Benzhydryl ethers, hydrolysis

Ethers are stable toward hydrolysis, yet are hydrolyzed under severe conditions of acidity and temperature. Furthermore, the presence of certain moieties can decrease the high stability of ethers. In the case of aminoalkyl benzhydryl ethers of the general structure (aryl)2CH-0-(CH2)n-NRR, the decrease in stability becomes marked enough to be of pharmaceutical and even pharmacological relevance. This structural motif is a component of various drugs, including some well-known antihistamines and anticholinergics, e.g., diphenhydramine, orphenadrine, and chlorphenoxamine. 

Fig. 11.2. Mechanism of proton-catalyzed, hydrolysis of aminoalkyl benzhydryl ethers 11.24, e.g., diphenhydramine (R = R = H), orphenadrine (R = 2-Me, R = H), and chlorphenoxamine...

A. M. de Roos, R. F. Rekker, W. T. Nauta, Investigation into the Stabihty of the Ether Bond in a Series of Benzhydryl Ethers. I. The Rate of Hydrolysis of Substituted Dimeth-ylaminoethylbenhydryl Ethers , Arzneim.-Forsch. 1963, 13, 534 - 537 A. M. de Roos, R. F. Rekker, W. T. Nauta, Investigation into the Stabihty of the Ether Bond in a Series of Benzhydryl Ethers. VI. The Rate of Hydrolysis in an Extended Series of Substituted 2-(Diphenylmethoxy)-V,A-Dimethylethylamines , Arzneim.-Forsch. 1971,21, 818 - 820. 

The hydrolysis of diphenhydramine and analogues (11.24, Fig. 11.2) has been studied extensively [46 - 48], These compounds are essentially inert toward base-catalyzed hydrolysis, but do undergo proton-catalyzed hydrolysis, the mechanism of which is shown in Fig. 11.2. The reaction begins with protonation of the ether O-atom and continues with the irreversible heterolytic cleavage of the C-0 bond to produce the benzhydryl cation. This reaction is greatly facilitated by the weakening effect of the benzhydryl moiety on the adjacent C-0 bond. The benzhydryl cation itself is stabilized by resonance, which also explains why the reaction is facilitated. The last step is the for-... 

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