Kinetics of the reduction of the tropylium and xanthylium cations by 1,4-dihydropyridine derivatives

JOHN W. BUNTING AND M. MORGAN CONN Department of Chemistry, University of Toronto, Toronto, Ont., Canada M5S 1Al

Received June 14. 1989

JOHN W. BUNTING and M. MORGAN CONN. Can. J. Chern. 68, 537 (1990). The pH-dependences of the apparent second-order rate constants (k2PP) for the reduction of 2,4,6-cycloheptatrien-1-01 and

9-xanthydrol by each of 1-benzyl-1,4-dihydronicotinamide (BNH) and 10-methyl-9,lO-dihydroacridine (MAH) have been measured in 20% acetonitrile - 80% water, at 25OC and ionic strength 1.0. For each of these reactions, the pH-dependence of kyp is only consistent with reduction occurring via the aromatic cation (either tropyliurn or xanthylium) that is present in equilibrium with these alcoholic species. The relative second-order rate constants (k2BNH/kYAH) for reductions by these two reducing agents (1700 for tropylium and 770 for xanthyliurn) are similar for these two cations. These ratios are also similar to those observed for a variety of nitrogen heteroarornatic hydride acceptors, even though the absolute magnitudes of these rate constants vary by 10''-fold. The second-order rate constants for the reductions of the tropyliurn and xanthyliurn cations are predicted reasonably well by their pKR+ values, with the latter cation being (7 x lo5)-fold more reactive than its T-isoelectronic N-methyl acridiniurn cation. The xanthyliurn cation has the greatest k!NH/koH ratio yet observed for any heteroarornatic cation, and this value further extends the known range of this ratio as a function of reactivity.

Key words: hydride transfer, kinetics of reduction, 1,4-dihydropyridine derivatives, tropyliurn cation, xanthyliurn cation.

JOHN W. BUNTING et M. MORGAN CONN. Can. J. Chem. 68, 537 (1990). Operant h 25°C et a une force ionique de 1,0, dans des solutions contenant 20% d'acetonitrile et 80% d'eau, on a mesure

la relation qui existe entre le pH et les constantes apparentes de vitesse du deuxikrne ordre (kyp) pour la reduction du cyclohepta-2,4,6-trikn- 1-01 et du xanthydr-9-01 soit par le I-benzyl-l,4-dihydronicotinamide (BNH) ou par la 10-methyl-9,10- dihydroacridine (MAH). Pour chacune de ces reactions, la relation entre le pH et le kyP ne correspond qu'h celle attendue pour une reduction se produisant par le biais d'un cation aromatique (soit tropyliurn ou xanthylium) qui est present l'equilibre dans ces espkces alcooliques. Les constantes relatives des vitesses de reaction du second ordre (k2BNH/kyAH) pour les reductions par ces deux agents riducteurs (1700 pour le tropyliurn et 770 pour le xanthyliurn) sont sernblables pour ces deux cations. MCme si les valeurs absolues de ces constantes de vitesse varient par des facteurs allant jusqu'h 101°, ces rapports sont aussi similaires h ceux observes pour un grand nornbre de derives hCtCroaromatiques azotks accepteurs d'hydrure. Utilisant les valeurs des pKR+ des cations, on peut aussi predire assez correcternent les constantes de vitesse du deuxikrne ordre pour les reductions des cations tropyliurn et xanthylium; ce dernier cation est environ 7 X lo5 fois plus rkactif que le cation N-methyl acridinium qui lui est T-isoelectronique. La valeur du rapport k!NH/koH du cation xanthyliurn est la plus ClevCe avoir CtC observee jusqu'h rnaintenant et cette valeur Clargit la plage connue de ce rapport en fonction de la rkactivitk.

Mots cle's : transfert d'hydrure, cinetique de la reduction, derives 1,4-dihydropyridines, cation tropyliurn, cation xanthyliurn. [Traduit par la revue]

Kinetic studies of the hydride transfer reaction described the rates of reduction of the tropylium (1) and xanthylium (2) by eq. [ l ] are currently under active investigation in many cations by both 1-benzyl-l,4-dihydronicotinamide (3 = BNH) laboratories ( 1-1 0). This reaction formally involves hydride and 10-methyl-9,lO-dihydroacridine (4 = MAH) . transfer from a donor (DH) to an acceptor (A+), and can be considered a hydride transfer between two heteroaromatic cations, when a dihydropyridine derivative (DH) is used to reduce a nitrogen heteroaromatic cation (A+).

