Quaternary ammonium conversion

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

Manufacture. For the commercial production of DPXN (di-/)-xylylene) (3), two principal synthetic routes have been used the direct pyrolysis of -xylene (4, X = Y = H) and the 1,6-Hofmaim elimination of ammonium (HNR3 ) from a quaternary ammonium hydroxide (4, X = H, Y = NR3 ). Most of the routes to DPX share a common strategy PX is generated at a controlled rate in a dilute medium, so that its conversion to dimer is favored over the conversion to polymer. The polymer by-product is of no value because it can neither be recycled nor processed into a commercially useful form. Its formation is minimised by careful attention to process engineering. The chemistry of the direct pyrolysis route is shown in equation 1 ... 

Analytical methods iaclude thin-layer chromatography (69), gas chromatography (70), and specific methods for determining amine oxides ia detergeats (71) and foods (72). Nuclear magnetic resonance (73—75) and mass spectrometry (76) have also been used. A frequentiy used procedure for iadustrial amine oxides (77) iavolves titratioa with hydrochloric acid before and after conversion of the amine to the quaternary ammonium salt by reaction with methyl iodide. A simple, rapid quaHty control procedure has been developed for the deterrniaation of amine oxide and unreacted tertiary amine (78). 

In the case of nicotinamide, the color yield is often low. This problem can be circumvented by either hydrolysis to nicotinic acid or by conversion of the amide to a fluorescent compound. Treatment of nicotinamide with methyl iodide yields the quaternary ammonium salt, /V-methyl nicotinamide (5). Reaction of this compound with acetophenone yields a fluorescent adduct (49). Other carbonyl compounds have also been used (50—54). 

Phase-tiansfei catalysis (PTC) is a technique by which leactions between substances located in diffeient phases aie biought about oi accelerated. Typically, one OI more of the reactants are organic Hquids or soHds dissolved in a nonpolar organic solvent and the coreactants are salts or alkah metal hydroxides in aqueous solution. Without a catalyst such reactions are often slow or do not occur at ah the phase-transfer catalyst, however, makes such conversions fast and efficient. Catalysts used most extensively are quaternary ammonium or phosphonium salts, and crown ethers and cryptates. Although isolated examples of PTC can be found in the early Hterature, it is only since the middle of the 1960s that the method has developed extensively. 

The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

Hofmann elimination (Section 22.14) Conversion of a quaternary ammonium hydroxide, especially an alkyltrimethyl-ammonium hydroxide, to an alkene on heating. Elimination occurs in the direction that gives the less substituted double bond. 

The preparation of an alkene 3 from an amine 1 by application of a /3-elimination reaction is an important method in organic chemistry. A common procedure is the Hofmann elimination where the amine is first converted into a quaternary ammonium salt by exhaustive methylation. Another route for the conversion of amines to alkenes is offered by the Cope elimination. 

Equation (1) shows the simple conversion of a quaternary ammonium anion exchange resin from the chloride form to the cyanate form. Equation (2) shows the reaction of the resin in the cyanate form with hydroxylamine hydrochloride whereby hydroxyurea is formed and the anion Cl is retained by the quaternary resin. 

Strongly basic anion exchangers (polystyrene quaternary ammonium resins). These resins (Duolite A113, Amberlite 400, etc.) are usually supplied in the chloride form. For conversion into the hydroxide form, treatment with 1M sodium hydroxide is employed, the volume used depending upon the extent of conversion desired two bed volumes are satisfactory for most purposes. The rinsing of the resin free from alkali should be done with de-ionised water free from carbon dioxide to avoid converting the resin into the carbonate form about 2 litres of such water will suffice for 100 g of resin. An increase in volume of about 20 per cent occurs in the conversion of the resin from the chloride to the hydroxide form. 

Polk et al. reported27 that PET fibers could be hydrolyzed with 5% aqueous sodium hydroxide at 80°C in the presence of trioctylmethylammonium bromide in 60 min to obtain terephthalic acid in 93% yield. The results of catalytic depolymerization of PET without agitation are listed in Table 10.1. The results of catalytic depolymerization of PET with agitation are listed in Table 10.2. As expected, agitation shortened the time required for 100% conversion. Results (Table 10.1) for the quaternary salts with a halide counterion were promising. Phenyltrimethylammonium chloride (PTMAC) was chosen to ascertain whether steric effects would hinder catalytic activity. Bulky alkyl groups of the quaternary ammonium compounds were expected to hinder close approach of the catalyst to the somewhat hidden carbonyl groups of the fiber structure. The results indicate that steric hindrance is not a problem for PET hydrolysis under this set of conditions since the depolymerization results were substantially lower for PTMAC than for die more sterically hindered quaternary salts. 

