The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-Bergman cycloaromatization is an
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, mechanistic organ ...
and more specifically a
rearrangement reaction taking place when an
enediyne is heated in presence of a suitable hydrogen donor (''Scheme 1''). It is the most famous and well-studied member of the general class of
cycloaromatization reactions. It is named for Japanese-American chemist
Satoru Masamune (b. 1928) and American chemist
Robert G. Bergman (b. 1942). The reaction product is a derivative of
benzene
Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
.
The reaction proceeds by a thermal reaction or
pyrolysis
Pyrolysis is a process involving the Bond cleavage, separation of covalent bonds in organic matter by thermal decomposition within an Chemically inert, inert environment without oxygen. Etymology
The word ''pyrolysis'' is coined from the Gree ...
(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
Carbon tetrachloride, also known by many other names (such as carbon tet for short and tetrachloromethane, also IUPAC nomenclature of inorganic chemistry, recognised by the IUPAC), is a chemical compound with the chemical formula CCl4. It is a n ...
the reaction product is a
1,4-dichlorobenzene and with
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...
the reaction product is
benzyl alcohol
Benzyl alcohol (also known as α-cresol) is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl a ...
.
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 organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles ar ...
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
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...
. These compounds generate the diradical intermediate described above which can cause single and double stranded
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
cuts. There are novel
drug
A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
s which attempt to make use of this property, including
monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Mon ...
such as
mylotarg.
A
biradical mechanism is also proposed for the formation of certain
biomolecule
A biomolecule or biological molecule is loosely defined as a molecule produced by a living organism and essential to one or more typically biological processes. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids ...
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
Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
as hydrogen source in
DMSO
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
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
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
intermediate B. The anion is a powerful base, stripping protons even from DMSO to final product. The dibromide or dihydrogen product (
tetralin) never form.

In 2015 IBM scientists demonstrated that a reversible Masamune-Bergman cyclisation of diyne can be induced by a tip of an
atomic force microscope
Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very-high-resolution type of scanning probe microscopy (SPM), with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the diffr ...
(AFM). They also recorded images of individual diyne molecules during this process. When learning about this direct experimental demonstration Bergman commented, "When we first reported this reaction I had no idea that it would be biologically relevant, or that the reaction could someday be visualized at the molecular level.
References
External links
* ''Bergman Cycloaromatization'
PowerpointWhitney M. Erwin 2002
{{Organic reactions
Rearrangement reactions
Carbon-carbon bond forming reactions
Name reactions
Enediynes