AM1 calculational and experimental evidence that a P-nitroxyl group significantly enhances the thermodynamic and kinetic acidities of ketones

NICK HENRY WERSTIUK' AND CHANDRA DEO ROY Department of Chernistq, McMnster University, Hnrniltorl, ON L8S 4M1, Ccir~ciilc~

Received June 24, 1994

NICK HENRY WERSTRTK and CHANDRA DEO ROY. Can. J. Chem. 72,2348 (1994). The kinetics of NaOD-catalysed HID exchange of 3,3,5,5-tetramethylcyclohexanone (I), I-hydroxy-4-0x0-2,2,6,6-tetrame-

thylpiperidine (2), 4-0x0-2,2,6,6-tetramethylpiperidine- I-oxyl (3), 9-hydroxynorpseudopelletierine (4), and norpseudopelle- tieiine-9-oxyl (5) have been studied in 60:40 dioxane-D20 (vlv) at 25.0°C. The second-order rate constants are 9.20 x 6.39 x lo-', 1.59, 2.20 x lo-', and 5.67 x lo-' L mol-I s-' for 1 ,2 ,3 ,4 , and 5, respectively. Gas-phase enthalpies of ionization (the values are 363.0,359.4, 352.0,360.7, and 354.1 kcal mol-I for 1,2,3,4, and 5, respectively) calculated with AM I correlate with the relative rates of enolization. Thus replacement of the P-hydroxylamino groups of 2 and 4 with a nitroxyl group produces sizable increases in the kinetic and thermodynamic acidities of the hydrogens a to the carbonyl group.

NICK HENRY WERSTIUK et CHANDRA DEO ROY. Can. J. Chem. 72,2348 (1994). OpCrant 25"C, dans un melange 60 : 40 de dioxane-D,O (vlv), on a CtudiC la cinCtique de I'Cchange HID, catalyse par le

NaOH, des 3,3,5,5-tCtramCthylcyclohexanone (I), 1-hydroxy-4-0x0-2,2,6,6-t6tramCthylpipCridine (2), 4-0x0-2,2,6,6-tktrameth- ylpipkridine- I-oxyl (3). 9-hydroxynorpseudopelletiCrine (4) et norpseudopelletiCrine (5). Les constantes de vitesse du deuxibme ordre sont 9.20 x 6,39 x lo-', 1,59, 2,20 x lo-' et 5,67 x lo-' L mol-I s-I respectivement pour les composks 1,2,3, 4 et 5. Les enthalpies d'ionisation en phase gazeuse (les valeurs sont de 363,0,359,4,352,0, 360,7 et 354,l kcal mol-I respectivement pour les cornposCs 1 ,2 ,3 ,4 et 5) calculees par la mCthode AM1 permettent d'ktablir une bonne correlation avec les vitesses rel- atives d'inolisation. Ainsi, le remplacement des groups 0-hydroxylamino des composCs 2 et 4 par une groupe nitroxyle pro- voque une augmentation importante des acidites cinktiques et thermodynamiques des hydrogbnes en a du groupe carbonyle.

[Traduit par la rkdaction]

Introduction

While a great deal of research work has been carried out to define the factors, e.g., orbital alignment, steric, torsional, and polar effects, that determine the rates of base-catalyzed a eno- lization of ketones (1-4), there have been no reports detailing the effect of remote heteroatom-centered radicals on the kinetic and thermodynamic acidities of carbonyl compounds. Our longstanding interest in establishing how remote polar substitu- ents enhance the rates of a and P(homoeno1ization) enolization of ketones and in using semiempirical calculations to predict and understand variations in the thermodynamic acidities of carbon and oxygen acids (5, 6 ) motivated us to undertake a cal- culational and kinetic study of the base-catalysed enolization of five ketones. The group included 3,3,5,5-tetramethylcyclohex- anone ( I ) , I-hydroxy-4-0x0-2,2,6,6-tetramethylpiperdine (2), 4-0x0-2,2,6,6-tetramethylpiperidine-1-oxyl (3), 9-hydrox- ynorpseudopelletierine (4), and norpseudopelletierine-9-oxyl (5), of which two, 3 and 5, have a polar nitroxyl group R,N-0. located P to the enolizable centers.* That the nitroxyl group is

