Organic synthesis
Encyclopedia
Organic synthesis is a special branch of chemical synthesis
and is concerned with the construction of organic compound
s via organic reaction
s. Organic
molecules can often contain a higher level of complexity compared to purely inorganic
compounds, so the synthesis of organic compound
s has developed into one of the most important branches of organic chemistry
. There are two main areas of research fields within the general area of organic synthesis: total synthesis
and methodology
.
of complex organic
molecule
s from simple, commercially available (petrochemical
) or natural
precursors. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete. The chemical compounds made in each step are usually deemed synthetic intermediates. For more complex molecules, a different approach may be preferable: convergent synthesis
involves the individual preparation of several "pieces" (key intermediates), which are then combined to form the desired product.
Robert Burns Woodward
, who received the 1965 Nobel Prize for Chemistry for several total syntheses (e.g., his 1954 synthesis of strychnine
), is regarded as the father of modern organic synthesis. Some latter-day examples include Wender's
, Holton's
, Nicolaou's
and Danishefsky's synthesis of Taxol
.
, and reagent
s and conditions for each of these reactions need to be designed to give a good yield and a pure product, with as little work as possible. A method may already exist in the literature for making one of the early synthetic intermediates, and this method will usually be used rather than "trying to reinvent the wheel". However most intermediates are compounds that have never been made before, and these will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields
, and to be reliable for a broad range of substrate
s. For practical applications, additional hurdles include industrial standards of safety and purity. Methodology research usually involves three main stages: discovery
, optimisation
, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimisation is where one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimum conditions for product yield and purity are found. Finally, the researcher tries to extend the method to a broad range of different starting materials, to find the scope and limitations. Total synthesis (see above) are sometimes used to showcase the new methodology and demonstrate its value in a real-world application. Such applications involved major industries focused especially on polymers (and plastics) and on pharmaceuticals.
. Traditional total syntheses targeted racemic mixtures, i.e., as an equal mixture of both possible enantiomer
s. The racemic mixture might then be separated via chiral resolution
.
In the latter half of the twentieth century, chemists began to develop methods of asymmetric catalysis
and kinetic resolution
whereby reactions could be directed to produce only one enantiomer rather than a racemic mixture. Early examples include Sharpless epoxidation
(K. Barry Sharpless
) and asymmetric hydrogenation
(William S. Knowles and Ryōji Noyori
). For their achievement, these workers went on to share the Nobel Prize in Chemistry
in 2001. Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start from, where previously only natural starting materials could be used. Using techniques pioneered by Robert B. Woodward and new developments in synthetic methodology, chemists became more able to take simple molecules through to more complex molecules without unwanted racemisation, by understanding stereocontrol. This allowed the final target molecule to be synthesised as one pure enantiomer without any resolution being necessary. Such techniques are referred to as asymmetric synthesis. hi there
brought a more formal approach to synthesis design, based on retrosynthetic analysis
, for which he won the Nobel Prize for Chemistry in 1990. In this approach, the research is planned backwards from the product, using standard rules. The steps are shown using retrosynthetic arrows (drawn as ⇒), which in effect means "is made from". Computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
and is concerned with the construction of organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
s via organic reaction
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
s. Organic
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
molecules can often contain a higher level of complexity compared to purely inorganic
Inorganic chemistry
Inorganic chemistry is the branch of chemistry concerned with the properties and behavior of inorganic compounds. This field covers all chemical compounds except the myriad organic compounds , which are the subjects of organic chemistry...
compounds, so the synthesis of organic compound
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
s has developed into one of the most important branches of organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
. There are two main areas of research fields within the general area of organic synthesis: total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
and methodology
Methodology
Methodology is generally a guideline for solving a problem, with specificcomponents such as phases, tasks, methods, techniques and tools . It can be defined also as follows:...
.
Total synthesis
A total synthesis is the complete chemical synthesisChemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
of complex organic
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s from simple, commercially available (petrochemical
Petrochemical
Petrochemicals are chemical products derived from petroleum. Some chemical compounds made from petroleum are also obtained from other fossil fuels, such as coal or natural gas, or renewable sources such as corn or sugar cane....
) or natural
Nature
Nature, in the broadest sense, is equivalent to the natural world, physical world, or material world. "Nature" refers to the phenomena of the physical world, and also to life in general...
precursors. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete. The chemical compounds made in each step are usually deemed synthetic intermediates. For more complex molecules, a different approach may be preferable: convergent synthesis
Convergent synthesis
In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multi-step chemical synthesis, most often in organic synthesis...
involves the individual preparation of several "pieces" (key intermediates), which are then combined to form the desired product.
Robert Burns Woodward
Robert Burns Woodward
Robert Burns Woodward was an American organic chemist, considered by many to be the preeminent organic chemist of the twentieth century...
, who received the 1965 Nobel Prize for Chemistry for several total syntheses (e.g., his 1954 synthesis of strychnine
Strychnine
Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...
), is regarded as the father of modern organic synthesis. Some latter-day examples include Wender's
Wender Taxol total synthesis
The Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis by the group of Paul A. Wender at Stanford University published in 1997. This synthesis has much in common with the Holton Taxol total synthesis in that it is a linear synthesis starting from a naturally...
, Holton's
Holton Taxol total synthesis
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol ....
, Nicolaou's
Nicolaou Taxol total synthesis
The Nicolaou Taxol total synthesis, published by K. C. Nicolaou and his group in 1994 concerns the total synthesis of Taxol. This organic synthesis was included in Nicolaou's book, 'Classics in Total Synthesis'....
and Danishefsky's synthesis of Taxol
Danishefsky Taxol total synthesis
The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996...