@ 1 2

[ l ] A + + D H + A H + D +

Reactions of this type originally attracted interest as mechan- istic probes of the chemistry of enzymic reactions employing the nicotinamide coenzyme redox couple (NAD(P)H-NAD(P)+) (1 1, 12). More recently, rate-equilibrium correlations of such reactions have been vigorously explored in connection with the application of Marcus theory to the hydride transfer process (1, 13-15). There is now a significant body of literature relating to the reduction of a variety of pyridinium, quinolinium, isoquinolinium, acridinium, and phenanthridinium cations (2). Various 1,2- and 1,4-dihydropyridine derivatives have been used as the hydride donor species, with 1 ,Cdihydronicotin- amides and 9,lO-dihydroacridines being the most commonly investigated hydride donors. We felt that a significant addition to this area would be provided by a quantitative investigation of the rates of reduction of a wider variety of cationic acceptor species (A+) than has been the case up until now. As an initial effort towards such an extension, we have chosen to measure

Several considerations were involved in the choice of these two cations. Firstly, we wished-to include aromatic cations other than the nitrogen heteroaromatic species that have been predominantly investigated to date. Secondly, we required cations for which the second-order rate constants for hydroxide ion attack were available (16, 17), since we wished to continue our comparisons (18) of the rates of reduction with the rates of reaction with hydroxide ion as a standard nucleophile. Thirdly, we wished to choose cations that might be expected to be more reactive than the cations investigated to date. Because the tropylium (16) and xanthylium (19) cations have pKR+ values

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538 CAN. I. CHEM. v 'OL. 68, 1990

considerably lower than any of the nitrogen heterocyclic cations previously studied, they should fulfill this third criterion since linear free energy relationships between the second-order rate constant for reduction and pKR+ have been established for other series of cations (18, 20, 21). Fourthly, the xanthylium cation is an attractive acceptor, since it is T-isoelectronic with the acridinium cations that have been the subjects of numerous investigations in this area.

The choice of 1 -benzyl- 1,4-dihydronicotinamide and 10- methyl-9,lO-dihydroacridine as hydride donors was based upon our earlier observations (2) of an approximately constant relative reactivity for these two donors towards several acceptor cations. We wished to explore whether this relative reactivity would also be applicable to two quite different cationic acceptors chosen according to the criteria indicated above.

Experimental Materials

Tropylium tetrafluoroborate and 9-hydroxyxanthene (9-xanthydrol) were both obtained from Aldrich Chemical Co. They were recrystallized from ethanol and aqueous ethanol, respectively, and characterized by 'H NMR spectroscopy. The tropylium salt displayed a clean singlet 6 9.34 (in CF3C02H relative to (CH3),Si), and 9-hydroxyxanthene showed 6 2.25 (br s, OH), 5.68 (s, lH), 6.90-7.60 (m, 8H) (in CDC13). I -Benzyl- l,4-dihydronicotinamide and 10-methyl-9,lO- dihydroacridine were synthesized as previously reported (2, 22). All compounds were stored in dark bottles in a vacuum desiccator over Drierite. Potassium chloride, potassium hydroxide, and all buffer species (CH2C1C02H/KOH (pH = 2.5-3.7), CH3C02H/KOH (pH = 4.0-53, NaH2PO4/Na2HPO4 (pH = 6.2-7.2), and (HOCH2)3CNH2/ HC1 (pH = 7.7-8.7)) were the best commercially available grades. Acetonitrile was spectroscopic grade.

Kinetic studies All rate data were obtained in buffered aqueous solutions containing

20% or 30% acetonitrile (v/v) (see below), at 25°C and ionic strength 1.0 (KC1). Stock solutions of reagents for kinetic studies were kept in the dark when not in use and discarded after a maximum of 48 h. Care was taken to ensure that complete solubility of the reactants and products was maintained before and during all kinetic runs. Solubility limitations were the major consideration in defining the highest accessible concentration of the excess component in each reaction system. The reaction between 2 and 3 proved to be incompatible with 20% acetonitrile containing phosphate buffer, although solubility was maintained under these conditions in 30% acetonitrile. The choice of specific experimental conditions was sometimes influenced by the occurrence of slow reactions of one or more of the individual components. In all cases, conditions were chosen so that such background reactions occurred at less than 1% of the rate of the reduction under investigation.

