Generation of Dihalocarbenes

Dihalocarbenes, synthetically useful intermediates, are normally generated by the action of a base on chloroform. 

However, use of crown ether gives better yield (48%). 

This is a convenient method compared to the two step process.  

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More useful for synthetic purposes, however, is the combination of the zinc-copper couple with methylene iodide to generate carbene-zinc iodide complex, which undergoes addition to double bonds exclusively to form cyclopropanes (7). The base-catalyzed generation of halocarbenes from haloforms (2) also provides a general route to 1,1-dihalocyclopropanes via carbene addition, as does the nonbasic generation of dihalocarbenes from phenyl(trihalomethyl)mercury compounds. Details of these reactions are given below. 

M Makosza at the Technical University in Warsaw led the field in a study of the application of phase-transfer catalysis, particular into the generation of dihalocarbenes. 

An excellent comprehensive review of the factors which influence the generation of dihalocarbenes under phase-transfer catalytic conditions, and their relative stabilities and reactivities has been presented by Dehmlow [1],... 

As Makosza s method has effectively replaced the classical procedures for the generation of dihalocarbenes, subsequent Sections of this Chapter present only representative examples of the reactions of the dihalocarbenes generated under phase-transfer conditions. 

The catalysts must supply the system with lipophilic cations in order to form, with required anions, ion pairs able to enter nonpolar media. The most typical catalysts are tetraalkyl ammonium (TAA) salts R4N+X, particularly those having at least 16 carbon atoms in the four R groups. Similar lipophilic catalysts are tetraalkylphosphonium and -arsonium or trialkylsulfonium salts, which are less available and usually less stable. They are therefore of negligible practical use. There are a few reports on the use of trialkylamines as catalysts in some two-phase reactions. Usually these amines are qua-ternized by a reactant actually these reactions are catalyzed by TAA salts. More complicated is the generation of dihalocarbenes with trialkylamines. The amines form, with the carbene, an ammonium ylide, which acts as a base in the organic phase. 

Generation of dihalocarbenes (2, 196 197). Buddrus1 has reviewed the use of ethylene oxide for generation of dihalocarbenes according to the formulation ... 

This result is due to specific properties of the phase-transfer catalytic system. Both trihalomethyl anions as well as halide ions form, with the quaternary ammonium cation, lipophilic ion pairs which are readily soluble in the organic phase. The generation of dihalocarbenes is in fact a reversible process and, if the starting haloform contains different halogen atoms, exchange reactions afford all possible dihalocarbenes (Houben-Weyl, Vol. E19b, pp 1591-1592). 

Generation of dihalocarbenes [before reference]. A German group2 has generated... 

Generation of dihalocarbenes [1, 852-853, after citation of ref. 7]. Allylamines, in which the ally chain contains at least four carbon atoms, react with phenyl(trichloro-methyl)mercury to give a cyclopropane derivative (2) and cleavage products (3) and (4).73... 

A very important and large field of application of PTC is generation of dihalocarbenes via a-elimination and their reactions with a variety of partners. Thus, when chloroform and an alkene is treated with concentrated aqueous NaOH in the presence of a PT catalyst, rapid formation of dichlorocyclopropane takes place [12] ... 

Elimination Reactions. t-BuOK is a widely used base for both a- and /3-elimination reactions. It is the most effective base in the conventional alkoxide-haloform reaction for the generation of dihalocarbenes. This procedure still finds general use (eq 19), but since it requires anhydrous conditions, it has been replaced to a degree by use of phase-transfer catalysts. Vinylidene carbenes have also been produced from the reaction of a-halo allenes with f-BuOK. ... 

The reaction involves the generation of dihalocarbene from haloform and a base, e.g., KOH, which then inserts into the pyrrole ring. The subsequent ring enlargement affords the pyridine derivative, as illustrated by the reaction of chloroform and pyrrole. 

In particular cases the presence of cosolvents seems to be somewhat useful. In the generation of dihalocarbenes, the addition of a small amount of ethanol to chloroform in some cases remarkably improves the yield of the corresponding carbene This is likely due, however, to the formation of a more lipophilic alkoxy anion, which participates in the reaction, rather than to a solvent effect. As a further example, the extraction of tetraalkylammonium hydroxides into aromatic hydrocarbons increases by 1 to 3 orders of magnitude when a small amoimt of alcohol is added however, the extracted species is mainly RO than OH ... 

In these reactions the quaternary salt transports the carbanion from the interface into the organic phase where the reaction occurs. This was proved as follows i) the deeply coloured 9-fluorenyl anion was transported into the organic phase from the interface by equilibrating an aqueous 50% NaOH solution with a solution of fluorene in benzene in the presence of Hex4N Cl ii) stirring rates must be at least 750-800 rpm to obtain reproducible results in the generation of dihalocarbenes starting from chloroform and 50% NaOH in the presence of a quaternary salt this is consistent with the typical behaviour of interfacial reactions, since usual PTC reactions proceed at a constant rate over 250-300 rpm (see Sect. 2.3.1). 

