Acyl ammonium salts

Additional work was carried out by the GE group on optimization of the reaction yield and to eliminate unwanted linear oligomers [14], Three side reactions which interfere with synthesis of cyclics were identified reaction of the amine with acid chloride to form an acyl ammonium salt, followed by decomposition to an amide (Equation (3.2)) reaction with CH2CI2 to form a salt (Equation (3.3)) hydrolysis of the acid chloride, forming carboxylate via catalysis... 

If the amine acts as an acylation catalyst, the potential exists for an unwanted side reaction to occur. It is well known that under anhydrous conditions acyl ammonium salts derived from the reaction of a chloroformate and a tertiary amine can decompose to form urethanes. We have recently reported a rate constant (1.3 0.2 min ) for the case involving triethylamine and phenyl chloroformate in methylene chloride at 39°C (see Scheme 4). Formation of urethanes in this manner under normal interfacial conditions to form high MW polymer would have minimal effects on the properties of the polymer and may not even be observed. However, urethane formation in the cyclization reaction would produce a capped oligomer which cannot cyclize, therefore leading only to polymer. In this manner, a fraction of the amine used in the reaction could produce a significant level of unwanted high MW polymer. Evidence for the formation of urethanes during the preparation of cyclics will be presented later in this paper. 

The reaction of a chloroformate with a tertiary amine to form an acyl ammonium salt is potentially a reversible reaction (see Equation 1).10... 

If so, an equilibrium mixture of the acyl ammonium salt and the starting materials would exist, and the relative proportions in solution would depend on the concentration of the... 

The other amines listed in Table 1 also displayed unique resonances in the NMR. Although no acyl ammonium salt was observed for the very hindered N-ethyl diisopropylamine (entry 12), peak broadening of the methylene protons and the methine protons was again observed. The sterically unhindered amine, MeNEt2, reacts completely with phenyl chloroformate to form the acyl ammonium salt, and produces two nonequivalent sets of methylenes (multiplets at 4.98 ppm and 4.11 ppm) indicative of a single conformational isomer, unlike the triethylamine case. 

Use of these various amines in cyclization reactions produced results which correlated well with the NMR data. The extremely sterically hindered N-ethyl diisopropylamine, which produced no acyl ammonium salt by NMR, left the chloroformate virtually unreacted under standard cyclization reaction conditions. Although tributylamine does form acyl ammonium salts, it has an equilibrium constant nearly an order of magnitude lower than triethylamine when compared at the same temperatures (Table 1, entries 7 and 4). This amine produced cyclics, but required much higher catalyst loadings, similar to tripropylamine which was aphically represented in Figure 1. The equilibrium constant for N-ethylpiperidine was twice the value for triethylamine at similar temperatures (Table 1, entries 8 and 4), and affords an optimum yield of cyclics at half the amine concentration required for triethylamine. 

Having established the necessary existence of an acyl ammonium salt intermediate for hydrolysis reactions and its likely existence for condensation reactions, and also the premise that the ratio of hydrolysis to condensation will control the relative proportions of cyclic and linear oligomers, the working model for cyclics formation under pseudo high... 

The rates and/or equilibria in each step which control the concentration of each reactant must be properly balanced to ensure that none of the intermediates increase in concentration during the reaction. Since the concentration of the incoming BPA-6/y-chloroformate or an oligomeric bischloroformate present in the reaction mixture must remain very low, the conversion of the chloroformate to an acyl ammonium salt must be very fast. Maintenance of a low level of chloroformate A will require a sufficiently high concentration of triethylamine to ensure that the chloroformate A is consumed very quickly. 

However, care must be taken not to produce high levels of the ftw-acyl ammonium salt B which may lead to extensive hydrolysis. 

A notable exception to the behavior of the pyridine class was seen in the case of DMAP. Unlike other pyridyl amines, DMAP behaved similarly to triethylamine producing a good yield of cyclics (65-75%) with exclusion of low MW linears. These results suggested that both acyl ammonium salt formation and differentiation between water/hydroxide and phenoxide of the acyl ammonium salt were better than with pyridine. It was clear from the NMR that an acyl ammonium salt formed readily with DMAP (Table 1, entry 11). This acyl ammonium salt would have a less electropositive carbonyl carbon due to donation of electrons from the p-dimethylamino moiety. A more stable acyl ammonium salt would be less susceptible to nucleophilic attack and should differentiate between nucleophiles better. 

Why does the amino alcohol not react with the acyl hahde at nitrogen in the last step After aU, amines are more nucleophilic than alcohols. The answer is It does, but because the amine function is tertiary, it can only form an acyl ammonium salt. This function has reactivity similar to that of an acyl chloride. Thus, attack by the hydroxy group on the acyl ammonium carbonyl carbon wins out thermodynamically to give the ester in the end (Section 20-2). 

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