Cyclopropanation

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In organic chemistry, cyclopropanation refers to any chemical process which generates cyclopropane ((CH2)3) rings. It is an important process in modern chemistry as many useful compounds bear this motif; for example pyrethroid insecticides and a number of quinolone antibiotics (ciprofloxacin, sparfloxacin, etc.). However, the high ring strain present in cyclopropanes makes them challenging to produce and generally requires the use of highly reactive species, such as carbenes, ylids and carbanions. [1] Many of the reactions proceed in a cheletropic manner.

Contents

The structures of the natural insecticides pyrethrin I, R = CH3 and pyrethrin II, R = CO2CH3. Pyrethrin.svg
The structures of the natural insecticides pyrethrin I, R = CH3 and pyrethrin II, R = CO2CH3.

Approaches

From alkenes using carbenoid reagents

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. [2]

Simmons–Smith reaction

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 [3] or diazomethane and zinc iodide. [4] The reactivity of the system can also be increased by exchanging the zinc‑copper couple for diethylzinc. [5] Asymmetric versions are known. [6]

Simmons Smith Reaktion Mechanismus1b.svg

Using diazo compounds

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 [7] [8] and can also be performed using hydrazine and α,β-unsaturated carbonyl compounds. [9] 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. [10] [11] 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.

Diazo cyclopropanation via pyrazoline.png

Using diazo compounds with metal catalysis

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. [12] [13] [14]

IntraCPGen.png

Using free carbenes

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. [15] These compounds can then be used to form allenes via the Skattebøl rearrangement.

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. [16]

StereospecificCarbeneAddition.svg

From alkenes using ylides

Cyclopropanes can be generated using a sulphur ylide in the Johnson–Corey–Chaykovsky reaction, [17] however this process is largely limited to use on electron-poor olefines, particularly α,β-unsaturated carbonyl compounds.

CCRcycloprop.png

Intramolecular cyclisation

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 [18] and cyclopropylacetylene [19] This mechanism also forms the basis of the Favorskii rearrangement.

Cyclopropylacetylene synthesis 2.png

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, [20] however the yield can be improved by exchanging this for zinc. [21]

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

Other approaches

Biosynthesis

Structure of U-106305, a derivative of a cyclopropane fatty acid with six cyclopropane rings, isolated from Streptomyces sp U-106305.png
Structure of U-106305, a derivative of a cyclopropane fatty acid 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. [23] 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. [24]

Related Research Articles

In organic chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is R−:C−R' or R=C: where the R represents substituents or hydrogen atoms.

In organic chemistry, the diazo group is an organic moiety consisting of two linked nitrogen atoms at the terminal position. Overall charge-neutral organic compounds containing the diazo group bound to a carbon atom are called diazo compounds or diazoalkanes and are described by the general structural formula R2C=N+=N−. The simplest example of a diazo compound is diazomethane, CH2N2. Diazo compounds should not be confused with azo compounds or with diazonium compounds.

The Simmons–Smith reaction is an organic cheletropic reaction involving an organozinc carbenoid that reacts with an alkene to form a cyclopropane. It is named after Howard Ensign Simmons, Jr. and Ronald D. Smith. It uses a methylene free radical intermediate that is delivered to both carbons of the alkene simultaneously, therefore the configuration of the double bond is preserved in the product and the reaction is stereospecific.

<span class="mw-page-title-main">Bamford–Stevens reaction</span> Synthesis of alkenes by base-catalysed decomposition of tosylhydrazones

The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.

Dichlorocarbene is the reactive intermediate with chemical formula CCl2. Although this chemical species has not been isolated, it is a common intermediate in organic chemistry, being generated from chloroform. This bent diamagnetic molecule rapidly inserts into other bonds.

In organic chemistry, the Arndt–Eistert reaction is the conversion of a carboxylic acid to its homologue. Named for the German chemists Fritz Arndt (1885–1969) and Bernd Eistert (1902–1978), the method entails treating an acid chlorides with diazomethane. It is a popular method of producing β-amino acids from α-amino acids.

<span class="mw-page-title-main">Ring expansion and contraction</span> Chemical phenomenon within ring systems

Ring expansion and ring contraction reactions expand or contract rings, usually in organic chemistry. The term usually refers to reactions involve making and breaking C-C bonds, Diverse mechanisms lead to these kinds of reactions.

<span class="mw-page-title-main">Tebbe's reagent</span> Chemical compound

Tebbe's reagent is the organometallic compound with the formula (C5H5)2TiCH2ClAl(CH3)2. It is used in the methylidenation of carbonyl compounds, that is it converts organic compounds containing the R2C=O group into the related R2C=CH2 derivative. It is a red solid that is pyrophoric in the air, and thus is typically handled with air-free techniques. It was originally synthesized by Fred Tebbe at DuPont Central Research.

