Organic synthesis

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Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the general subject of organic synthesis, there are many different types of synthetic routes that can be completed including total synthesis, [1] stereoselective synthesis, [2] automated synthesis, [3] and many more. Additionally, in understanding organic synthesis it is necessary to be familiar with the methodology, techniques, and applications of the subject.

Contents

Total synthesis

A total synthesis refers to the complete chemical synthesis of molecules from simple, natural precursors. [1] Total synthesis is accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed sequentially until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates. [1] Most often, each step in a synthesis is a separate reaction taking place to modify the starting materials. For more complex molecules, a convergent synthetic approach may be better suited. This type of reaction scheme involves the individual preparations of several key intermediates, which are then combined to form the desired product. [4]

Robert Burns Woodward, who received the 1965 Nobel Prize for Chemistry for several total syntheses [5] including his synthesis of strychnine, [6] is regarded as the grandfather of modern organic synthesis. [7] Some latter-day examples of syntheses include Wender's, [8] Holton's, [9] Nicolaou's, [10] and Danishefsky's [11] total syntheses of the anti-cancer drug paclitaxel (trade name Taxol). [12]

Methodology and applications

Before beginning any organic synthesis, it is important to understand the chemical reactions, reagents, and conditions required in each step to guarantee successful product formation. When determining optimal reaction conditions for a given synthesis, the goal is to produce an adequate yield of pure product with as few steps as possible. [13] When deciding conditions for a reaction, the literature can offer examples of previous reaction conditions that can be repeated, or a new synthetic route can be developed and tested. For practical, industrial applications additional reaction conditions must be considered to include the safety of both the researchers and the environment, as well as product purity. [14]

Synthetic techniques

Organic Synthesis requires many steps to separate and purify products. Depending on the chemical state of the product to be isolated, different techniques are required. For liquid products, a very common separation technique is liquid–liquid extraction and for solid products, filtration (gravity or vacuum) can be used. [15] [16]

Liquid–liquid extraction

Liquid liquid extraction

Liquid–liquid extraction uses the density and polarity of the product and solvents to perform a separation. [16] Based on the concept of "like-dissolves-like", non-polar compounds are more soluble in non-polar solvents, and polar compounds are more soluble in polar solvents. [17] By using this concept, the relative solubility of compounds can be exploited by adding immiscible solvents into the same flask and separating the product into the solvent with the most similar polarity. Solvent miscibility is of major importance as it allows for the formation of two layers in the flask, one layer containing the side reaction material and one containing the product. As a result of the differing densities of the layers, the product-containing layer can be isolated and the other layer can be removed.

Heated reactions and reflux condensers

Reflux apparatus Reflux labled.svg
Reflux apparatus

Many reactions require heat to increase reaction speed. [18] However, in many situations increased heat can cause the solvent to boil uncontrollably which negatively affects the reaction, and can potentially reduce product yield. To address this issue, reflux condensers can be fitted to reaction glassware. Reflux condensers are specially calibrated pieces of glassware that possess two inlets for water to run in and out through the glass against gravity. This flow of water cools any escaping substrate and condenses it back into the reaction flask to continue reacting [19] and ensure that all product is contained. The use of reflux condensers is an important technique within organic syntheses and is utilized in reflux steps, as well as recrystallization steps.

When being used for refluxing a solution, reflux condensers are fitted and closely observed. Reflux occurs when condensation can be seen dripping back into the reaction flask from the reflux condenser; 1 drop every second or few seconds. [19]

For recrystallization, the product-containing solution is equipped with a condenser and brought to reflux again. Reflux is complete when the product-containing solution is clear. Once clear, the reaction is taken off heat and allowed to cool which will cause the product to re-precipitate, yielding a purer product. [20]

Gravity and vacuum filtration

Gravity filtration apparatus Cold Filtration.jpg
Gravity filtration apparatus

Solid products can be separated from a reaction mixture using filtration techniques. To obtain solid products a vacuum filtration apparatus can be used.

Vacuum filtration uses suction to pull liquid through a Büchner funnel equipped with filter paper, which catches the desired solid product. [15] This process removes any unwanted solution in the reaction mixture by pulling it into the filtration flask and leaving the desired product to collect on the filter paper.

Vacuum filtration apparatus FilterFunnelApparatus.png
Vacuum filtration apparatus

Liquid products can also be separated from solids by using gravity filtration. [15] In this separatory method, filter paper is folded into a funnel and placed on top of a reaction flask. The reaction mixture is then poured through the filter paper, at a rate such that the total volume of liquid in the funnel does not exceed the volume of the funnel. [15] This method allows for the product to be separated from other reaction components by the force of gravity, instead of a vacuum.

Stereoselective synthesis

Most complex natural products are chiral, [2] [21] and the bioactivity of chiral molecules varies with the enantiomer. [22] Some total syntheses target racemic mixtures, which are mixtures of both possible enantiomers. A single enantiomer can then be selected via enantiomeric resolution.  