'Author to whom correspondence may be addressed. '1n principle, a 0-nitroxyl group can stabilize a carbanion via a polar

effect, through bond and through space, and a hyperconjugative inter- action involving a o* orbital of a C-N bond. It is also possible that the polarity of the nitroxyl group increases upon deprotonation at a P car- bon, giving rise to a reflex polar stabilization of the enolate. In terms of resonance theory, the dipolar canonical form written for the nitroxyl group is a more important contributor for the enolate than the ketone.

electron withdrawing is well documented in the literature (7). We chose to study these compounds because the enthalpies of ionization (AHi's) calculated with AM1 (8) indicated that 3 and 5 should enolize much more quickly than 1, 2, and 4. In this communication we report and discuss the results of calcula- tional and experimental studies on 1-5.

The enthalpies of ionization (Table 1) were obtained from the calculated heats of formation of 1-5 and their corresponding e n ~ l a t e s . ~ The geometrical structures of the optimized geome- tries of 1-hydroxy-4-0x0-2,2,6,6-tetramethylpiperidin (2), 4- 0x0-2,2,6,6-tetramethylpiperidine-1-oxyl (3), 9-hydroxynorps- eudopelletierine (4), and norpseudopelletierine-9-oxyl (5) (2c, 3tb, 4cc, and 5cc) and their enolates (2c-enolate, 3tb-enolate, 4cc-enolate, and kc-enolate) are given in Fig. 1. It is seen that the nitroxyl nitrogens of the ketones and enolates are nearly tri- angular planar. While chair conformations are found to be the most stable geometrical structures of 1 and 2, the twist-boat conformer 3 tb of the piperidinoxyl radical is 0.29 kcal mol-I lower in energy than the chair conformer 3c, in accord with the results of gas-phase electron diffraction studies carried out by Nakken and co-workers on 2 and 3 (10, 11). In the case of 9-

Support for such a reflex polar stabilization by a nitroxyl group is found in the fact that the AM 1 calculations show that there is a differential in- crease in negative charge on the oxygens of the nitroxyl groups of 3tb and 5cc relative to the oxygens of the hydroxyl groups of 2c and 4cc upon enolate formation: 2c, -0.270, 2c-enolate, -0.291; 3tb, -0.319, 3tb-enolate, -0.404; 4cc -0.27 1,4cc-enolate, -0.306; Scc, -0.306,Scc- enolate, -0.40 1.

'PCMODEL (9) was used to generate input geometries for the AM1 cal-

b A ~ 6 culations, which were carried out with the keyword PRECISE to tighten 0 the convergence criteria. UHF calculations were carried out for the R R R R hydroxy compounds, the nitroxyl radicals, and their enolates.

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COMMUNICATION 2349

TABLE 1. Calculated enthalpies of formation and ionization

Ketone AHf Ketoneu AHf Enolate AHi" Mi

-77.40

-65.82

-58.74

-67.04(syn) -6 1.76(anti)

-70.04(syn) -64.72(anti)

-52.1 1 (syn) -52.55(anti)

-54.90)(syn) -55.50(anti)

"In kcal mol-'. bAHi = [AHf (enolate) - AHf (ketone)] - AHAH+); AHAH+) taken as

365.4 kcal mol-'. 'The values for the -OH group syn and anti to the carbonyl and enolate

groups, respectively.

TABLE 2. Second-order rate constants and relative rates of WD ex- change of ketones

Relative Ketoneu k(L mol-' s-I)' rate Calculated A M i -

1 0.92 x 1 0.0 2 6.39 x lo-" 6.9 -3.6 3 1 .59Ctd 173.1 -1 1.1 4 2.20 x 2.4 -7.1 (OH syn), -2.3(anti) 5 5.67 x 10-''*~ 61.7 -8.9(OH syn), -9.4(anti)

"Substrates 2, 4, and 5 were synthesized using procedures reported in the literature (I 1-14).

"n 60:40 dioxane-D20(v/v). Ketone concentrations ranged from 0.10 to 0.12 M. Second-order rate constants were obtained by dividing the measured pseudo-first-order rate constant by the base concentration, which was in the range of 0.005-0.04 M. Rates were reproducible with a maximum deviation of &S% except for 1 where the deviation was f7.5%.

