Pyridinolysis of Aryl N,N-Dimethyl Phosphoroamidochloridates

Results and Discussion

Tables 1-3 list the second-order rate constants, ρX and βX with X, and ρY with Y, respectively. The effects of substituents X and Y in the incoming pyridine and leaving group on reactivity, respectively, are in line with those for a typical nucleophilic substitution reaction. The Brönsted [Fig. 1; log k2 vs pKa(X)] and Hammett (Fig. S1; log k2 vs σX) plots for substituent X variations in the nucleophiles, however, exhibit biphasic concave upwards with a break point at X = 3-Ph, while the Hammett plots (Fig. S2; log k2 vs σY) for substituent Y variations in the substrates exhibit linear. The magnitudes of the βX and ρX values with a-block (X = 4-MeO, 4-Me, 3-Me, H, 3-Ph) are 5-6 times greater than those with b-block (X = 3-Ph, 3-Ac, 4-Ac), suggesting greater degree of bond formation with a-block than with b-block. The ρX values consistently decrease (or more negative value; ∂ρX < 0) as the substituent Y becomes more electronwithdrawing (∂σY > 0), giving ∂ρX/∂σY = (–)/(+) < 0 for both a- and b-block, while the ρY values invariably decrease (or less positive value; ∂ρY < 0) as the pyridine becomes less basic (∂σX > 0), giving ∂ρY/∂σX = (–)/(+) < 0 for both a- and b-block.

Table 1.Second-Order Rate Constants (k2 × 104/M–1 s–1) of Reactions of 1 with X-Pyridines in MeCN at 35.0 ℃

Table 2.aCorrelation coefficients (r) are better than 0.998. br = 0.999

Table 3.ar = 0.945-0.991

Figure 1.Brönsted plots with X of reactions of 1 with X-pyridines in MeCN at 35.0 ℃.

Figure 2.Plots of ρY vs σX and ρX vs σY of the reactions of 1 with X-pyridines in MeCN at 35.0 ℃. The obtained ρXY values by multiple regression are: (a) ρXY = –1.15 ± 0.05 (r = 0.996) with a-block; (b) ρXY = –0.13 ± 0.01 (r = 0.998) with b-block.

The pyridinolysis rate is faster than the anilinolysis rate, e.g., kPyr/kAn = (16.8 × 10–4)/(1.10 × 10–4) = 15.3 when X = Y = H in MeCN at 55.0 ℃.2 This is in accord with the basicity (or nucleophilicity) of the nucleophiles: pKa(Pyr) = 12.33 and pKa(An) = 10.56 in MeCN;3 pKa(Pyr) = 5.17 and pKa(An) = 4.58 in water.4

Figure 2 shows the two ρXY values with a- and b-block, respectively, because the Hammett plots with X are biphasic. The cross-interaction constants (CICs; ρXY) are obtained according to the definition: log (kXY/kHH) = ρXσX + ρYσY + ρXYσXσY and ρXY = ∂2log (kXY/kHH)/∂σX∂σY = ∂ρX/∂σY = ∂ρY/∂σX.5 The sign of ρXY is negative for both a- (ρXY = −1.15) and b-block (ρXY = −0.13).6 A concerted mechanism is proposed for both a- and b-block despite the biphasic concave upward free energy correlations for substituent X variations, because ρXY has a negative value in a concerted SN2 (or a stepwise mechanism with a rate-limiting bond formation) while a positive value in a stepwise mechanism with a rate-limiting leaving group expulsion from the intermediate.5 The anilinolysis of 1 proceeds via a stepwise process with a rate-limiting leaving group departure from the intermediate,1 whereas the pyridinolysis of 1 proceeds via SN2. This is not consistent with the general suggestion in which the concerted path becomes more likely to be followed with the weaker nucleophile while a stepwise path is favored with the stronger nucleophile.7,8