All reactions were followed spectrophotometrically under pseudo- first-order conditions with 17- to 200-fold excesses of the acceptor species over the hydride donors ([BNH] = 0.04 mM and [MAH] = 0.02 mM). Most reactions were followed on a Varian Cary 210 spectrophotometer, with digitized absorbance data being recorded on a Commodore 4048 computer. Occasional runs were also followed on a Unicam SP- 1800 spectrophotometer equipped with a Unicam AR-25 linear recorder. Data were collected for at least 95% of each reaction, with the exception of some very slow reactions between 2 and 3 in which data were only obtained over the first 75% of the reaction. The pH was measured at the end of each kinetic run on a Radiometer PHM82 pH meter equipped with a GK2401B combination electrode.

Pseudo-first-order rate constants were calculated by fitting the absorbance ( A ) at time ( t ) to the relationship:

A = Af + (Ai - Af) exp (-kobSt)

via the Marquardt algorithm, treating the initial absorbance (Ai), the final absorbance (Af), and the pseudo-first-order rate constant as parameters to be evaluated.

Results In aqueous solutions, the tropylium (pKR+ = 4.76 (16)) and

xanthylium (pKR+ = -0.83 (19)) cations exist in equilibrium with their hydroxide adducts (5 and 6, respectively). The alcohols 5 and 6 are the predominant species present in most of the reactions in the current study, although the tropylium cation is the major species in the most acidic solutions investigated for the reaction with MAH. The predominance of these alcoholic species in these reactions had both advantages and disadvan- tages. The advantage lay in the fact that what proved to be very fast reactions of these cationic acceptors could be studied under routine pseudo-first-order conditions in which only low equilibrium concentrations of the acceptor species were present. The disadvantage lay in the limited solubilities of 5 and 6 in the

- ~

predominantly aqueous media in use. Clean kinetic data were only obtainable below 3.5 rnM for 5 and below 2.2 mM for 6.

1-Benzyl-l,4-dihydronicotinamide (3, A,,, = 357 nm) and the 10-methylacridinium cation (the oxidation product from 4) are the only species with significant absorbances above 300 nm in the current studies. Reactions of BNH were followed by the disappearance of the absorbance due to this species at 357 nm. Reactions of MAH produced the very characteristic absorption spectrum (23) of the 10-methylacridinium cation over the range 330-450 nm. Kinetic data were obtained by following the increase in absorbance at the intense maximum at 356 nm.

Pseudo-first-order rate constants (kobs) were evaluated at six acceptor concentrations at each pH. In all cases kobs was found to be cleanly proportional to the total concentration ([A+] + [AOH]) of the acceptor species in solution (e.g., Figs. 1 and 2). Apparent second-order rate constants (kTp) were evaluated from the slopes of plots of kobs VS. ([A+] + [AOH]) at each pH. Standard errors in each k y were in the range ?2%- ?6%. The pH dependences of kyp are displayed in Figs. 3 and 4.

The pH-dependent pseudo-second-order rate constants are defined by:

= kyp(1 + KR+/[H+])[A+][DH]

= k2 [A+] [DH]

The pH-dependence shown in Fig. 3 for the reaction of 1 with 4 was fitted to eq. [2], with k2 = 15.1(-+0.6) M- ' s-' and pKR+ = 4.82(&0.05). For the other three reactions, log kTP appears to be linear in pH with negative unit slope. These latter three reactions were investigated over pH ranges for which KR+ >> [H+], and under this condition eq. [2] simplifies to k y p = k2[Ht]/KR+; i.e.,

log k y p = log k2 + pKR+ - pH

Thus for each of these reactions, k2 may be readily evaluated from the experimental data in Figs. 3 and 4.

The second-order rate constants (k2) for each of these four reactions are summarized in Table 1. Data for the reaction of 2 with 3 in 30% acetonitrile have been corrected to 20%

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AND CONN 539

FIG. 1. Concentration dependence of the pseudo-first-order rate constants for reduction of the tropylium cation (T') inequilibrium with its hydroxide adduct (TOH): (a) by 10-methyl-9,lO-dihydroacridine (0.02 mM); (b) by 1-benzyl-l,4-dihydronicotinamide (0.04 mM) in solutions with pH as indicated. All data are in 20% acetonitrile - water.

FIG. 2. Concentration dependence of the pseudo-first-order rate constants for the reduction of 9-xanthydrol (XOH): (a) by 10-methyl- 9,lO-dihydroacridine (0.02 mM); (b) by 1-benzyl-1,4-dihydronicotin- amide (0.04 mM) in solutions with pH as indicated. Data for pH 3.61 in (a) and all data in (b) are in 30% acetonitrile - water; other data are in 20% acetonitrile - water.

acetonitrile using a factor of 4.6. This factor was obtained from the observation that k y p for the reaction of 2 with 4 is 4.6-fold smaller in 30% acetonitrile than in 20% acetonitrile at pH 3.6. We have assumed that the solvent effects on the reduction of the xanthylium cation will be similar for the two different reductants.

