Synthesis, Chemical

Over twenty-one million chemical compounds were known as of 2003. Most have been synthesized by chemists; only a small fraction of these are compounds isolated from natural sources. The final proof of a naturally occurring compound's structure is established by synthesizing the compound from simpler molecules by means of identifiable and reproducible reactions.

Protecting Groups

When synthesizing a molecule with more than one functional group, it may be difficult to carry out a reaction with one group without unintentionally

interfering or reacting with another group. Use of a protecting group helps to prevent this. The protecting group must be removed after the desired reaction is completed. In the simple example shown in Figure 1, HBr could not be eliminated from the bromopropionaldehyde because the aldehyde group would react with the base. Protecting the aldehyde group by converting it to an acetal allows the HBr elimination to take place. Other examples can be noted: alcohols or phenols can be converted to esters or ethers, aldehydes or ketones to acetals, carboxylic acids to esters, and amino groups to amides.

Retrosynthetic Analysis

For synthesis of fairly complicated molecules, the concept of retrosynthetic analysis (also called the disconnection approach), stated formally as a principle by American chemist E. J. Corey, is generally employed. In this approach, the molecule is broken up into two or more parts called synthons. A symbol used to indicate a retrosynthetic step is an open arrow written from product to suitable precursors or fragments of those precursors (Figure 2). Each synthon is similarly broken up and the process repeated until the fragments are available starting molecules. The synthesis is essentially worked backwards to the actual process followed in the laboratory. Beginning in the 1960s the strategy of organic synthesis became sufficiently systematic that computers could be used for syntheses planning.

Some of the better-known compounds synthesized by retrosynthetic analysis are strychnine, penicillin, prostaglandins, progesterone, vitamin B12, biotin, L-hexoses, menthol, and taxol.

Coordination Compounds

A coordination compound or complex refers to the grouping that is formed when a metal ion or atom accepts a pair of electrons from a molecule or ion. Metal ions—even in very low concentrations—function as powerful catalysts in many important industrial organic processes, as well as with enzymes (catalysts in living tissues). The total number of electron-donor atoms or donor pairs bonded to a given metal atom or metal cation is referred to as the coordination number. The coordination number of a compound can range from two to twelve and determines geometrical shape and physical properties.

Coordination number zero corresponds to an isolated atom; coordination number one occurs for very simple molecule combinations such as Ni-NN that are stable only in very cold matrices such as argon. Coordination

number three is fairly rare since the metal can still serve as acceptor to more Lewis bases. Coordination number four refers to the smallest number of ligands commonly found in transition metal complexes. Coordination number five was thought to be nonexistent or rare at one time; more recently, studies have revealed stable five-coordinate complexes. Most transition metal complexes have a coordination number of six and show octahedral geometry, although other geometry is possible. Coordination numbers greater than six are rare because of high ligand-ligand steric repulsion. Only small ligand atoms such as fluorine (F) and oxygen (O) have low enough repulsion to form stable seven-coordinate complexes. For coordination number eight, the number of examples is limited because of high ligand-ligand repulsion; most examples involve small ligand atoms. However, eight is a relatively favorable number for complexes of f-block elements (the lanthanides and actinides), since these are large in size and also have a larger number of valence orbitals. Higher coordination numbers of nine and ten are known that also involve f-block elements.

In 1937 English chemist Nevil V. Sidgwick suggested a rule (the octet rule for first-row p-block elements) for complex formation under which a metal can acquire ligands until the total number of electrons around it is equal to the number surrounding the next noble gas. This rule was later expanded as the eighteen-electron rule under which a d-block transition metal atom has eighteen electrons in its nine valence orbitals [five n d; one (n + 1) s, and three (n + 1) p] and will form the stablest compounds when engaged in nine bonding molecular orbitals containing eighteen electrons.

Catalysts

Catalytic processes abound in nature. From enzymes to mineral surfaces, catalysts increase the rate of a given reaction, often by reducing the activation energy that the reactants must overcome before they go on to form products. Catalysts have been developed for a wide spectrum of reactions; a common example is the catalytic converter, used in cars to reduce toxic emissions. Inexpensive transportation fuels, high-temperature lubricants, chlorine-free refrigerants, high-strength polymers, stain-resistant fibers, cancer treatment drugs, and many thousands of other products would not be possible without the existence of catalysts. Catalysts are also essential for the reduction of air and water pollution, contributing to the reduction of product emissions that are harmful to human health and the environment.