Another wide area of application of this two-phase system is the generation of dihalocarbenes, particularly dichloro- and dibro-mocarbenes via the a-elimination of hydrogen halide from the corresponding haloforms(5). 

Carbene Generation.—One of the best investigated areas of PTC application is the generation of dihalocarbenes in a two-phase system of haloform and aqueous sodium hydroxide (Scheme 6), catalysed often by benzyltriethylammonium chloride, and earlier work has been fully surveyed.The substrate for reaction with the carbene can be present in the organic phase, and, for example, cyclopropanes are produced by insertion into any alkenes present (Equation 6). Even normally poor substrates show good reactivity towards carbenes generated under these conditions... 

The reaction of dihalocarbenes with isoprene yields exclusively the 1,2- (or 3,4-) addition product, eg, dichlorocarbene CI2C and isoprene react to give l,l-dichloro-2-methyl-2-vinylcyclopropane (63). The evidence for the presence of any 1,4 or much 3,4 addition is inconclusive (64). The cycloaddition reaction of l,l-dichloro-2,2-difluoroethylene to isoprene yields 1,2- and 3,4-cycloaddition products in a ratio of 5.4 1 (65). The main product is l,l-dichloro-2,2-difluoro-3-isopropenylcyclobutane, and the side product is l,l-dichloro-2,2-difluoro-3-methyl-3-vinylcyclobutane. When the dichlorocarbene is generated from CHCl plus aqueous base with a tertiary amine as a phase-transfer catalyst, the addition has a high selectivity that increases (for a series of diolefins) with a decrease in activity (66) (see Catalysis, phase-TRANSFEr). For isoprene, both mono-(l,2-) and diadducts (1,2- and 3,4-) could be obtained in various ratios depending on which amine is used. 

Before our studies, high temperatures (>600°C) had usually been used to generate dichlorocarbene in the gas phase. Based on trapping experiments we have shown that the trihalomethyl mercury derivatives RHgCHals, which were successfully used earlier as sources of dihalocarbenes in solution (Seyferth, 1972), are also convenient precursors of carbenes in the gas phase (Mal tsev etaL, 1971a,b). 

The advantages of this method of carbene synthesis are that reaction can be carried out in neutral solution, and that reaction yields are often dramatically improved. Thus, although reactions of dihalocarbenes generally do not give rise to products corresponding to single bond insertion, Seyferth has reported insertion of phenyl (trihalomethyl) mercury-generated carbenes into... 

Phase-transfer catalysis, 35 375 22 general description, 35 376-378 generation and reactions of dihalocarbenes, 35 408 14... 

Although the trihalolithiomethanes seem to be predestined to deliver the corresponding dihalocarbenes by spontaneous a-elimination, they have been shown to be stable at temperatures below —100 °C so that they could be characterized by NMR spectroscopy . Furthermore, their nucleophilic reactivity has been demonstrated by the addition to ketones. Herein, the in situ generation of trichloro- and tribromo-lithio-methane 128 and 129 provides a convenient protocol (equation 65) . ... 

Carbene precursors are compounds that have or acquire good leaving groups (e.g., halide ions). Thus, halogen compounds frequently are carbene sources. Trihalomethanes are the oldest known sources of dihalocarbenes but there are other methods for generating carbenes, and some of these are listed for reference in Table 14-2 (see also Section 14-10C). There is a question as to whether a free carbene actually is formed in some of these reactions, particularly those involving metals, but for our purposes we will classify them as routes to carbenes or carbenelike species. 

Dihalocyclopropanes are generally prepared by the addition of dihalocarbenes to alkenic substrates. As indicated in the introduction, the first synthesis of a dihalocyclopropane was accomplished by Doering and Hoffmann by the addition of dichlorocarbene, generated from chloroform and potassium r-butoxide (Bu OK), to cyclohexene giving dichloronorcarane (1), as shown in equation (l).s... 

The formation of dihalocarbene is one of the most useful phase-transfer processes developed in organic chemistry. The dihalocarbenes, once generated from haloform and base, can undergo addition or insertion reactions (3, 11, 12). If the double bond is complexed to a metal, addition by the carbene will not occur, but rather insertion into a saturated carbon-hydrogen bond will take place. 

The scope of this process is evident from extensive studies which have shown that the dihalocarbene can be generated from most of the usual precursors by using the phase transfer method . The reactivity of dihalocarbenes " and carbenoids " towards acetylenes has also been reported. 

Dihalocarbenes generated from haloforms and strong bases e.g. alkoxides) or from haloforms and alkali metal hydroxides under phase transfer conditions " or organomeicuiytrihalomethanes, add to azomethines to yield 2,2-dihaloaziridines (49 equation 30). The following carbenes have been used for such purposes dichlorocarbene, " dibromocarbene, " difluorocarbene, bromochlorocar-bene and bromofluorocarbene. The addition of dihalocarbenes to azoxybenzene or azobenzene affords dihaloaziridines e.g. 50 equation 31) among other products. 

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