FIG. 3. The pH-dependence of kyp for the reduction of the tropylium cation: (A) by 10-methyl-9,lO-dihydroacridine (the curve is eq. [2] with k2 = 15.1 and ~ K R + = 4.82); (B) by 1-benzyl-1,4- dihydronicotinamide (the line has slope - 1). All data in 20% acetonitrile - water.

FIG. 4. The pH-dependence of k y p for the reduction of 9-xanthydrol: (A) by 10-methyl-9,lO-dihydroacridine (20% acetonitrile - water); (B) by 1-benzyl-l,4-dihydronicotinamide (30% acetonitrile - water). Both lines have slope - 1.

TABLE 1. Second-order rate constants for reduction of tropylium and xanthylium cationsa

Oxidant Reductant k2(M-' s-')

Tropylium cation MAH 15.1(+0.6) BNH 2.5(*0.3)x lo4

Xanthylium cation MAH 3 . 5 ( * 0 . 3 ) ~ lo5 RNH 2.7(+-0.2)x108

"At 25"C, in 20% CH,CN - 80% H20, ionic strength 1.0 (unless stated otherwise).

bAt 25"C, in 30% CH,CN - 70% H20, ionic strength 1 .O.

Discussion The pH-rate profiles shown in Figs. 3 and 4 are consistent

with a reaction that occurs as outlined in Scheme 1. This scheme generates the rate constant relationship given in eq. [2].

Of the four reactions included in the current study, only one reaction appears to have been investigated previously. Grishin and Yasnikov (24) reported a kinetic investigation of the

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540 CAN. J. CHEM. \. 'OL. 68, 1990

reaction of the tropylium cation with three N-substituted 1,4-dihydronicotinamides in 50% ethanol - water at 25°C. For the N-benzyl derivative (3), they reported a third-order rate constant, kg = 5.4 X 10' M - ~ min-', which was defined in a way that is equivalent to eq. [3] at neutral pH. This equation is equivalent to eq. [4], and so a second-order rate constant k2 = k3KR+ can be evaluated provided that pKR+ for the tropylium cation can be evaluated in 50% ethanol - water. If one uses pKR+ = 3.1 for this cation in this solvent (25), then k2 =

7000 M-' s-I, which is only 28% of the value obtained for this same reaction in 20% acetonitrile - water in the current study. In this light, the 4.6-fold decrease in rate reported above, for the reaction of the xanthylium cation with MAH upon going from 20% to 30% acetonitrile, is not unreasonable. Other dramatic rate changes with small changes in solvent polarity have also been reported in related reductions (26, 27), although, in general, solvent effects seem to be quite variable for this type of reaction (5, 28).

[3] Rate = k3 [DY] [AOH] [H+ ]

141 = k3KR+ [DH] [A+]

As anticipated above, the tropylium and xanthylium cations proved to be much more reactive than any of the nitrogen heteroaromatic cations that have previously been examined with these two reductants. For instance, the 10-methylacridinium cation reacts with 1 -benzyl- l,4-dihydronicotinamide with k2 = 400 M-I s f 1 under the current experimental conditions (29). Thus, the xanthylium cation reacts with this reductant (7 X

lo5)-fold faster than does the n-isoelectronic acridinium cation. Interestingly, A(log k2)/ApKR+ = -0.54 when one compares these two cations reacting with this reductant. This value is similar to the slopes of the relationships in eqs. [5] and [6], respectively, for the reduction of quinolinium (21) and iso- quinolinium (20) cations by BNH.

The reactivity of the tropylium cation with BNH is predicted reasonably well by the linear free energy relationship for C-4 reduction of quinolinium cations. Thus extrapolation of eq. [5] to pKR+ = 4.82 gives k2 = 4.0 x lo4 M-'s- ' compared with the value of 2.5 X lo4 M-' s-I that is experimentally observed. The tropylium cation is much more reactive than predicted by eq. [6] for isoquinolinium cations (k2 = 310 M-' s-I for pKR+ = 4.82). The 10-methylacridinium cation and the xanthylium cation are both somewhat more reactive (8-fold and 5-fold, respectively) than predicted by eq. [5] for quinolinium cations.

