Bergman cyclization
Encyclopedia
The Bergman cyclization or Bergman reaction or Bergman cycloaromatization is an organic reaction
and more specifically a rearrangement reaction
taking place when an enediyne
is heated in presence of a suitable hydrogen donor (Scheme 1) . It is named for the American chemist Robert George Bergman (b. 1942). The reaction product is a derivative of benzene
.
The reaction proceeds by a thermal reaction or pyrolysis
(above 200°C) forming a short-lived and very reactive para-benzyne biradical species. It will react with any hydrogen donor such as 1,4-cyclohexadiene
which converts to benzene. When quenched by tetrachloromethane the reaction product is a 1,4-dichlorobenzene
and with methanol
the reaction product is benzyl alcohol
.
When the enyne
moiety is incorporated into a 10-membered hydrocarbon ring (e.g. cyclodeca-3-ene-1,5-diyne in scheme 2) the reaction, taking advantage of increased ring strain
in the reactant, is possible at the much lower temperature of 37°C.
Naturally occurring compounds such as calicheamicin
contain the same 10-membered ring and are found to be cytotoxic. These compounds generate the diradical intermediate described above which can cause single and double stranded DNA
cuts. There are novel drug
s which attempt to make use of this property, including monoclonal antibodies
such as mylotarg .
A biradical mechanism is also proposed for the formation of certain biomolecule
s found in marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the enediyene cyclodeca-1,5-diyn-3-ene, lithium bromide
as halogen source and acetic acid
as hydrogen source in DMSO
at 37°C supports the theory :
The reaction is found to be first-order
in enediyne with the formation of p-benzyne A as the rate-limiting step. The halide ion then donates its two electrons in the formation of a new Br-C bond and radical electron involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a powerful base, stripping protons even from DMSO to final product. The dibromide or dihydrogen product (tetralin
) never form.
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,...
and more specifically a rearrangement reaction
Rearrangement reaction
A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule...
taking place when an enediyne
Enediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...
is heated in presence of a suitable hydrogen donor (Scheme 1) . It is named for the American chemist Robert George Bergman (b. 1942). The reaction product is a derivative of benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
.
The reaction proceeds by a thermal reaction or pyrolysis
Pyrolysis
Pyrolysis is a thermochemical decomposition of organic material at elevated temperatures without the participation of oxygen. It involves the simultaneous change of chemical composition and physical phase, and is irreversible...
(above 200°C) forming a short-lived and very reactive para-benzyne biradical species. It will react with any hydrogen donor such as 1,4-cyclohexadiene
1,4-Cyclohexadiene
1,4-Cyclohexadiene is a highly flammable cycloalkene that occurs as a colorless clear liquid.1,4-Cyclohexadiene and related compounds may be prepared from benzene using lithium or sodium in liquid ammonia, this process being known as a Birch reduction. However 1,4-cyclohexadiene is easily oxidised...
which converts to benzene. When quenched by tetrachloromethane the reaction product is a 1,4-dichlorobenzene
1,4-Dichlorobenzene
1,4-Dichlorobenzene is an organic compound with the formula C6H4Cl2. This colorless solid has a strong odor. It consists of two chlorine atoms substituted at opposing sites on a benzene ring. p-DCB is used a pesticide and a deodorant, most familiarly in mothballs in which it is a replacement for...
and with methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
the reaction product is benzyl alcohol
Benzyl alcohol
Benzyl alcohol is an organic compound with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn", thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is a useful solvent due to its polarity, low toxicity, and low vapor...
.
When the enyne
Enyne
An enyne is a functional group in organic chemistry consisting of a conjugated alkyne and alkene group....
moiety is incorporated into a 10-membered hydrocarbon ring (e.g. cyclodeca-3-ene-1,5-diyne in scheme 2) the reaction, taking advantage of increased ring strain
Ring strain
In organic chemistry, ring strain is the tendency of a cyclic molecule, such as cyclopropane, to destabilize when its atoms are in non-favorable high energy spatial orientations...
in the reactant, is possible at the much lower temperature of 37°C.
Naturally occurring compounds such as calicheamicin
Calicheamicin
The calicheamicins are a class of enediyne antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally from a rock collected by a Scripps Research Institute chemist while hiking in Waco, Texas. It is extremely toxic to...
contain the same 10-membered ring and are found to be cytotoxic. These compounds generate the diradical intermediate described above which can cause single and double stranded DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
cuts. There are novel drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s which attempt to make use of this property, including monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
such as mylotarg .
A biradical mechanism is also proposed for the formation of certain biomolecule
Biomolecule
A biomolecule is any molecule that is produced by a living organism, including large polymeric molecules such as proteins, polysaccharides, lipids, and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products...
s found in marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the enediyene cyclodeca-1,5-diyn-3-ene, lithium bromide
Lithium bromide
Lithium bromide, or LiBr, is a chemical compound of lithium and bromine. Its extreme hygroscopic character makes LiBr useful as a desiccant in certain air conditioning systems.-Production and properties:...
as halogen source and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
as hydrogen source in DMSO
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
at 37°C supports the theory :
The reaction is found to be first-order
First-order reaction
First-order reaction may refer to:* Order of reaction, in chemical kinetics, the power to which the concentration term of a certain reactant in the rate equation is raised...
in enediyne with the formation of p-benzyne A as the rate-limiting step. The halide ion then donates its two electrons in the formation of a new Br-C bond and radical electron involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a powerful base, stripping protons even from DMSO to final product. The dibromide or dihydrogen product (tetralin
Tetralin
Tetralin is a hydrocarbon having the chemical formula C10H12. This molecule is similar to the naphthalene chemical structure except that one ring is saturated.The compound can be synthesized in a Bergman cyclization...
) never form.
External links
- Bergman Cycloaromatization Powerpoint Whitney M. Erwin 2002