Quaternary ammonium compounds (quats) are prepared - by moderate heating of the amine and the alkyl halide in a suitable solvent - as the chlorides or the bromides. Subsequently conversion to the hydroxides may be carried out. Major applications of the quat chlorides are as fabric softeners and as starch cationizing agent. Several bio-active compounds (agrochemicals, pharmaceuticals) possess the quat-structure. Important applications of quat bromides are in phase transfer catalysis and in zeolite synthesis. 

Syn elimination and the syn-anti dichotomy have also been found in open-chain systems, though to a lesser extent than in medium-ring compounds. For example, in the conversion of 3-hexyl-4-d-trimethylammonium ion to 3-hexene with potassium ec-butoxide, 67% of the reaction followed the syn-anti dichotomy. In general syn elimination in open-chain systems is only important in cases where certain types of steric effect are present. One such type is compounds in which substituents are found on both the P and the y carbons (the unprimed letter refers to the branch in which the elimination takes place). The factors that cause these results are not completely understood, but the following conformational effects have been proposed as a partial explanation. The two anti- and two syn-periplanar conformations are, for a quaternary ammonium salt ... 

In order to imderstand the effects of the cation structure in the transesterification between methanol and EC, quaternary ammonium chloride catalysts of different alkyl cations such as TPAC, TBAC, THAC, TOAC, and TDodAC were used at 140 C. Table 1 shows EC conversions after 1 h... 

In the synthesis of DMC fiom the transesterification of EC and methanol, quaternary ammonium salt catalysts showed good catalytic activity. The main byproduct was ethylene glycol. The quaternary salt with the cation of bulkier alkyl chain laigth and witii more nucleophilic anion showed better reactivity. Hi temperature and large amount of catalyst increased the conversion of EC. The EC conversion and DMC selectivity increased as the pressure of CO2 increased from 250 to 350 psig. 

Typically, Cl Basic Red 24 (4-97) has a structure reminiscent of a disperse dye, except that a quaternary ammonium group is carried on the pendant alkyl chain in the coupling component. This coupling component is prepared by reaction of N-ethylaniline with ethylene oxide followed by conversion of the resulting P-hydroxyethyl derivative into the p-... 

The conversion of acyl chlorides, sulphonyl chlorides and phosphoryl chlorides into the corresponding fluorides using potassium fluoride in the presence of a quaternary ammonium salt has been recorded [44-47]. Optimum yields are obtained when the dry potassium fluoride contains ca. 1% water. 

There are relatively few reports of phase-transfer catalysed syntheses of phenols from activated haloarenes using quaternary ammonium salts, presumably because of the instability of the ammonium salts under the reaction conditions. A patented procedure for the conversion of, for example, 2,6-dichloropyridine into 6-chloropyrid-2-one (98%) using aqueous sodium hydroxide in the presence of benzyl-triethylammonium chloride at 120-150°C has been filed [32], A possible route to the phenols, however, comes from the observed reaction of phenols with potassium carbonateipotassium hydrogen carbonate to yield the aryl carbonates (80-85%) using the procedure described for the preparation of dialkyl carbonates (3.3.13) [50]. 

As an alternative to radical chlorination, use has been made of carbon tetrachloride and hexachloroethane in the presence of a quaternary ammonium salt, as source of the chloronium ion for reaction with activated alkylbenzenes [38], Benzyl chlorides need the additional activation of a nitro group for their conversion into the corresponding nitrobenzotrichlorides, whereas benzal chlorides do not need the extra activation for a similar conversion. The same synthetic protocol, using hexachloroethane, has been used for the conversion of allylic sulphones into the 1,1-dichloro derivatives [39],... 