.
Methodology and applications
Each step of a synthesis involves a chemical reactionChemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
, and reagent
Reagent
A reagent is a "substance or compound that is added to a system in order to bring about a chemical reaction, or added to see if a reaction occurs." Although the terms reactant and reagent are often used interchangeably, a reactant is less specifically a "substance that is consumed in the course of...
s and conditions for each of these reactions need to be designed to give a good yield and a pure product, with as little work as possible. A method may already exist in the literature for making one of the early synthetic intermediates, and this method will usually be used rather than "trying to reinvent the wheel". However most intermediates are compounds that have never been made before, and these will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields
Yield (chemistry)
In chemistry, yield, also referred to as chemical yield and reaction yield, is the amount of product obtained in a chemical reaction. The absolute yield can be given as the weight in grams or in moles...
, and to be reliable for a broad range of substrate
Substrate (chemistry)
In chemistry, a substrate is the chemical species being observed, which reacts with a reagent. This term is highly context-dependent. In particular, in biochemistry, an enzyme substrate is the material upon which an enzyme acts....
s. For practical applications, additional hurdles include industrial standards of safety and purity. Methodology research usually involves three main stages: discovery
Discovery (observation)
Discovery is the act of detecting something new, or something "old" that had been unknown. With reference to science and academic disciplines, discovery is the observation of new phenomena, new actions, or new events and providing new reasoning to explain the knowledge gathered through such...
, optimisation
Process optimization
Process optimization is the discipline of adjusting a process so as to optimize some specified set of parameters without violating some constraint. The most common goals are minimizing cost, maximizing throughput, and/or efficiency...
, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimisation is where one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimum conditions for product yield and purity are found. Finally, the researcher tries to extend the method to a broad range of different starting materials, to find the scope and limitations. Total synthesis (see above) are sometimes used to showcase the new methodology and demonstrate its value in a real-world application. Such applications involved major industries focused especially on polymers (and plastics) and on pharmaceuticals.
Asymmetric synthesis
Most complex natural products are chiral, and the bioactivity of chiral molecules varies with the enantiomerEnantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
. Traditional total syntheses targeted racemic mixtures, i.e., as an equal mixture of both possible enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s. The racemic mixture might then be separated via chiral resolution
Chiral resolution
Chiral resolution in stereochemistry is a process for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active drugs...
.
In the latter half of the twentieth century, chemists began to develop methods of asymmetric catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
and kinetic resolution
Kinetic resolution
In kinetic resolution, two enantiomers show different reaction rates in a chemical reaction, thereby creating an excess of the less reactive enantiomer. This excess goes through a maximum and disappears on full completion of the reaction. Kinetic resolution is a very old concept in organic...
whereby reactions could be directed to produce only one enantiomer rather than a racemic mixture. Early examples include Sharpless epoxidation
Sharpless epoxidation
The Sharpless Epoxidation reaction is an enantioselective chemical reaction to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols....
(K. Barry Sharpless
K. Barry Sharpless
Karl Barry Sharpless is an American chemist known for his work on stereoselective reactions.-Early years:Sharpless was born in Philadelphia. He graduated from Friends' Central School in 1959. He continued his studies at Dartmouth College and earned his Ph.D from Stanford University in 1968...
) and asymmetric hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
(William S. Knowles and Ryōji Noyori
Ryoji Noyori
is a Japanese chemist. He won the Nobel Prize in Chemistry in 2001. Noyori shared half of the prize with William S. Knowles for the study of chirally catalyzed hydrogenations; the second half of the Prize went to K. Barry Sharpless for his study in chirally catalyzed oxidation reactions...
). For their achievement, these workers went on to share the Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
in 2001. Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start from, where previously only natural starting materials could be used. Using techniques pioneered by Robert B. Woodward and new developments in synthetic methodology, chemists became more able to take simple molecules through to more complex molecules without unwanted racemisation, by understanding stereocontrol. This allowed the final target molecule to be synthesised as one pure enantiomer without any resolution being necessary. Such techniques are referred to as asymmetric synthesis. hi there
Synthesis design
Elias James CoreyElias James Corey
Elias James Corey is an American organic chemist. In 1990 he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis...
brought a more formal approach to synthesis design, based on retrosynthetic analysis
Retrosynthetic analysis
Retrosynthetic analysis is a technique for solving problems in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures without assumptions regarding starting materials. Each precursor material is examined using the same method. This...
, for which he won the Nobel Prize for Chemistry in 1990. In this approach, the research is planned backwards from the product, using standard rules. The steps are shown using retrosynthetic arrows (drawn as ⇒), which in effect means "is made from". Computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".
See also
- Organic SynthesesOrganic SynthesesOrganic Syntheses is a scientific journal that since 1921 has provided the chemistry community with annual collections of detailed and checked procedures for the organic synthesis of organic compounds. The journal is peer reviewed...
, a publication which gives detailed peer-tested laboratory procedures. - Methods in Organic SynthesisMethods in Organic SynthesisMethods in Organic Synthesis is a fully searchable online, text and graphical database that is updated weekly with the latest developments in organic synthesis...
, a journal
External links
- The Organic Synthesis Archive
- Chemical synthesis database
- http://www.webreactions.net/search.html
- http://www.organic-chemistry.org/synthesis/
- Natural product syntheses
- Chemical synthesis semantic wiki