional heating in the presence or absence of solvent(s), and also by the applications of microwave irradiation, ultrasound irradiation and mechanochemical mixings.
1.3 Overview of the Book
More than 130 catalyst-free organic reactions yielding a variety of useful organic molecules have been thoroughly researched and discussed in this book under five distinct chapters – Chapter 2 to Chapter 6 – classified based on their varying reaction conditions. Chapter 2 presents catalyst-free organic transformations occurring under room-temperature conditions, while Chapter 3 discusses those catalyst-free organic reactions accomplished under conventional heating. Catalyst-free organic transformations performed by means of the applications of microwave irradiation, ultrasound irradiation and ball-milling are presented in Chapter 4, 5 and 6, respectively.
1.4 How to Read
As mentioned above, this single volume incorporates more than 130 comprehensively screened organic synthetic protocols with catalyst-free conditions for the generation of carbon–carbon and carbon–heteroatom bonds which result in a wide spectrum of chemical compounds — aliphatic, aromatic, alicyclic and heterocycles. The reactions are classified in five distinct chapters (Chapter 2 to 6) based on reaction conditions (viz. at room temperature, conventional heating, microwave irradiation, ultrasound irradiation, and ball-milling). Clearly structured for easy access to the information, each selected reaction is discussed in a very compact manner through point-wise discussion such as: reaction type; reaction conditions; reaction strategy; keywords; general reaction scheme; mechanism; representative examples; experimental procedure; characterization data of representative entries; critical views; literature. Literature references are continuously numbered and presented at the end of each chapter. Reaction scheme, plausible mechanism (if any) and illustrative examples relating to a particular reaction are presented under that reaction and are self-explanatory in nature. Each organic synthesis is supplemented with all its details including the experimental procedure, representative examples and their physical and spectral properties so that one can reproduce the same with ease.
1.5 Concluding Remarks
Ongoing developments in greener and more efficient methodologies for the syntheses of organic compounds of interest are vital for making chemical processes more sustainable. Among various developments in this direction, designs for catalyst-free organic methodologies have drawn the attention of the researchers in their fields in recent times. The book successfully integrates cutting-edge research advances in designing catalyst-free reaction procedures for useful organic transformations with the inclusion of a comprehensive range of examples and chemistries that illustrate the significant strides made in this research area over the past few years. This research area is growing progressively, and many different alternatives to further advancements in the field of greener synthetic processes are to come! Further developments in more innovative, cost-efficient, and sustainable strategies would surely be disclosed in the near future. Under this purview, the present book is an endeavor to boost the ongoing green chemistry research and also to motivate the young minds to this truly dynamic field of chemistry!
CHAPTER 2
Catalyst-free Organic Reactions under Room Temperature Conditions
2.1 Introduction
With the advent of the concept of 'green and sustainable chemistry', modern organic synthesis encompasses a number of agenda, such as the avoidance of extensive use of toxic and hazardous reagents and solvents, harsh reaction conditions, and expensive and sophisticated catalysts. The past decade has seen a tremendous effort toward savings in energy consumption, use of eco-friendly solvents, proficiency in atom economy, and minimization of wastes from reactions in order to design novel green synthetic protocols for organic compounds of interest. Among various energy-efficient processes, the most effective way to save energy is to develop strategies/protocols that are capable of carrying out the transformations at ambient conditions (i.e. room temperature and pressure). In addition, room temperature offers a mild reaction condition, essentially required for many temperature-sensitive organic substrates as a key step in multistep sequence reactions. Designing reactions at room temperature and pressure coupled with other green aspects is, thus, a current area of emphasis. The concept of developing reaction strategies at ambient conditions is now an emerging field of research in organic chemistry and is progressing considerably. It becomes more interesting when such an energy consideration is coupled with the catalyst-free strategy in performing syntheses of certain useful organic molecules. With this view, the present chapter offers detailed descriptions of a wide variety of 75 comprehensively screened catalyst-free organic synthetic protocols, which occur at room temperature and pressure, for the generation of carbon–carbon and carbon–heteroatom bonds resulting a wide spectrum of synthetically and pharmaceutically useful chemical compounds – aliphatic, aromatic, alicyclic and heterocycles.
2.2 Room Temperature Organic Transformations Under Catalyst-free Conditions
An appreciable number of room temperature organic reactions leading to the synthesis of a variety of organic compounds under catalyst-free conditions have been reported in the literature. This section presents such useful organic transformations in an entry-based format, highlighting the key aspects for each of them.