The standard conversion of alcohols into their xanthate esters through reaction with carbon disulphide and an alkylating agent is improved by the addition of a quaternary ammonium salt [69]. Excellent yields (>90%) are obtained in relatively short reaction times under mild conditions. The formation over relatively short reaction times of O-glycosyl xanthates from partly protected glycosides has been described using a stoichiometric amount of the quaternary ammonium salt [70]. 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

Arylamines and hydrazines react with tosyl azide under basic conditions to yield aryl azides [1] and arenes [2], respectively, by an aza-transfer process (Scheme 5.25). Traditionally, the reaction of anilines with tosyl azides requires strong bases, such as alkyl lithiums, but acceptable yields (>50%) have been obtained under liquidiliquid phase-transfer catalytic conditions. Not surprisingly, the best yields are obtained when the aryl ring is substituted by an electron-withdrawing substituent, and the yields for the corresponding reaction with aliphatic amines are generally poor (-20%). Comparison of the catalytic effect of various quaternary ammonium salts showed that tetra-/i-butylammonium bromide produces the best conversion, but differences between the various catalysts were minimal [ 1 ]. 

The simplest C-C bond formation reaction is the nucleophilic displacement of a halide ion from a haloalkane by the cyanide ion. This was one of the first reactions for which the kinetics under phase-transfer catalysed conditions was investigated and patented [l-3] and is widely used [e.g. 4-12], The reaction has been the subject of a large number of patents and it is frequently used as a standard reaction for the assessment of the effectiveness of the catalyst. Although the majority of reactions are conducted under liquiddiquid two-phase conditions, it has also been conducted under solidrliquid two-phase conditions [13] but, as with many other reactions carried out under such conditions, a trace of water is necessary for optimum success. Triphase catalysis [14] and use of the preformed quaternary ammonium cyanide [e.g. 15] have also been applied to the conversion of haloalkanes into the corresponding nitriles. Polymer-bound chloroalkanes react with sodium cyanide and cyanoalkanes under phase-transfer catalytic conditions [16],... 

One-pot conversions of 2-hydroxy(acylbenzenes) with anhydrides or acid chlorides to produce coumarins [52-54] and flavones [54-58] under mild liquiddiquid or solidtliquid two-phase conditions via a Baker-Venkataraman type reaction (Scheme 6.19) are catalysed by quaternary ammonium salts. 3-Substituted coumarins are produced from salicylaldehyde and malonodinitrile, or substituted acetonitriles, in high yield (>85%) in a one-pot catalysed sequential aldol-type reaction and cycliza-tion in the absence of an added organic solvent [59]. When 2 -hydroxychalcones are reduced under catalytic two-phase conditions with sodium borohydride, 2,4-cis-flavan-4-ols are produced [60] (see Section 11.3). 

The dehydrohalogenation of 1- or 2-haloalkanes, in particular of l-bromo-2-phenylethane, has been studied in considerable detail [1-9]. Less active haloalkanes react only in the presence of specific quaternary ammonium salts and frequently require stoichiometric amounts of the catalyst, particularly when Triton B is used [ 1, 2]. Elimination follows zero order kinetics [7] and can take place in the absence of base, for example, styrene, equivalent in concentration to that of the added catalyst, is obtained when 1-bromo-2-phenylethane is heated at 100°C with tetra-n-butyl-ammonium bromide [8], The reaction is reversible and 1-bromo-l-phenylethane is detected at 145°C [8]. From this evidence it is postulated that the elimination follows a reverse transfer mechanism (see Chapter 1) [5]. The liquidrliquid two-phase p-elimination from 1-bromo-2-phenylethanes is low yielding and extremely slow, compared with the PEG-catalysed reaction [4]. In contrast, solid potassium hydroxide and tetra-n-butylammonium bromide in f-butanol effects a 73% conversion in 24 hours or, in the absence of a solvent, over 4 hours [3] extended reaction times lead to polymerization of the resulting styrene. 

In an interesting catalysed conversion of trichloroethene by secondary amines into aminoacetamides, the initial steps are thought to involve the p-elimination of HC1 to produce dichloroethyne (Scheme 9.1), which reacts with the secondary amine under the wet conditions to produce the amide [35] the reaction does not work with N-alkylanilines. Such a mechanism is realistic, as it is well known [36] that trichloroethene is converted into the inflammable and explosive dichloroethyne by bases, and quaternary ammonium salts catalyse the formation of the alkyne when trichloroethene is reacted with oxiranes [37]. Chloroethynes have also been obtained by the catalysed reaction of terminal ethynes with carbon tetrachloride under basic conditions [38]. 

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