Most catalysts can be described as either homogeneous or heterogeneous . Homogeneous catalysts are molecularly dispersed with the reactants in the same phase, which provides easy access to the catalytic site but can make the separation of catalyst and products difficult. Heterogeneous catalysts—usually solids—are in a different phase from the reactants, reducing separation problems but providing more limited access to the catalytic site. Approaches to dealing with these disparate properties include anchoring the catalyst to a soluble or insoluble support, effectively "heterogenizing" the catalyst, or designing the catalyst so that it is soluble in a solvent that, under some conditions, does not mix with the reaction product. Some reactions will not take place (or will take place at a slower rate) without a catalyst being present. Actually an intermediate reaction of one of the reagents with

the catalyst (or catalyst surface) takes place at a faster rate than without it being present.

Enantiomers. Different enantiomers (mirror image forms) of a given biomolecule can exhibit dramatically different biological activities. Enzymes have evolved to catalyze reactions with selectivity for the formation of one enantiomeric form over the other. Chemists have developed various synthetic small-molecule catalysts that can achieve levels of selectivity approaching (and in some cases matching) those observed in enzymatic reactions. American chemist William S. Knowles pointed out in his 2001 Nobel Prize address that the best synthetic catalysts demonstrate useful levels of enantioselectivity for a wide range of substrates. Such catalysts have been called "privileged chiral catalysts." Such generality of scope is not observed in enzymatic catalysis.

see also Acid-Base Chemistry; Catalysis and Catalysts; Coordination Compounds; Inorganic Chemistry; Organic Chemistry.

A. G. Pinkus

Bibliography

Basolo, Fred, and Pearson, Ralph G. (1967). "The Theory of the Coordinate Bond" (Chapter 2) and "Metal Ion Catalysis of Organic Reactions" (Chapter 8). In Mechanisms of Inorganic Reactions: A Study of Chemical Complexes in Solution, 2nd edition. New York: Wiley.

"Catalysis" (2003). Science 299:1,683–1,706.

Corey, E. J., and Chen, Xue-Min (1989). The Logic of Chemical Synthesis. New York: Wiley.

Cotton, F. Albert, and Wilkinson, Geoffrey (1980). Advanced Inorganic Chemistry: A Comprehensive Text. New York: Wiley.

Greene, T. W., and Wuts, P. G. M. (1991). Protective Groups in Organic Synthesis, 2nd edition. New York: Wiley-Interscience.

Hanson, James R. (1999). Protecting Groups in Organic Chemistry. Sheffield, England: Blackwell.

House, James E., and House, Kathleen A. (2001). "Structure and Bonding in Coordination Compounds" (Chapter 19) and "Synthesis and Reactions of Coordination Compounds" (Chapter 20). In Descriptive Inorganic Chemistry. San Diego: Harcourt/Academic Press.

Knowles, W. S. (2002). "Asymmetric Hydrogenations." Angewandte Chemie International Edition 41(12): 1,998–2,007.

Nicolaou, K. C., and Sorensen, E. J. (1996). Classics in Total Synthesis: Targets, Strategies, Methods. Weinheim, NY: VHF.

Porterfield, William W. (1993). Inorganic Chemistry A Unified Approach. San Diego: Academic Press.

Solomons, T. W. Graham (1992). Organic Chemistry, 5th edition. New York: Wiley.

Warren, Stuart (1982). Organic Synthesis: The Disconnection Approach. New York: Wiley.

Synthesis, Chemical

Resources

Chemical synthesis is the preparation of a compound, usually an organic compound, from easily available or inexpensive commercial chemicals. Compounds are prepared or synthesized by performing various chemical reactions using an inexpensive starting material and changing its molecular structure, by reactions with other chemicals. The best chemical syntheses are those that use cheap starting materials, require only a few steps, and have a good output of product based on the amounts of starting chemicals. The starting materials for organic synthesis can be simple compounds removed from oil and natural gas or more complex chemicals isolated in large amounts from plant and animal sources. The goal of chemical synthesis is to make a particular product that can be used commercially; for example as a drug, a fragrance, a polymer coating, a food or cloth dye, a herbicide, or some other commercial or industrial use. Compounds are also synthesized to test a chemical theory, to make a new or better chemical, or to confirm the structure of a material isolated from a natural source. Chemical synthesis can also be used to supplement the supply of a drug that is commonly isolated in small amounts from natural sources.

Chemical synthesis has played an important role in eradicating one of the major infectious diseases associated with the tropical regions of the world. Malaria is a disease that affects millions of people and is spread by mosquito bites. It causes a person to experience chills followed by sweating and intense fever, and in some cases can cause death.