As chemistry has developed methods of stereoselective catalysis and kinetic resolution have been introduced whereby reactions can be directed, producing only one enantiomer rather than a racemic mixture. [23] Early examples include stereoselective hydrogenations (e.g., as reported by William Knowles [24] and Ryōji Noyori, [25] and functional group modifications such as the asymmetric epoxidation by Barry Sharpless; [26] for these advancements in stereochemical preference, these chemists were awarded the Nobel Prize in Chemistry in 2001. [27] Such preferential stereochemical reactions give chemists a much more diverse choice of enantiomerically pure materials.

Using techniques developed by Robert B. Woodward paired with advancements in synthetic methodology, chemists have been able synthesize stereochemically selective complex molecules without racemization. Stereocontrol provides the target molecules to be synthesized as pure enantiomers (i.e., without need for resolution). Such techniques are referred to as stereoselective synthesis .

Synthesis design

Many synthetic procedures are developed from a retrosynthetic framework, a type of synthetic design developed by Elias James Corey, for which he won the Nobel Prize in Chemistry in 1990. [28] In this approach, the synthesis is planned backwards from the product, obliging to standard chemical rules. [1] Each step breaks down the parent structure into achievable components, which are shown via the use of graphical schemes with retrosynthetic arrows (drawn as ⇒, which in effect, means "is made from"). Retrosynthesis allows for the visualization of desired synthetic designs.

Automated organic synthesis

A recent development within organic synthesis is automated synthesis. To conduct organic synthesis without human involvement, researchers are adapting existing synthetic methods and techniques to create entirely automated synthetic processes. This type of synthesis is advantageous as synthetic automation can increase yield with continual "flowing" reactions. In flow chemistry, substrates are continually fed into the reaction to produce a higher yield. Previously, this type of reaction was reserved for large-scale industrial chemistry but has recently transitioned to bench-scale chemistry to improve the efficiency of reactions on a smaller scale. [3]

Currently integrating automated synthesis into their work is SRI International, a nonprofit research institute. Recently SRI International has developed Autosyn, an automated multi-step chemical synthesizer that can synthesize many FDA-approved small molecule drugs. This synthesizer demonstrates the versatility of substrates and the capacity to potentially expand the type of research conducted on novel drug molecules without human intervention. [29]

Automated chemistry and the automated synthesizers used demonstrate a potential direction for synthetic chemistry in the future.

Characterization

Necessary to organic synthesis is characterization. Characterization refers to the measurement of chemical and physical properties of a given compound, and comes in many forms. Examples of common characterization methods include: nuclear magnetic resonance (NMR), [30] mass spectrometry, [31] Fourier-transform infrared spectroscopy (FTIR), [32] and melting point analysis. [33] Each of these techniques allow for a chemist to obtain structural information about a newly synthesized organic compound. Depending on the nature of the product, the characterization method used can vary.

Relevance

Organic synthesis is an important chemical process that is integral to many scientific fields. Examples of fields beyond chemistry that require organic synthesis include the medical industry, pharmaceutical industry, and many more. Organic processes allow for the industrial-scale creation of pharmaceutical products. An example of such a synthesis is Ibuprofen. Ibuprofen can be synthesized from a series of reactions including: reduction, acidification, formation of a Grignard reagent, and carboxylation. [34]

Synthesis of ibuprofen by Kjonass et al. Synthesis of Ibuprofen.png
Synthesis of ibuprofen by Kjonass et al.

In the synthesis of Ibuprofen proposed by Kjonass et al., p-isobutylacetophenone, the starting material, is reduced with sodium borohydride (NaBH4) to form an alcohol functional group. The resulting intermediate is acidified with HCl to create a chlorine group. The chlorine group is then reacted with magnesium turnings to form a Grignard reagent. [34] This Grignard is carboxylated and the resulting product is worked up to synthesize ibuprofen.

This synthetic route is just one of many medically and industrially relevant reactions that have been created, and continued to be used.

See also

Related Research Articles

In chemistry, chemical synthesis is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In modern laboratory uses, the process is reproducible and reliable.

<span class="mw-page-title-main">Williamson ether synthesis</span> Method for preparing ethers

The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ion with a primary alkyl halide via an SN2 reaction. This reaction is important in the history of organic chemistry because it helped prove the structure of ethers.

<span class="mw-page-title-main">Aldol reaction</span> Chemical reaction

The aldol reaction is a reaction in organic chemistry that combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. Its simplest form might involve the nucleophilic addition of an enolized ketone to another:

Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. Syntheses may sometimes conclude at a precursor with further known synthetic pathways to a target molecule, in which case it is known as a formal synthesis. Total synthesis target molecules can be natural products, medicinally-important active ingredients, known intermediates, or molecules of theoretical interest. Total synthesis targets can also be organometallic or inorganic, though these are rarely encountered. Total synthesis projects often require a wide diversity of reactions and reagents, and subsequently requires broad chemical knowledge and training to be successful.

