Cyclopropanation

Several methods exist for converting alkenes to cyclopropane rings using carbene type reagents. As carbenes themselves are highly reactive it is common for them to be used in a stabilised form, referred to as a carbenoid.{{GoldBookRef|title=carbenoids| file = C00813.html}}

In the Simmons–Smith reaction the reactive carbenoid is iodomethylzinc iodide, which is typically formed by a reaction between diiodomethane and a zinc-copper couple. Modifications involving cheaper alternatives have been developed, such as dibromomethane{{cite journal|last=Fabisch|first=Bodo|author2=Mitchell, Terence N.|title=An inexpensive modification of the Simmons-Smith reaction: The formation of bromomethylzinc bromide as studied by NMR spectroscopy|journal=Journal of Organometallic Chemistry|year=1984|volume=269|issue=3|pages=219–221|doi=10.1016/0022-328X(84)80305-8}} or diazomethane and zinc iodide.{{cite journal|last=Wittig|first=Georg|author2=Wingler, Frank|title=Über methylenierte Metallhalogenide, IV. Cyclopropan-Bildung aus Olefinen mit Bis-halogenmethyl-zink|journal=Chemische Berichte|date=1 August 1964|volume=97|issue=8|pages=2146–2164|doi=10.1002/cber.19640970808}} The reactivity of the system can also be increased by exchanging the zinc‑copper couple for diethylzinc.{{cite journal|last=Furukawa|first=J.|author2=Kawabata, N. |author3=Nishimura, J. |title=Synthesis of cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide|journal=Tetrahedron|year=1968|volume=24|issue=1|pages=53–58|doi=10.1016/0040-4020(68)89007-6}} Asymmetric versions are known.{{cite book | last1 = Charette | first1 = A. B. | last2 = Beauchemin | first2 = A. | year = 2001 | title = Org. React. | chapter = Simmons-Smith Cyclopropanation Reaction | volume = 58 | page = 1 | doi = 10.1002/0471264180.or058.01 | isbn = 978-0471264187 }}

:File:Simmons Smith Reaktion Mechanismus1b.svg

Certain diazo compounds, such as diazomethane, can react with olefins to produce cyclopropanes in a 2 step manner. The first step involves a 1,3-dipolar cycloaddition to form a pyrazoline which then undergoes denitrogenation, either photochemically or by thermal decomposition, to give cyclopropane. The thermal route, which often uses KOH and platinum as catalysts, is also known as the Kishner cyclopropane synthesis after the Russian chemist Nikolai Kischner{{cite journal|last1=Lewis|first1=David E.|title=Disability, Despotism, Deoxygenation-From Exile to Academy Member: Nikolai Matveevich Kizhner|journal=Angewandte Chemie International Edition|date=4 November 2013|volume=52|issue=45|pages=11704–11712|doi=10.1002/anie.201303165|pmid=24123691}}N. M. Kishner, A. Zavadovskii, J. Russ. Phys. Chem. Soc. 43, 1132 (1911). and can also be performed using hydrazine and α,β-unsaturated carbonyl compounds.{{cite journal|last1=J. Petersen|first1=R.|last2=P. S. Skell|first2=P.|title=PHENYLCYCLOPROPANE|journal=Org. Synth.|date=1967|volume=47|page=98|doi=10.15227/orgsyn.047.0098}} The mechanism of decomposition has been the subject of several studies and remains somewhat controversial, although it is broadly thought to proceed via a diradical species.{{cite journal|last1=Crawford|first1=Robert J.|last2=Mishra|first2=Anupama|title=The Mechanism of the Thermal Decomposition of 1-Pyrazolines and Its Relationship to Cyclopropane Isomerizations|journal=Journal of the American Chemical Society|date=September 1966|volume=88|issue=17|pages=3963–3969|doi=10.1021/ja00969a014}}{{cite journal|last1=Muray|first1=Elena|last2=Illa|first2=Ona|last3=Castillo|first3=José A.|last4=Álvarez-Larena|first4=Ángel|last5=Bourdelande|first5=José L.|last6=Branchadell|first6=Vicenç|last7=Ortuño|first7=Rosa M.|title=Photolysis of Chiral 1-Pyrazolines to Cyclopropanes: Mechanism and Stereospecificity|journal=The Journal of Organic Chemistry|date=June 2003|volume=68|issue=12|pages=4906–4911|doi=10.1021/jo0342471|pmid=12790598}} In terms of green chemistry this method is superior to other carbene based cyclopropanations; as it does not involve metals or halogenated reagents, and produces only N₂ as a by-product. However the reaction can be dangerous as trace amounts of unreacted diazo compounds may explode during the thermal rearrangement of the pyrazoline.

