Inorganic chemistry,cyclopropanation refers to any chemical process which generatescyclopropane ((CH2)3)rings. It is an important process in modern chemistry as many useful compounds bear this motif; for examplepyrethroidinsecticides and a number ofquinolone antibiotics (ciprofloxacin,sparfloxacin, etc.). However, the highring strain present in cyclopropanes makes them challenging to produce and generally requires the use of highlyreactive species, such ascarbenes,ylids andcarbanions.[1] Many of the reactions proceed in acheletropic manner.
Several methods exist for converting alkenes to cyclopropane rings usingcarbene type reagents. As carbenes themselves are highly reactive it is common for them to be used in a stabilised form, referred to as acarbenoid.[2]
In theSimmons–Smith reaction the reactive carbenoid isiodomethylzinc iodide, which is typically formed by a reaction betweendiiodomethane and azinc-copper couple. Modifications involving cheaper alternatives have been developed, such asdibromomethane[3] ordiazomethane andzinc iodide.[4] The reactivity of the system can also be increased by exchanging the zinc‑copper couple fordiethylzinc.[5] Asymmetric versions are known.[6]
Certaindiazo compounds, such asdiazomethane, can react with olefins to produce cyclopropanes in a 2 step manner. The first step involves a1,3-dipolar cycloaddition to form apyrazoline which then undergoes denitrogenation, eitherphotochemically or bythermal decomposition, to give cyclopropane. The thermal route, which often usesKOH andplatinum as catalysts, is also known as theKishner cyclopropane synthesis after the Russian chemistNikolai Kischner[7][8] and can also be performed usinghydrazine andα,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 ofgreen 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.
Methyl phenyldiazoacetate and many related diazo derivatives are precursors todonor-acceptor carbenes, which can be used for cyclopropanation or to insert into C-H bonds of organic substrates. These reactions are catalyzed byrhodium(II) trifluoroacetate and related chiral derivatives.[12][13][14]
Freecarbenes 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 asdichlorocarbene ordifluorocarbene, which are reasonably stable and will react to formgeminal dihalo-cyclopropanes.[15] These compounds can then be used to formallenes via theSkattebøl rearrangement.
TheBuchner ring expansion reaction also involves the formation of a stabilised carbene.Cyclopropanation is alsostereospecific as the addition of carbene and carbenoids to alkenes is a form of acheletropic reaction, with the addition taking place in asyn manner. For example,dibromocarbene andcis-2-butene yieldcis-2,3-dimethyl-1,1-dibromocyclopropane, whereas thetrans isomer exclusively yields thetrans cyclopropane.[16]
Cyclopropanes can be generated using a sulphurylide in theJohnson–Corey–Chaykovsky reaction,[17] however this process is largely limited to use on electron-poor olefines, particularly α,β-unsaturatedcarbonyl compounds.
Cyclopropanes can be obtained by a variety of intramolecularcyclisation reactions. A simple method is to use primary haloalkanes bearing appropriately placed electron withdrawing groups. Treatment with a strong base will generate acarbanion which will cyclise in a3-exo-trig manner, with displacement of the halide. Examples include the formation ofcyclopropyl cyanide[18] andcyclopropylacetylene[19] This mechanism also forms the basis of theFavorskii rearrangement.
A related process is the cyclisation of1,3-dibromopropane via aWurtz coupling. This was used for the first synthesis ofcyclopropane byAugust Freund in 1881. Originally this reaction was performed using sodium,[20] however the yield can be improved by exchanging this forzinc.[21]
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 interpenoids.Cyclopropane fatty acids are derived from the attack ofS-adenosylmethionine (SAM) on unsaturated fatty acids. The precursor to the hormoneethylene,1-aminocyclopropane-1-carboxylic acid, is derived directly from SMM via intramolecular nucleophilic displacement of the SMe2 group subsequent to condensation withpyridoxal phosphate.[23] Direct carbene transfer from diazoesters to olefins has also been achieved throughin vitro biocatalysis using engineered variants of thecytochrome P450 enzyme fromBacillus megaterium that were optimized bydirected evolution.[24]