The ky' values for the reduction of the tropylium (1700) and xanthylium cations (770) by BNH and MAH are given in Table 2. This table also includes all literature data that we have

been able to locate for the reduction of a common oxidant by these two reductants. With two exceptions, the ky' values in this table lie within the range 770-1700. One of these exceptions (the 2-methyl-5-nitroisoquinolinium cation with kyl = 120) is not unexpected since the reduction of this cation by BNH is known to be complicated by the presence of nonproductive complexation between these two reactants (2, 22). The other exception involves the 10-methylacridinium cation for which ky' appears to be "normal" in acetonitrile solution (4) but is reported to be threefold larger in 80% 2-propanol - 20% water (13). Thus, aside from these two exceptions, ky' varies by only twofold despite the fact that the individual reactivities of these oxidants vary by 10"-fold with either of these reducing agents individually. Note that the neutral oxidant, 7, shows the same kF1 as the cationic oxidants in Table 2. There is almost constant selectivity towards these two reducing agents over a 10"-fold change in reactivity. This phenomenon represents a further expression of a Ritchie N+ correlation (3 1) for organic cation reactivity.

0

Although these organic cations show essentially constant selectivity towards two reducing agents, such a constant selectivity is not observed if one compares the relative reactivi- ties of these same cations towards one of these reducing agents and nucleophilic attack by hydroxide ion. Such a comparison is presented in Table 3 for reduction by 1-benzyl-l,4-dihydro- nicotinamide. This table includes data for the xanthvlium and tropylium cations, and also data for several nitrogen hetero- aromatic cations for which both kOH and k2 (for reduction by BNH in 20% acetonitrile - 80% water) are available. The k 2 / k o ~ ratios vary (9 x lo6)-fold. Enhanced k2/koH reactivi- ties have previously been demonstrated (18) for cations that give 1,4-dihydropyridine reduction products when compared with the N-methyl isoquinolinium cation, which gives a 1,2- dihydropyridine. In that work it was also noted that the k2/koH ratio shows a significant increase with increasing reactivity (k2). Consistent with this conclusion, we now find that the xanthylium cation, which is the most reactive cation in reductions by BNH, also displays by far the largest kZ/koH ratio (= 7.7). The tropylium cation has k2/koH smaller than might have been expected in terms of this reactivity-selectivity rela- tionship. Nevertheless, this cation does display k2 consistent with its pKR+, and k2/koH is greater for this cation than for any N-heteroaromatic cation other than the N-methyl acridinium ion.

We have recently suggested (32) that the order of k2/koH ratios that is observed for cations generating 1,4-dihydropyri- dine reduction products can be traced to the importance of charge-transfer interactions between the cation and reductant. other workers have also concluded that such charge-transfer species may lie on the reaction coordinate for these formal hydride transfer processes (3, 30). It should be noted that it has been established (32-34) that the order of charge-transfer absorption maxima (A,,,) with a common donor species follows the order: xanthylium > tropylium > 10-methylacri- dinium > 1-methylquinolinium > 1-methylpyridinium. Fur-

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BUNTING AND CONN 54 1

TABLE 2. Relative reactivities of 1-benzyl-l,4-dihydronicotinamide (BNH) and 10-methyl-9,lO-dihydroacridine (MAH) in hydride transfer reactions

Cationic oxidant Conditions Ref.

Xanthy lium 2.7 X lo8

Tropylium 2.5 x lo4

Compound 7 0.032

"Current work. ' l,5-Dihydro-3,10-dimethyl-5-deazaisoalloxazine

TABLE 3. Relative reactivities of aromatic cations towards reduction by 1-benzyl-1,4-dihydronicotinamide and attack by hydroxide ion

Rel. pKR+ k o ~ ( M - ' s- ') k 2 N H ( ~ - ' s-')' kFNH/koH k:NH/koH Cation

-

N-Me ~1~ridinium(C-4)~ 20.5 0.01 1 N-Me quinolinium(C-4)c 17.4 2 N-Me isoquinoliniumd 16.3 940 N-Me acridiniume 10.0 550 ~ r o ~ ~ l i u m ~ 4.76 3.1 x lo5 Xanthyliumg -0.83 3.5 x lo7

"At 25"C, in 20% CH,CN - 80% H,O, ionic strength 1 .O. bData from refs. 18, 35. 'Data from refs. 21, 36. dData from refs. 20, 37. 'Data from refs. 29, 38. fData from ref. 16 and current work; koH at 23°C. 8Data from refs. 17, 19 and current work; koH at 20°C.

thermore, this order also reflects the order of stabilities of 4. M. F. POWELL and T. C. BRUICE. J. Am. Chem. Soc. 105,7139 charge-transfer complexes between these cations and a common (1983). donor species (32). It therefore transpires that the choice of the 5. A. LAAR, H. J . VAN RAMESDONK, and J. W. V E R H O E v E ~ .

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1 We appreciate the continued support of this work by the

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