Chloroform reactions with amines

Aliphatic Alcohols and Thiols. Ahphatic alcohols on reaction with chloroformates give carbonates and hydrogen chloride. Frequendy, the reaction proceeds at room temperature without a catalyst or hydrogen chloride acceptor. However, faster reactions and better yields are obtained in the presence of alkaU metals or their hydroxides, or tertiary amines. Reactions of chloroformates with thiols yield monothiolocarbonates (14). 

Heterocyclic Alcohols. Thek reactions with chloroformates lead to carbonates. Thus furan- and tetrahydrofuran-derived alcohols give the corresponding carbonates in 75% yield (15). Inorganic bases and tertiary amines as acid acceptors increase the rate and yield in this reaction. 

Reaction with chloroform under basic conditions is a common test for primary amines, both aliphatic and aromatic, since isocyanides have very strong bad odors. The reaction probably proceeds by an SnIcB mechanism with dichlorocarbene as an intermediate ... 

Aminotetrazole behaves like a normal primary amine in reactions with chloroform in base,328 phenyl isocyanate,328 p-toluenesulfonyl chloride,328 and aromatic aldehydes,43 and the expected derivatives of the amino moiety are obtained without interference at the tetrazole ring. With acid chlorides and anhydrides acylation of the amino group is accompanied by ring cleavage and yields 2-acylamino-1,3,4-oxadiazoles.43,328 Flash vacuum pyrolysis of 1 -phenyltetrazole at 500° has recently been reported to give phenylcyanamide as the only detectable product.333... 

Carbamates. Alcoholysis of the chloroformate leads to mixed carbonates, which are reactive toward amines. Reaction with 2-amino alcohols directly furnishes oxazolones. 

Tertiary amines 657 are cleaved by reaction with chloroformate (for example, a-chloroethyl chloroformate, or phenyl chloroformate, 658), resulting in carbamates 659 (for an extended discussion, see Section 4.7). 

Chloroformates are reactive intermediates that combine acid chloride and ester functions. They undergo many reactions similar to those of acid chlorides however, the rates are usually slower (4—8). Those containing smaller organic (hydrocarbon) substituents react faster than those containing large organic (hydrocarbon) substituents (3). Reactions of chloroformates and other acid chlorides proceed faster with better yields when alkaU hydroxides or tertiary amines are present to react with the HCl as it forms. These bases act as stoichiometric acid acceptors rather than as tme catalysts. 

Reactivities of several chlorinated solvents, including chloroform, with aluminum, iron, and 2inc in both dry and wet systems have been deterrnined, as have chemical reactivities in oxidation reactions and in reactions with amines (11). Unstabilized wet chloroform reacts completely with aluminum and attacks zinc at a rate of >250 //m/yr and iron at <250 //m/yr. The dry, uiiinhibited solvent attacks aluminum and zinc at a rate of 250 )J.m/yr and iron at 25 ]lni / yr. 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

The alkanephosphonic acid dichlorides obtained by these methods are converted with amines, with all reactions carried out in solvents such as acetone, benzene, or diethyl ether at 10°C with triethylamine as HC1 captor. The conversion runs quantitatively followed by a purification with the help of column chromatography with chloroform/methanol in a ratio of 9 1 as mobile phase. The alkanephosphonic acid bisdiethanolamides could be obtained as pure substances with alkane residues of C8, C10, C12, and Ci4. The N-(2-hydroxyethane) alkanephosphonic acid 0,0-diethanolamide esters were also prepared in high purity. The obtained surfactants are generally stable up to 100°C. Only the alkanephosphonic acid bismonomethylamides are decomposed beneath this temperature forming cyclic compounds. 

Tertiary aliphatic amines are also cleaved by HI, but useful products are seldom obtained. Tertiary amines can be cleaved by reaction with phenyl chloroformate R3N -h ClCOOPh —> RCl 4- R2NCOOPh. a-Chloroethyl chloroformate behaves similarly.Alkyl halides may be formed when quaternary ammonium salts are heated R4N+X" R3N -)- RX. ... 