T h e uptake of deuterium was monitored with 'H nmr spectroscopy by integrating the appropriate resonances. The signals of the C4 methylene hydrogens of 1 and methyl hydrogens of 2 were used as internal standards. For bicyclic compounds 4 and 5, the resonances of the bridgehead hydrogens or the equatorial hydrogens a to the carbonyl group (the equatorial hydrogens of 5 exchange at least 100 times more slowly than the axial hydrogens) were used as the internal standards. The radicaIs were catalytically hydrogenated (PtO, in ethanol) to 2 and 4, which were analysed with 'H nlnr spectroscopy.

he H/D exchange of radicals 3 and 5 was extremely fast. The pseudo-first- order rate constants obtained from one-point kinetic runs were divided by the base concentration to calculate the second-order rate constants. The first-order rate constants exhibited a Iinear relationship with base concentration.

hydroxy.norpseudopelletierine, the chair-chair conformation 4cc is 3.10 kcal mol-I lower in energy than the chair-boat con- formation 4cb, and the isomer with the -OH group syn to the carbonyl was found to be only marginally lower in energy than the anti diastereomer. But the orientation of the N-OH group has a dramatic effect on the stability of the gas-phase enolates derived from 4cb and 4cc; the syn enolates (the -OH group is syn to the enolate) are 5-6 kcal mol-I lower in energy than the anti diastereomers, indicating that a gas-phase enolate ion is sta- bilized markedly by a singleintramolec~lar hydrogen bond that is aligned perpendicular to the plane of the enolate anion. Even so, we expected that 4 would not exhibit an enhanced acidity in

FIG. I . Geometrical structures of the AM1 optimized geometries of 2c, 3tb, 4cc, 5cc, and their enolates.

aqueous solution4 because enolates are solvated intermolecu- larly by solvent, and axial approach by OH-at C2 should hinder formation of an intramolecular hydrogen bond to the incipient enolate. In the case of norpseudopelletierine-9-oxyl, the chair- chair conformation 5cc is 2.86 kcal mol-' lower in energy than the chair-boat conformation 5cb and the orientation of the nitroxyl oxygen has little effect on the stability of enolates. Because the AAHi's of 3tb and 5 were found to be nearly three times the values calculated for 2 and 4, we expected the nitroxyl compounds to enolize much more quickly than 2 and 4, and 2 to be more reactive than 1.

The second-order rate constants for H/D exchange in NaODI D 2 0 60:40 dioxane-D20 along with the relative rates and the AAHi's are given in Table 2. It is seen that the relative rates of

4 ~ e are modelling polycyclic cage compounds bearing hydrophobic cavities calculationally with AM1 to design substrates that will be use- ful for probing the stabilization of enolates by intramolecular hydrogen bonding in solution.

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2350 CAN. J. CHEM. VOL. 72,1994

enolization correlate with the calculational gas-phase AHi's and, as predicted, piperidine-1-oxyl3 is more reactive than pel- letierine-9-oxyl5; 1-hydroxypiperidine 2 is slightly more reac- tive than 4 and both compounds are substantially less reactive than 3 and 5. As expected, the kinetic acidity of 4 correlates with the calculational AHi of the anti diastereomer and not with the AHi of the syn isomer. Because there are no a substituent constants for the nitroxyl and hydroxylamino groups, it will be difficult to assess the relative importances of the polar (induc- tive and field) and hyperconjugation effects. Even so, the group electronegativities ( X values) calculated by Boyd and Boyd (15) on the basis of a bond critical point model indicate that through- bond electron-withdrawing effects of the nitroxyl and hydroxy- lamino groups are virtually i d e n t i ~ a l . ~ Because the calculated N-C(CH,),-CH---C (34.9") and N-C(R),-CH-L (30.2") tor- sional angles of 3tb-enolate and 5cc-enolate are far from the optimal angle of 90°, hyperconjugation with an adjacent C-N bond plays a minor role in stabilizing the enolates.

Acknowledgements We thank the Natural Sciences and Engineering Research

Council of Canada for financial support.

'we thank Professor Susan Boyd of Mount St. Vincent University, Halifax, Nova Scotia, for providing the x values of the nitroxyl (X = 3.18) and hydroxylamino (X = 3.17) groups evaluated with calculations on CH,NHO' and CH,NHOH.

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