2.2.1 Entry-1: Synthesis of α-Amino Nitriles
Type of reaction: C–C and C–N bond formation
Reaction conditions: Catalyst-free, water, room temperature
Synthetic strategy: One-pot multicomponent reaction
Keywords: Aldehydes, ketones, amines, acetone cyanohydrin, aqueous medium, catalyst-free, room temperature, Strecker reaction, α-amino nitriles, one-pot three-component reaction, chemoselectivity
2.2.1.1 General Reaction Scheme
Synthesis of racemic α-amino nitriles in a chemoselective and convenient manner through a one-pot, three-component Strecker reaction of carbonyl compounds (1/5), amines (2), and acetone cyanohydrin (3) in water at room temperature in the absence of any added catalyst was documented by Galletti and coworkers (Scheme 2.1).
2.2.1.3 Experimental Procedure
A vial equipped with a screw cap was charged with a magnetic stir bar, aldehydes (1; 1 mmol) or ketones (5; 1mmol) and amines (2; 1 mmol), and stirred well to mix the reactants thoroughly. After 10 minutes, water (4 mL) and acetone cyanohydrin (1 mmol) were added, and the cap was closed. The resulting mixture continued to be stirred for up to 20 h to complete the reaction (monitored by TLC). The reaction mixture was then poured into brine (5 mL) and extracted with ethyl acetate (2x10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified either by flash chromatography or simply by recrystallization to yield pure α-amino nitriles (4/6). All the products were characterized by means of elemental analyses and detailed spectral studies including IR, 1HNMR, 13CNMR and HRMS.
2.2.1.4 Characterization Data of Two Representative Compounds
2-(Benzylamino)-2-(pyridin-2-yl)acetonitrile (4b): oil; yield: 98%; IR (NaCl): 3300, 2228, 1673 cm-1; 1H NMR (CDCl3, 400 MHz): δ 2.75 (1H, br. s, NH), 3.97 (1H, d, JAB = 12.8 Hz, CHHPh), 4.04 (1H, d, JAB = 12.8 Hz, CHHPh), 4.79 (1 H, s, CHCN), 7.25–7.48 (7H, m, ArH), 7.76 (1H, dd, J = 10.0, 10 Hz, ArH), 8.60 (1H, d, J = 8.0 Hz, ArH); 13C NMR (CDCl3, 100 MHz,): δ 51.4, 54.9, 122.0, 123.9, 127.7, 128.5, 128.6, 128.8, 137.4, 138.0, 149.9, 153.7; LCMS: m/z (tr = 7.1 min): 224 [M + 1]+; C14H13N3 (223.27): Calc. C, 75.31; H, 5.87; N, 18.82; found C, 75.44; H, 5.94; N, 18.98.
2-(Benzylamino)-2-methylhexanenitrile (6a): oil; yield: 47%; IR (NaCl): 3318, 2219, 1455 cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.95 (3H, t, J = 7.2 Hz, CH3), 1.39 (2H, quint, J = 7.2 Hz, CH2CH2CH2), 1.44–1.57 (6H, m, NH, CH2, CH3), 1.67–1.82 (2H, m, CH2), 3.90 (2H, s, CH2Ph), 7.27–7.40 (5H, m, ArH); 13C NMR (CDCl3, 100 MHz,): δ 13.7, 22.5, 24.6, 25.8, 39.5, 49.0, 55.6, 122.1, 127.2, 128.1, 128.3, 139.1; C14H20N2 (216.32): Calc. C, 77.73; H, 9.32; N, 12.95; found C, 77.82; H, 9.41; N, 12.91.
2.2.1.5 Critical Views
The investigators reported on the development of a convenient and catalyst-free protocol for the synthesis of racemic α-amino nitriles with high chemoselectivity through one-pot, three-component Strecker reaction in water at room temperature. Both aliphatic and aromatic aldehydes, and cyclic ketones, in combination with primary and secondary amines were found to undergo smooth reaction. In some cases, pure a-amino nitriles can be obtained just by direct separation fromwater. An unusual application of the Strecker reaction to 1,2-diamines to obtain 1,2-diamino nitriles, and to cyclic secondary amines was also reported. This cyanation process is atom-economic and operationally simple. Dialkyl and alkyl aryl ketones practically did not undergo this reaction but cyclic ketones afforded excellent yields, which is in accordance to the difference in the reactivity and internal strain effect (I-strain) of linear versus cyclic ketones in nucleophilic addition reactions. The present method is overall relatively superior to the previously reported methods, mainly in respect of using (i) mild reaction conditions, (ii) water as reaction medium, and (iii) no catalyst. The mild reaction conditions and the operational simplicity, thus, anticipate making this atom-economic cyanation process attractive to the development of cleaner and environmentally friendlier processes for the synthesis of a-amino nitriles and their analogs of synthetic importance.
(Continues…)
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Copyright © 2018 Goutam Brahmachari.
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