In about 1633, the Inca Indians told the Jesuit priests that the bark from the cinchona or quinaquina tree could be used to cure malaria. The cinchona tree is an evergreen tree that grows in the mountains of Peru. The healing properties of the bark were quickly introduced in Europe and used by physicians to treat the disease. The chemical responsible for the healing properties of the cinchona bark was isolated in 1820 and named quinine, after the quina-quina tree. By 1850, the demand for cinchona bark was so great that the trees in Peru were near extinction. To supplement the supply of quinine, plantations of cinchona trees were started in India, Java, and Ceylon, but by 1932, they were only able to supply 13% of the world’s demand for the antimalarial drug.

Chemical synthesis was used by German scientists from 1928 to 1933 to make thousands of new compounds that could be used to treat malaria and make up for the deficiency of natural quinine. They were able to identify two new antimalarial drugs and one of them, quinacrine, was used as a substitute for quinine until 1945.

During World War II (1939–1945), the supply of cinchona bark to the Allied Forces was constantly interrupted and a new drug had to be found. British and American scientists began to use chemical synthesis to make compounds to be tested against the disease. Over 150 different laboratories cooperated in synthesizing 12,400 new substances by various and often long, involved chemical sequences. In just four years, they were able to identify the new antimalarial chloroquine and large quantities were quickly prepared by chemical synthesis for use by the Allied Forces in malarial regions. Today, there are more than half a dozen different drugs available to treat malaria and they are all prepared in large quantities by chemical synthesis from easily available chemicals.

Taxol is an anticancer drug that was isolated in the 1960s from the Pacific yew tree. In 1993, taxol was approved by the Food and Drug Administration (FDA) for treatment of ovarian cancer and is also active against various other cancers. The demand for this compound is expected to be very large, but only small amounts of the drug can be obtained from the yew bark, so rather than destroy all the Pacific yew trees in the world, chemists set out to use chemical synthesis to make the compound from more accessible substances. One chemical company found that they could convert 10-deacetylbaccatin III, a compound isolated from yew twigs and needles, into taxol by a series of chemical reactions. Furthermore, in 1994, two research groups at different universities devised a chemical synthesis to synthesize taxol from inexpensive starting materials.

Chemical synthesis can also be used to prove the chemical structure of a compound. In the early nineteenth century, the structure of a compound isolated from natural sources was deduced by chemical reactions that converted the original compound into substances of known, smaller molecular arrangements.

In 1979, chemical synthesis was used as a tool to determine the molecular structure of periplanone B, the sex excitant of the female American cockroach. In the Netherlands in 1974, C. J. Persons isolated 200 micrograms of periplanone B from the droppings of 75,000 virgin female cockroaches. He was able to deduce the gross chemical structure of the compound by modern analytical methods, but not its exact three dimensional structure. Without knowing the stereochemistry or three dimensional arrangement of the carbonatoms, larger quantities of the excitant could not be prepared and tested.

In 1979, W. Clark Still at Columbia University in New York, set out to determine the structure of periplanone B. He noted that four compounds had to be made by chemical synthesis in order to determine the structure of the cockroach excitant. He chose an easily prepared starting material and by a series of chemical reactions was able to make three of the four compounds he needed to determine the chemical structure. One of the new substances matched all the analytical data from the natural material. When it was sent to the Netherlands for testing against the natural product isolated from cockroaches, it was found to be the active periplanone B.

Resources

BOOKS

McMurry, John E. Organic Chemistry. 6th ed. Pacific

Grove, CA: Brooks/Cole Publishing Company, 2003.

Turton, Richard, et. al., eds. Analysis, Synthesis, and Design of Chemical Processes. 2nd ed. Indianapolis, Indiana: Prentice Hall PTR, 2002.

Andrew Poss

Synthesis, chemical

Chemical synthesis is the preparation of a compound, usually an organic compound, from easily available or inexpensive commercial chemicals. Compounds are prepared or synthesized by performing various chemical reactions using an inexpensive starting material and changing its molecular structure, by reactions with other chemicals. The best chemical syntheses are those that use cheap starting materials, require only a few steps, and have a good output of product based on the amounts of starting chemicals. The starting materials for organic synthesis can be simple compounds removed from oil and natural gas or more complex chemicals isolated in large amounts from plant and animal sources. The goal of chemical synthesis is to make a particular product that can be used commercially; for example as a drug, a fragrance, a polymer coating, a food or cloth dye, a herbicide, or some other commercial or industrial use. Compounds are also synthesized to test a chemical theory, to make a new or better chemical, or to confirm the structure of a material isolated from a natural source. Chemical synthesis can also be used to supplement the supply of a drug that is commonly isolated in small amounts from natural sources.

