Phenylethyl derivatives

New derivatives and analogues of cyclophosphamide (35 R = H) have been reported80 and the diastereoisomeric jY-l-phenylethyl derivatives (35 ... 

In retrospect, it should have been clear to me - as I am sure it was to Bill Jencks -that the rate and equilibrium constants for addition of solvent to 1-phenylethyl carbocation intermediates of solvolysis of 1-phenylethyl derivatives would serve as the first step in the characterization of the dynamics of the reactions of their ion pair intermediates. Therefore, this earlier work has served as a point of departure for our experiments to determine relative and absolute barriers to the reactions of ion pair intermediates of solvolysis. 

We have examined the competing isomerization and solvolysis reactions of 1-4-(methylphenyl)ethyl pentafluorobenzoate with two goals in mind (1) We wanted to use the increased sensitivity of modern analytical methods to extend oxygen-18 scrambling studies to mostly aqueous solutions, where we have obtained extensive data for nucleophilic substitution reactions of 1-phenylethyl derivatives. (2) We were interested in comparing the first-order rate constant for internal return of a carbocation-carboxylate anion pair with the corresponding second-order rate constant for the bimolecular combination of the same carbocation with a carboxylate anion, in order to examine the effect of aqueous solvation of free carboxylate anions on their reactivity toward addition to carbocations. 

Figure 2.2. The change with changing aromatic ring substituent X in the azide (az) ion selectivities (feaz/ s)obsd ( ) determined by analysis of the products of the reactions of ring-substituted 1-phenylethyl derivatives (X-l-Y) and ring-substituted cumyl derivatives (X-2-Y) in 50/50 (v/v) water/trifluoroethanol at 25 The selectivities are plotted...

Figure 2.5. Nucleophile selectivities determined from product analysis for the reactions of ring-suhstituted 1-phenylethyl derivatives (X-l-Y) with azide ion, acetate ion and methanol in 50 50 (v/v) water/trifluoroethanol. The selectivities are plotted against the appropriate Hammett substituent constant or a. Leaving group Y ( ) ring-suhstituted benzoates ( ) chloride (T) dimethyl sulfide (A) tosylate.

We have assumed that the values of Kas for formation weak encounter complexes between nucleophile and substrate, and between nucleophile and carbocation are similar. This is supported by the observation of similar values of Kas [see above] for formation of encounter complexes between neutral substrate and anionic nucleophile (0.7 M-1),2 between cationic substrate and anionic nucleophile (0.2 M 1),27 and between neutral substrate and neutral nucleophile (0.3 M-1).20 We use the value of k-d= 1.6 X 10los-1 that can be calculated from Xas = 0.3 M-1 formation of encounter complexes with 1-phenylethyl derivatives and kA = 5 X 109 M-1 s-1 (equation (2)).20 The uncertainty in this value for fc d is approximately equal to the range of experimental values for Xas (0.2-0.7 m 1) 2-20-27... 

For the recombination of a-phenylethyl cations with strong nucleophiles, Richard and Jencks (1984a,b,c) obtained good Y-T correlations with the same r value of 1.15 as observed for the solvolysis (Fig. 35). The p value of -2.7 for the bimolecular substitution reaction of azide ion with 1-phenylethyl derivatives is significantly more positive than the value of p = -5.7 for the solvolysis reaction. This shows that there is a smaller development of positive charge in the transition state for the reaction of azide ion than for solvolysis. It is consistent with a coupled concerted reaction with a transition state in which positive charge development at the benzylic carbon is neutralized by bonding to azide ion. 

Kaldor, S. B. Saunders, W. H., Jr. 1979 J. Am. Chem. Soc. 101, 7594-7599 Mechanisms of eleimination reactions 30. The contributions of tunneling and heavy-atom motions in the reaction coordinate to deuterium kinetic isotope effects in eliminations from 2-phenylethyl derivatives. 

It may be noted that pyrolysis of isoindoline (V-oxides may also furnish isoindoles,32 although in general this is a less useful preparative route since other reactions (deoxygenation, Cope elimination of the 2-substituent) may intervene,6 as shown for the 2-(/J-phenylethyl) derivative in Scheme 2. 

COMPARISON OF THE RATE COEFFICIENTS FOR ELIMINATION FROM SOME 2-PHENYLETHYL DERIVATIVES IN HjO TO DjO CONTAINING THEIR RESPECTIVE LYATE IONS AT 80.45°C ... 

Reduction of the benzylic carbonyl group of desfluoro-ketanserin decreases the affinity for S-HTjy receptors 100 times [11] (Table 4). The N-ethyl substituted analogue even lost all affinity. However contrary to the expectations high affinity is maintained in the phenylethyl derivatives [12] (Table 4). 

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