Bergman cyclization

{{Reactionbox

|Name = Masamune-Bergman cyclization

|Type = Ring forming reaction

|NamedAfter = Satoru Masamune

Robert George Bergman

|Section3 = {{Reactionbox Identifiers

|OrganicChemistryNamed = bergman-cyclization

|RSC_ontology_id = 0000240

}}

}}

The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-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).{{cite journal|doi = 10.1039/C29710001516|last1 = Darby|first1 = N.|last2 = Kim|first2 = C. U.|last3 = Salaun|first3 = J. A.|last4 = Shelton|first4 = K. W.|last5 = Takada|first5 = S.|last6 = Masamune|first6 = S.|journal = J. Chem. Soc. D|year = 1971|volume = 1971|issue = 23|title = Concerning the 1,5-didehydro[10]annulene system|pages = 1516–1517}}{{cite journal|title=p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure |doi=10.1021/ja00757a071 |first1 = Richard R. |last1 = Jones |authorlink1 = Richard R. Jones |first2 = Robert G. |last2 = Bergman |authorlink2 = Robert G. Bergman |journal=J. Am. Chem. Soc. |year=1972 |volume= 94 |issue=2 |pages=660–661}} It is the most famous and well-studied member of the general class of cycloaromatization reactions.{{cite journal|first1=R. K. |last1=Mohamed |first2=P. W. |last2=Peterson |first3=I. V. |last3=Alabugin |title=Concerted Reactions that Produce Diradicals and Zwitterions: Electronic, Steric, Conformational and Kinetic Control of Cycloaromatization Processes |journal= Chem. Rev. |year= 2013 |volume= 113 |issue=9 |pages=7089–7129 |pmid=23600723 |doi=10.1021/cr4000682}} 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.

Image:Bergman cyclization.svg

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.

Image:Bergman ring.png

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.{{Cite journal|last1=Lee|first1=May D.|last2=Ellestad|first2=George A.|last3=Borders|first3=Donald B.|year=1991|title=Calicheamicins: discovery, structure, chemistry, and interaction with DNA|doi=10.1021/ar00008a003|journal=Accounts of Chemical Research|volume=24|issue=8|pages=235–243}} There are novel drugs which attempt to make use of this property, including monoclonal antibodies such as mylotarg.{{cite journal |title=Design and synthesis of heterocycle fused enediyne prodrugs activable at will |first1=Luca |last1=Banfi |first2=Andrea |last2=Basso |first3=Giuseppe |last3=Guanti |first4=Renata |last4=Riva |journal=Arkivoc |year=2006 |volume=HL-1786GR |issue=7 |pages=261–275 |doi=10.3998/ark.5550190.0007.719 |url=http://www.arkat-usa.org/ark/journal/2006/I07_ICHC-20/1786/HL-1786GR%20as%20published%20mainmanuscript.pdf}}

A biradical mechanism is also proposed for the formation of certain biomolecules 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:{{cite journal|title=Nucleophilic Addition to a p-Benzyne Derived from an Enediyne: A New Mechanism for Halide Incorporation into Biomolecules |first1=Charles L. |last1=Perrin |first2=Betsy L. |last2=Rodgers |first3=Joseph M.|last3=O'Connor |journal=J. Am. Chem. Soc. |volume=129 |issue=15 |pages=4795–4799 |year=2007 |doi=10.1021/ja070023e |pmid=17378569}}{{cite magazine|title=New Route For Halide Addition|first=Stu|last=Borman|magazine=Chemical & Engineering News|date=April 2, 2007|url=http://pubs.acs.org/cen/news/85/i15/8515news1.html|access-date=December 30, 2021}}

Image:Bergman cyclization nuclSubst.png

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.

File:Bergman cyclization IBM2.png

In 2015 IBM scientists demonstrated that a reversible Masamune-Bergman cyclisation of diyne can be induced by a tip of an atomic force microscope (AFM). They also recorded images of individual diyne molecules during this process.{{cite journal|last1=Schuler|first1=Bruno|last2=Fatayer|first2=Shadi|last3=Mohn|first3=Fabian|last4=Moll|first4=Nikolaj|last5=Pavliček|first5=Niko|last6=Meyer|first6=Gerhard|last7=Peña|first7=Diego|last8=Gross|first8=Leo|s2cid=21611919|title=Reversible Bergman cyclization by atomic manipulation|journal=Nature Chemistry|volume=8|issue=3|pages=220–224|year=2016|doi=10.1038/nchem.2438|pmid=26892552|bibcode=2016NatCh...8..220S}} 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.{{cite news|last=Sciacca|first=Chris|title=30 Years of Atomic Force Microscopy: IBM Scientists Trigger and Observe Reactions in an Individual Molecule|work=IBM Research News|url=http://ibmresearchnews.blogspot.ch/2016/01/30-years-of-atomic-force-microscopy-ibm.html|access-date=25 January 2016|date=25 January 2016|publisher=IBM}}