Chemical synthesis has played an important role in eradicating one of the major infectious diseases associated with the tropical regions of the world. Malaria is a disease that affects millions of people and is spread by mosquito bites. It causes a person to experience chills followed by sweating and intense fever, and in some cases can cause death. In about 1633, the Inca Indians told the Jesuit priests that the bark from the cinchona or quina-quina tree could be used to cure malaria. The cinchona tree is an evergreen tree that grows in the mountains of Peru. The healing properties of the bark were quickly introduced in Europe and used by physicians to treat the disease. The chemical responsible for the healing properties of the cinchona bark was isolated in 1820 and named quinine , after the quina-quina tree. By 1850, the demand for cinchona bark was so great that the trees in Peru were near extinction . To supplement the supply of quinine, plantations of cinchona trees were started in India, Java, and Ceylon, but by 1932, they were only able to supply 13% of the world's demand for the antimalarial drug. Chemical synthesis was used by German scientists from 1928 to 1933 to make thousands of new compounds that could be used to treat malaria and make up for the deficiency of natural quinine. They were able to identify two new antimalarial drugs and one of them, quinacrine, was used as a substitute for quinine until 1945. During World War II, the supply of cinchona bark to the Allied Forces was constantly interrupted and a new drug had to be found. British and American scientists began to use chemical synthesis to make compounds to be tested against the disease. Over 150 different laboratories cooperated in synthesizing 12,400 new substances by various and often long, involved chemical sequences . In just four years, they were able to identify the new antimalarial chloroquine and large quantities were quickly prepared by chemical synthesis for use by the Allied Forces in malarial regions. Today, there are more than half a dozen different drugs available to treat malaria and they are all prepared in large quantities by chemical synthesis from easily available chemicals.

Taxol is an anticancer drug that was isolated in the 1960s from the Pacific yew tree. In 1993, taxol was approved by the Food and Drug Administration (FDA) for treatment of ovarian cancer and is also active against various other cancers. The demand for this compound is expected to be very large, but only small amounts of the drug can be obtained from the yew bark, so rather than destroy all the Pacific yew trees in the world, chemists set out to use chemical synthesis to make the compound from more accessible substances. One chemical company found that they could convert 10-deacetylbaccatin III, a compound isolated from yew twigs and needles, into taxol by a series of chemical reactions. Furthermore, in 1994, two research groups at different universities devised a chemical synthesis to synthesize taxol from inexpensive starting materials.

Chemical synthesis can also be used to prove the chemical structure of a compound. In the early nineteenth century, the structure of a compound isolated from natural sources was deduced by chemical reactions that converted the original compound into substances of known, smaller molecular arrangements.

In 1979, chemical synthesis was used as a tool to determine the molecular structure of periplanone B, the sex excitant of the female American cockroach. In the Netherlands in 1974, C. J. Persons isolated 200 micrograms of periplanone B from the droppings of 75,000 virgin female cockroaches . He was able to deduce the gross chemical structure of the compound by modern analytical methods, but not its exact three dimensional structure. Without knowing the stereochemistry or three dimensional arrangement of the carbon atoms , larger quantities of the excitant could not be prepared and tested. In 1979, W. Clark Still at Columbia University in New York, set out to determine the structure of periplanone B. He noted that four compounds had to be made by chemical synthesis in order to determine the structure of the cockroach excitant. He chose an easily prepared starting material and by a series of chemical reactions was able to make three of the four compounds he needed to determine the chemical structure. One of the new substances matched all the analytical data from the natural material. When it was sent to the Netherlands for testing against the natural product isolated from cockroaches, it was found to be the active periplanone B.

Resources

books

McMurry, J. Organic Chemistry. 5th ed. Pacific Grove, CA: Brooks/Cole Publishing Company, 1999.

Mundy, B.P. Concepts of Organic Synthesis. New York: Marcel Dekker Inc, 1980.

Warren, S. Organic Synthesis: The Disconnection Approach. New York: John Wiley & Sons, 1983.

periodicals

Borman, S. Chemical and Engineering News (February 21, 1994), 32.

Stinson, S.C. Chemical and Engineering News (April 30, 1979): 24.

Andrew Poss