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

Peroxidic groups in oxidized polyolefins have frequently been employed as sources of free radicals to allow grafting of vinyl monomers to polyolefins (2f[). Some of the products from the gas reactions also have interesting potential as reactive sites. For example, chloroformate groups are well known to react with alcohols, and amines 2J[). Thus chloroformate groups could be useful for example in coupling highly oriented polyolefin fibres to resins such as epoxy based systems. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

Figure 25.4 An SC derivative of mPEG was first prepared through the use of phosgene to form a chloroformate intermediate. Reaction with NHS gives the amine-reactive SC-mPEG.

The hydrochloric acid is removed by the strong tertiary base, methyldibutylamine, which has a soluble hydrochloride. In B.P. s 631,549 and 652,981 it was shown that compound (II) could be prepared by the action of dimethylamine on P0C13 in chloroform containing an excess of methylbutylamine. The further reaction with water is very conveniently carried out in the same system by adding an excess of aqueous sodium hydroxide solution. The chloroform layer contains the tertiary amine and (I). The solvent and amine are stripped off leaving the product. Side reactions take place, and the commercial product also contains some triphosphoric pentadimethylamide (I A) and smaller amounts of other phosphoric amides. The compound (I A) is itself also a valuable systemic insecticide. 

Isonitrile Reaction.—Like the primary aliphatic amines of the methylamine type, aniline and its analogues give a characteristic odour with chloroform and alkali. 

The SjvAr reactions with amines in chloroform show a peculiar behaviour and the rates cannot usually be correlated with reactions in other solvents. It has been observed in the reaction of 2,4-dinitrochlorobenzene with piperidine480 and in the reaction of 1,2-DNB with butylamine115 that chloroform exerts a special solvent effect due to its known hydrogen-bond donor ability. Thus, an association between the solvent and the nucleophile can be postulated as a side-reaction to the S Ar115. Associations of chloroform with amines are known122 and the assumption of a partial association between piperidine or butylamine and chloroform as the cause of the downward curvature in the plots of k vs [amine] seems plausible. 

Although the extraction of primary amines from a basic medium with chloroform is an inadvisable procedure, on account of the formation of trace amounts of the pungent isonitriles, the specific synthesis of isonitriles by the two-phase reaction of primary amines with chloroform is unreliable. However, the application of the phase-transfer technique [e.g. 1 -5] for the controlled release of dichlorocarbene facilitates the synthesis of isonitriles in relatively high yields (Table 7.12). 

Compared with primary and secondary amines, tertiary amines are virtually unreac-tive towards carbenes and it has been demonstrated that they behave as phase-transfer catalysts for the generation of dichlorocarbene from chloroform. For example, tri-n-butylamine and its hydrochloride salt have the same catalytic effect as tetra-n-butylammonium chloride in the generation of dichlorocarbene and its subsequent insertion into the C=C bond of cyclohexene [20]. However, tertiary amines are generally insufficiently basic to deprotonate chloroform and the presence of sodium hydroxide is normally required. The initial reaction of the tertiary amine with chloroform, therefore, appears to be the formation of the A -ylid. This species does not partition between the two phases and cannot be responsible for the insertion reaction of the carbene in the C=C bond. Instead, it has been proposed that it acts as a lipophilic base for the deprotonation of chloroform (Scheme 7.26) to form a dichloromethylammonium ion-pair, which transfers into the organic phase where it decomposes to produce the carbene [21]. 

Non-linear kinetics have been reported for aminolysis of sulfamate esters RNHSO2ONP (Np=/7-N02C6H4) in chloroform. The first-order rate constants obs for reaction with imidazoles (primarily) under pseudo-first-order conditions display saturation curvature with increasing amine concentration, according to the expression... 

There was no evidence of a second-order term in amine, nor did amine self-association account for the non-linear behaviour. Hammett p values (for variation of RNHSO2) determined for formation of the complex [S.amine] (p = 1.64) and for expulsion of the anion ( ONp) (pacyi = -1-78) are consistent with an E cB process and uncomplicated by any steric effects of bound amine in the complex. The value of Pacyi is identical with that reported previously for ElcB reaction of the same esters in 50% acetonitrile-water and much greater than for their 2-type reactions in chloroform. Consequently, an ElcB mechanism involving extensive S-O bond cleavage with the formation of a A(-sulfonylamine, ArN=S02, is supported. 

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