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{{Main|Metal-catalyzed cyclopropanations}}

Methyl phenyldiazoacetate and many related diazo derivatives are precursors to donor-acceptor carbenes, which can be used for cyclopropanation or to insert into C-H bonds of organic substrates. These reactions are catalyzed by rhodium(II) trifluoroacetate and related chiral derivatives.{{cite journal|author=Davies, H. M. L.|author2=Morton, D.|title=Guiding Principles for Site Selective and Stereoselective Intermolecular C–H Functionalization by Donor/Acceptor Rhodium Carbenes|journal= Chemical Society Reviews|year=2011|volume=40|issue=4|pages=1857–1869|doi=10.1039/C0CS00217H|pmid=21359404 }}{{cite journal|title=Methyl Phenyldiazoacetate|author=Huw M. L. Davies|author2=Wen‐hao Hu|author3=Dong Xing|journal=EEROS|pages=1–10|doi=10.1002/047084289X.rn00444.pub2|year=2015|isbn=9780470842898}}{{cite journal|last=Lebel|first=Hélène|author2=Marcoux, Jean-François |author3=Molinaro, Carmela |author4= Charette, André B. |title=Stereoselective Cyclopropanation Reactions|journal=Chemical Reviews|date=1 April 2003|volume=103|issue=4|pages=977–1050|doi=10.1021/cr010007e|pmid=12683775}}

:File:IntraCPGen.png

Free carbenes can be employed for cyclopropanation reactions, however there is limited scope for this as few can be produced conveniently and nearly all are unstable (see: carbene dimerization). An exception are dihalocarbenes such as dichlorocarbene or difluorocarbene, which are reasonably stable and will react to form geminal dihalo-cyclopropanes.{{cite journal|last=Fedoryński|first=Michał|title=Syntheses of Dihalocyclopropanes and Their Use in Organic Synthesis|journal=Chemical Reviews|date=1 April 2003|volume=103|issue=4|pages=1099–1132|doi=10.1021/cr0100087|pmid=12683778}} These compounds can then be used to form allenes via the Skattebøl rearrangement.

:File:Dichlorocarbene reaction cyclohexene.svg

The Buchner ring expansion reaction also involves the formation of a stabilised carbene.

Cyclopropanation is also stereospecific as the addition of carbene and carbenoids to alkenes is a form of a cheletropic reaction, with the addition taking place in a syn manner. For example, dibromocarbene and cis-2-butene yield cis-2,3-dimethyl-1,1-dibromocyclopropane, whereas the trans isomer exclusively yields the trans cyclopropane.{{cite journal |author1=Skell, P.S. |author2=Garner, A.Y. | title = The Stereochemistry of Carbene-Olefin Reactions. Reactions of Dibromocarbene with the cis- and trans-2-Butenes | journal = Journal of the American Chemical Society | year = 1956 | volume = 78 | pages = 3409–3411 | doi=10.1021/ja01595a040 | issue = 14}}

:stereospecific carbene reaction

Cyclopropanes can be generated using a sulphur ylide in the Johnson–Corey–Chaykovsky reaction,{{cite journal |author1=Li, A.-H. |author2=Dai, L.-X. |author3=Aggarwal, V. K. |title=Asymmetric Ylide Reactions: Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement|journal=Chemical Reviews|year=1997|volume=97|issue=6|pages=2341–2372|doi=10.1021/cr960411r|pmid=11848902 }} however this process is largely limited to use on electron-poor olefines, particularly α,β-unsaturated carbonyl compounds.