In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite: both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used.

<span class="mw-page-title-main">Enolate</span> Organic anion formed by deprotonating a carbonyl (>C=O) compound

In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.

The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, sugars, and terpenes. Their use improves the efficiency of total synthesis. Not only does the chiral pool contribute a premade carbon skeleton, their chirality is usually preserved in the remainder of the reaction sequence.

<span class="mw-page-title-main">Trimethylsilyl group</span> Functional group

A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si(CH3)3], which is in turn bonded to the rest of a molecule. This structural group is characterized by chemical inertness and a large molecular volume, which makes it useful in a number of applications.

<span class="mw-page-title-main">Henry reaction</span>

The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols. This type of reaction is also referred to as a nitroaldol reaction. It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols". The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.

<span class="mw-page-title-main">Tröger's base</span> Chemical compound

Tröger's base is a white solid tetracyclic organic compound. Its chemical formula is (CH
3C
6H
3NCH
2)
2CH
2. Tröger's base and its analogs are soluble in various organic solvents and strong acidic aqueous solutions due to their protonation. It is named after Julius Tröger, who first synthesized it in 1887.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

A pinacol coupling reaction is an organic reaction in which a carbon–carbon bond is formed between the carbonyl groups of an aldehyde or a ketone in presence of an electron donor in a free radical process. The reaction product is a vicinal diol. The reaction is named after pinacol, which is the product of this reaction when done with acetone as reagent. The reaction is usually a homocoupling but intramolecular cross-coupling reactions are also possible. Pinacol was discovered by Wilhelm Rudolph Fittig in 1859.

The Marcusson apparatus, Dean-Stark apparatus, Dean–Stark receiver, distilling trap, or Dean–Stark Head is a piece of laboratory glassware used in synthetic chemistry to collect water from a reactor. It is used in combination with a reflux condenser and a distillation flask for the separation of water from liquids. This may be a continuous removal of the water that is produced during a chemical reaction performed at reflux temperature, such as in esterification reactions. The original setup by Julius Marcusson was refined by the American chemists Ernest Woodward Dean (1888–1959) and David Dewey Stark (1893–1979) in 1920 for determination of the water content in petroleum.

<span class="mw-page-title-main">Condenser (laboratory)</span> Laboratory apparatus used to condense vapors

In chemistry, a condenser is laboratory apparatus used to condense vapors – that is, turn them into liquids – by cooling them down.

Iodolactonization is an organic reaction that forms a ring by the addition of an oxygen and iodine across a carbon-carbon double bond. It is an intramolecular variant of the halohydrin synthesis reaction. The reaction was first reported by M. J. Bougalt in 1904 and has since become one of the most effective ways to synthesize lactones. Strengths of the reaction include the mild conditions and incorporation of the versatile iodine atom into the product.

Air-free techniques refer to a range of manipulations in the chemistry laboratory for the handling of compounds that are air-sensitive. These techniques prevent the compounds from reacting with components of air, usually water and oxygen; less commonly carbon dioxide and nitrogen. A common theme among these techniques is the use of a fine (100–10−3 Torr) or high (10−3–10−6 Torr) vacuum to remove air, and the use of an inert gas: preferably argon, but often nitrogen.

<span class="mw-page-title-main">Trimethylsilyl trifluoromethanesulfonate</span> Chemical compound

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) is an organosilicon compound with the formula (CH3)3SiO3SCF3. It is a colorless moisture-sensitive liquid. It is the trifluoromethanesulfonate derivative of trimethylsilyl. It is mainly used to activate ketones and aldehydes in organic synthesis.

<span class="mw-page-title-main">Organoindium chemistry</span> Chemistry of compounds with a carbon to indium bond

Organoindium chemistry is the chemistry of compounds containing In-C bonds. The main application of organoindium chemistry is in the preparation of semiconducting components for microelectronic applications. The area is also of some interest in organic synthesis. Most organoindium compounds feature the In(III) oxidation state, akin to its lighter congeners Ga(III) and B(III).

<span class="mw-page-title-main">Reflux</span> Condensation of vapors and their return to where they originated

Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to reactions over a long period of time.

<span class="mw-page-title-main">Vinyl iodide functional group</span>

In organic chemistry, a vinyl iodide functional group is an alkene with one or more iodide substituents. Vinyl iodides are versatile molecules that serve as important building blocks and precursors in organic synthesis. They are commonly used in carbon-carbon forming reactions in transition-metal catalyzed cross-coupling reactions, such as Stille reaction, Heck reaction, Sonogashira coupling, and Suzuki coupling. Synthesis of well-defined geometry or complexity vinyl iodide is important in stereoselective synthesis of natural products and drugs.

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