<span class="mw-page-title-main">Wolff rearrangement</span> Chemical reaction

The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four-membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene-mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The reaction was discovered by Ludwig Wolff in 1902. The Wolff rearrangement has great synthetic utility due to the accessibility of α-diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α-diazocarbonyl compounds, which can undergo a variety of competing reactions.

<span class="mw-page-title-main">Schwartz's reagent</span> Chemical compound

Schwartz's reagent is the common name for the organozirconium compound with the formula (C5H5)2ZrHCl, sometimes called zirconocene hydrochloride or zirconocene chloride hydride, and is named after Jeffrey Schwartz, a chemistry professor at Princeton University. This metallocene is used in organic synthesis for various transformations of alkenes and alkynes.

<span class="mw-page-title-main">Organozinc chemistry</span>

Organozinc chemistry is the study of the physical properties, synthesis, and reactions of organozinc compounds, which are organometallic compounds that contain carbon (C) to zinc (Zn) chemical bonds.

The Wulff–Dötz reaction (also known as the Dötz reaction or the benzannulation reaction of the Fischer carbene complexes) is the chemical reaction of an aromatic or vinylic alkoxy pentacarbonyl chromium carbene complex with an alkyne and carbon monoxide to give a Cr(CO)3-coordinated substituted phenol. Several reviews have been published. It is named after the German chemist Karl Heinz Dötz (b. 1943) and the American chemist William D. Wulff (b. 1949) at Michigan State University. The reaction was first discovered by Karl Dötz and was extensively developed by his group and W. Wulff's group. They subsequently share the name of the reaction.

Metal-catalyzed cyclopropanations are chemical reactions that result in the formation of a cyclopropane ring from a metal carbenoid species and an alkene. In the Simmons–Smith reaction the metal involved is zinc. Metal carbenoid species can be generated through the reaction of a diazo compound with a transition metal). The intramolecular variant of this reaction was first reported in 1961. Rhodium carboxylate complexes, such as dirhodium tetraacetate, are common catalysts. Enantioselective cyclopropanations have been developed.

An insertion reaction is a chemical reaction where one chemical entity interposes itself into an existing bond of typically a second chemical entity e.g.:

A tosylhydrazone in organic chemistry is a functional group with the general structure RR'C=N-NH-Ts where Ts is a tosyl group. Organic compounds having this functional group can be accessed by reaction of an aldehyde or ketone with tosylhydrazine.

The Buchner ring expansion is a two-step organic C-C bond forming reaction used to access 7-membered rings. The first step involves formation of a carbene from ethyl diazoacetate, which cyclopropanates an aromatic ring. The ring expansion occurs in the second step, with an electrocyclic reaction opening the cyclopropane ring to form the 7-membered ring.

<span class="mw-page-title-main">Carbene radical</span> Special class of organometallic carbenes

Carbene radicals are a special class of organometallic carbenes. The carbene radical can be formed by one-electron reduction of Fischer-type carbenes using an external reducing agent, or directly upon carbene formation at an open-shell transition metal complex using diazo compounds and related carbene precursors. Cobalt(III)-carbene radicals have found catalytic applications in cyclopropanation reactions, as well as in a variety of other catalytic radical-type ring-closing reactions.

Cobalt(II)–porphyrin catalysis is a process in which a Co(II) porphyrin complex acts as a catalyst, inducing and accelerating a chemical reaction.

<span class="mw-page-title-main">Methyl phenyldiazoacetate</span> Chemical compound

Methyl phenyldiazoacetate is the organic compound with the formula C6H5C(N2)CO2Me. It is a diazo derivative of methyl phenylacetate. Colloguially referred to as "phenyldiazoacetate", it is generated and used in situ after isolation as a yellow oil.

In organic chemistry, methylenation is a chemical reaction that inserts a methylene group into a chemical compound:

References

  1. ↑ Pellissier, Hélène (July 2008). "Recent developments in asymmetric cyclopropanation". Tetrahedron. 64 (30–31): 7041–7095. doi:10.1016/j.tet.2008.04.079.
  2. ↑ IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " carbenoids ". doi : 10.1351/goldbook.C00813.html
  3. ↑ Fabisch, Bodo; Mitchell, Terence N. (1984). "An inexpensive modification of the Simmons-Smith reaction: The formation of bromomethylzinc bromide as studied by NMR spectroscopy". Journal of Organometallic Chemistry. 269 (3): 219–221. doi:10.1016/0022-328X(84)80305-8.
  4. ↑ Wittig, Georg; Wingler, Frank (1 August 1964). "Über methylenierte Metallhalogenide, IV. Cyclopropan-Bildung aus Olefinen mit Bis-halogenmethyl-zink". Chemische Berichte. 97 (8): 2146–2164. doi:10.1002/cber.19640970808.
  5. ↑ Furukawa, J.; Kawabata, N.; Nishimura, J. (1968). "Synthesis of cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide". Tetrahedron. 24 (1): 53–58. doi:10.1016/0040-4020(68)89007-6.
  6. ↑ Charette, A. B.; Beauchemin, A. (2001). "Simmons-Smith Cyclopropanation Reaction". Org. React. Vol. 58. p. 1. doi:10.1002/0471264180.or058.01. ISBN   978-0471264187.
  7. ↑ Lewis, David E. (4 November 2013). "Disability, Despotism, Deoxygenation-From Exile to Academy Member: Nikolai Matveevich Kizhner". Angewandte Chemie International Edition. 52 (45): 11704–11712. doi:10.1002/anie.201303165. PMID   24123691.
  8. ↑ N. M. Kishner, A. Zavadovskii, J. Russ. Phys. Chem. Soc. 43, 1132 (1911).
  9. ↑ J. Petersen, R.; P. S. Skell, P. (1967). "PHENYLCYCLOPROPANE". Org. Synth. 47: 98. doi:10.15227/orgsyn.047.0098.
  10. ↑ Crawford, Robert J.; Mishra, Anupama (September 1966). "The Mechanism of the Thermal Decomposition of 1-Pyrazolines and Its Relationship to Cyclopropane Isomerizations". Journal of the American Chemical Society. 88 (17): 3963–3969. doi:10.1021/ja00969a014.
  11. ↑ Muray, Elena; Illa, Ona; Castillo, José A.; Álvarez-Larena, Ángel; Bourdelande, José L.; Branchadell, Vicenç; Ortuño, Rosa M. (June 2003). "Photolysis of Chiral 1-Pyrazolines to Cyclopropanes: Mechanism and Stereospecificity". The Journal of Organic Chemistry. 68 (12): 4906–4911. doi:10.1021/jo0342471. PMID   12790598.
  12. ↑ Davies, H. M. L.; Morton, D. (2011). "Guiding Principles for Site Selective and Stereoselective Intermolecular C–H Functionalization by Donor/Acceptor Rhodium Carbenes". Chemical Society Reviews. 40 (4): 1857–1869. doi:10.1039/C0CS00217H. PMID   21359404.
  13. ↑ Huw M. L. Davies; Wen‐hao Hu; Dong Xing (2015). "Methyl Phenyldiazoacetate". EEROS: 1–10. doi:10.1002/047084289X.rn00444.pub2. ISBN   9780470842898.
  14. ↑ Lebel, Hélène; Marcoux, Jean-François; Molinaro, Carmela; Charette, André B. (1 April 2003). "Stereoselective Cyclopropanation Reactions". Chemical Reviews. 103 (4): 977–1050. doi:10.1021/cr010007e. PMID   12683775.
  15. ↑ Fedoryński, Michał (1 April 2003). "Syntheses of Dihalocyclopropanes and Their Use in Organic Synthesis". Chemical Reviews. 103 (4): 1099–1132. doi:10.1021/cr0100087. PMID   12683778.
  16. ↑ Skell, P.S.; Garner, A.Y. (1956). "The Stereochemistry of Carbene-Olefin Reactions. Reactions of Dibromocarbene with the cis- and trans-2-Butenes". Journal of the American Chemical Society . 78 (14): 3409–3411. doi:10.1021/ja01595a040.
  17. ↑ Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. (1997). "Asymmetric Ylide Reactions: Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement". Chemical Reviews . 97 (6): 2341–2372. doi:10.1021/cr960411r. PMID   11848902.
  18. ↑ Schlatter, M. J. (1943). "Cyclopropyl Cyanide". Organic Syntheses . 23: 20. doi:10.15227/orgsyn.023.0020 ; Collected Volumes, vol. 3, p. 223..
  19. ↑ Huntington, Martha; Corley, Edward G.; Thompson, Andrew S. (2000). "Cyclopropylacetylene". Organic Syntheses . 77: 231. doi:10.15227/orgsyn.077.0231 .
  20. ↑ Freund, August (1881). "Über Trimethylen" [On Trimethylene]. Journal für Praktische Chemie (in German). 26 (1): 625–635. doi:10.1002/prac.18820260125.
  21. ↑ Gustavson, G. (1887). "Ueber eine neue Darstellungsmethode des Trimethylens" [On a new method of representation of trimethylene]. J. Prakt. Chem. (in German). 36: 300–305. doi:10.1002/prac.18870360127.
  22. ↑ IUPAC Gold book definition
  23. ↑ Wessjohann, Ludger A.; Brandt, Wolfgang; Thiemann, Thies (April 2003). "Biosynthesis and Metabolism of Cyclopropane Rings in Natural Compounds". Chemical Reviews. 103 (4): 1625–1648. doi:10.1021/cr0100188. PMID   12683792.
  24. ↑ Coelho, P. S.; Brustad, E. M.; Kannan, A.; Arnold, F. H. (20 December 2012). "Olefin Cyclopropanation via Carbene Transfer Catalyzed by Engineered Cytochrome P450 Enzymes" (PDF). Science. 339 (6117): 307–310. Bibcode:2013Sci...339..307C. doi:10.1126/science.1231434. PMID   23258409.
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