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Cyclopropanes can be obtained by a variety of intramolecular cyclisation reactions. A simple method is to use primary haloalkanes bearing appropriately placed electron withdrawing groups. Treatment with a strong base will generate a carbanion which will cyclise in a 3-exo-trig manner, with displacement of the halide. Examples include the formation of cyclopropyl cyanide{{OrgSynth|last = Schlatter|first = M. J.|title = Cyclopropyl Cyanide|year = 1943|volume = 23|pages = 20|prep = CV3P0223|collvol = 3|collvolpages = 223|doi = 10.15227/orgsyn.023.0020}}. and cyclopropylacetylene{{OrgSynth|last1 = Huntington|first1 = Martha|first2 = Edward G.|last2 = Corley|first3 = Andrew S.|last3 = Thompson|title = Cyclopropylacetylene|year = 2000|volume = 77|pages = 231|prep = V77P0231|doi = 10.15227/orgsyn.077.0231}} This mechanism also forms the basis of the Favorskii rearrangement.

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A related process is the cyclisation of 1,3-dibromopropane via a Wurtz coupling. This was used for the first synthesis of cyclopropane by August Freund in 1881. Originally this reaction was performed using sodium,{{cite journal | title = Über Trimethylen | language = de |trans-title= On Trimethylene | first = August | last = Freund | volume = 26 | issue = 1 | year = 1881 | doi = 10.1002/prac.18820260125 | journal = Journal für Praktische Chemie | pages = 625–635| url = https://zenodo.org/record/1427896 }} however the yield can be improved by exchanging this for zinc.{{cite journal | first = G. | last = Gustavson | title = Ueber eine neue Darstellungsmethode des Trimethylens | language = de |trans-title= On a new method of representation of trimethylene | journal = J. Prakt. Chem. | volume = 36 | pages = 300–305 | year = 1887 | url = http://gallica.bnf.fr/ark:/12148/bpt6k90799n/f308.table | doi = 10.1002/prac.18870360127}}

:BrCH₂CH₂CH₂Br + 2 Na → (CH₂)₃ + 2 NaBr

• The Kulinkovich reaction form cyclopropanols via a reaction between esters and Grignard reagents in presence of a titanium alkoxide.
• The Bingel reaction is a specialised cyclopropanation reaction used to functionalise a fullerene.
• In the di-π-methane rearrangement, photochemical stimulation causes 1,4-dienes to rearrange to form vinylcyclopropanes.IUPAC Gold book [https://goldbook.iupac.org/terms/view/D01745 definition] These can then undergo vinylcyclopropane rearrangements
• Cyclopropane-fatty-acyl-phospholipid synthase performs cyclopropanation in biological systems
• Using Cobalt(II)–porphyrin catalysis, using diazo compounds and olefins.

File:U-106305.png with six cyclopropane rings, isolated from Streptomyces sp]]

Although cyclopropanes are relatively rare in biochemistry, many cyclopropanation pathways have been identified in nature. The most common pathways involve ring closure reactions of carbocations in terpenoids. Cyclopropane fatty acids are derived from the attack of S-adenosylmethionine (SAM) on unsaturated fatty acids. The precursor to the hormone ethylene, 1-aminocyclopropane-1-carboxylic acid, is derived directly from SMM via intramolecular nucleophilic displacement of the SMe₂ group subsequent to condensation with pyridoxal phosphate.{{cite journal|last1=Wessjohann|first1=Ludger A.|last2=Brandt|first2=Wolfgang|last3=Thiemann|first3=Thies|title=Biosynthesis and Metabolism of Cyclopropane Rings in Natural Compounds|journal=Chemical Reviews|date=April 2003|volume=103|issue=4|pages=1625–1648|doi=10.1021/cr0100188|pmid=12683792}} Direct carbene transfer from diazoesters to olefins has also been achieved through in vitro biocatalysis using engineered variants of the cytochrome P450 enzyme from Bacillus megaterium that were optimized by directed evolution.{{cite journal|last1=Coelho|first1=P. S.|last2=Brustad|first2=E. M.|last3=Kannan|first3=A.|last4=Arnold|first4=F. H.|title=Olefin Cyclopropanation via Carbene Transfer Catalyzed by Engineered Cytochrome P450 Enzymes|journal=Science|date=20 December 2012|volume=339|issue=6117|pages=307–310|doi=10.1126/science.1231434|pmid=23258409|bibcode=2013Sci...339..307C|url=https://authors.library.caltech.edu/36827/7/Coelho.SM.pdf}}

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{{Reflist|20em}}

{{Cycloalkanes}}

{{Alkenes}}

Category:Cyclopropanes

Category:Cycloadditions

Category:Cheletropic reactions