Bipasic concave upward free energy correlations with X can be substantiated by a change in the nucleophilic attacking direction towards the chlorde leaving group. A weakly basic group has a greater apicophilicity so that apical approach is favored for such nucleophiles.8 The apical nucleophilic attack should lead to a looser P−N bond in the TBP- 5C structure because the apical bonds are longer than the equatorial bonds. Thus, greater magnitudes of the βX (= 1.12- 1.27) values with a-block involving equatorial nucleophilic attack (e.g., frontside attack TSf in Scheme 2) are obtained compared to those (βX = 0.19-0.21) with b-block involving apical nucleophilic attack (e.g., backside attack TSb in Scheme 2). The magnitudes of the ρXY (= –1.15 and –0.13 with a- and b-block, respectively) values are consistent with the βX (= 0.12-1.27 and 0.19-0.21 with a- and b-block, respectively) values because the magnitude of the ρXY value is inversely proportional to the distance between X and Y through the reaction center.5

Scheme 2.Backside apical attack TSb with b-block and frontside equatorial attack TSf with a-block.

In general, the nonlinear free energy correlation of a concave upward plot is diagnostic of a change in the reaction mechanism where the reaction path is changed depending on the substituents, while nonlinear free energy correlation of the concave downward plot is diagnostic of a rate-limiting step change from bond breaking with the weakly basic nucleophiles to bond formation with the strongly basic nucleophiles. 9 It is the suggestion of the authors that the biphasic concave upward free energy correlation is also diagnostic of a change in the direction of the nucleophilic attack towards the leaving group from frontside equatorial with the strongly basic nucleophiles (a-block) to backside apical with the weakly basic nucleophiles (b-block).10

Table 4 lists the activation parameters, enthalpies and entropies of activation. The enthalpies of activation are relatively low (ca. 6 kcal mol–1) and entropies of activation are relatively large negative value (ca. –50 cal mol–1 K–1). There is no activation enthalpy-entropy compensation phenomena depending on the substituent Y in the substrates.11 The relatively low value of activation enthalpy and large negative value of activation entropy are typical for the aminolyses of P=O (and P=S) systems regardless of the mechanism, either concerted (or stepwise with a rate-limiting bond formation) or stepwise with a rate-limiting bond cleavage.12

Table 4.Activation parameters for the reactions of 1 with C5H5N in MeCN

In summary, the nucleophilic substitution reactions of Yaryl N,N-dimethyl phosphoroamidochloridates with X-pyridines are studied kinetically in acetonitrile at 35.0 ℃. The free energy correlations for substituent X variations in the nucleophiles exhibit biphasic concave upwards with a break point at X = 3-Ph. The negative sign of ρXY suggests that the reaction proceeds through a concerted mechanism for both a- (X = 4-MeO, 4-Me, 3-Me, H, 3-Ph) and b-block (X = 3- Ph, 3-Ac, 4-Ac). The biphasic concave upward free energy relationships with X are rationalized by a change in the nucleophilic attacking direction from frontside with a-block to backside with b-block.

 

Experimental Section

Materials. The substrates of Y-aryl N,N-dimethyl phosphoroamidochloridates were prepared as described previously. 1

Kinetic Procedure. The second-order rate constants and selectivity parameters were obtained as reported earlier.12b The initial concentrations are as follows: [substrate] = 5 × 10−3 M and [XC5H4N] = (0.10-0.30) M.

Product Analysis. Phenyl N,N-dimethyl phosphoroamidochloridate was reacted with excess pyridine, for more than 15 half-lives at 35.0 ℃ in MeCN. Solvent was removed under reduced pressure. The product was isolated by adding ether and insoluble fraction was collected. The product was purified to remove excess pyridine by washing several times with ether and MeCN. Analytical and spectroscopic data of the product gave the following results (supporting information):

[(Me2N)(PhO)P(=O)NC5H5]+Cl–. White gummy solid; 1H-NMR (400 MHz, MeCN-d3) δ 2.47-2.72 (d, 6H), 6.98- 7.00 (t, 1H), 7.16-7.21 (d, 3H), 7.35-7.37 (t, 1H), 7.84-7.88 (t, 2H), 8.35-8.38 (t, 1H), 8.67-8.69 (d, 2H); 13C-NMR (100 MHz, MeCN-d3) δ 35.0, 36.9, 121.2, 121.6, 124.8, 126.4, 127.9, 130.5, 131.0, 143.0, 143.1, 146.1, 153.6; 31P-NMR (162 MHz, MeCN-d3) δ −5.55 (1P, s, P=O); LC-MS for C13H16ClN2O2P (EI, m/z), 298 (M+).