Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione...

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Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione and bicyclo[2.2.2]octane-2,6-dione: a study of homoconjugation, inductive, and steric effects on the rates and diastereo- selectivities of a enolization Nick Henry Werstiuk and Chandra Deo Roy Abstract: The kinetics of NaOD-catalyzed HID exchange (enolization) at C3 u to the carbonyl group of bicyclo[2.2.2loctane-2,5-dione (I) and bicyclo[2.2.2]octane-2.6-dione (2) have been studied in 60:40 (v/v) dioxane-D,O at 25.0°C. The second-order rate constants for exchange are (9.7 + 1.5) x lo-' and (3.4 t 1.2) x lo-' L mol-' s-I for 1 and 2, respectively. Thus, 1, exchanges 76 times faster than bicyclo[2.2.2]octan-2-one (3) (k= (1.27 + 0.02) x L mol-I s ' ) , but the 2,6-dione 2 unexpectedly is much less reactive (2.7 x lo-') than the monoketone. Unlike the large ex0 selectivity of 658 observed in the case of bicyclo[2.2.1]heptan-2- one, small and opposite selectivities, exo (1.2) for 1 and erzdo (2.1) for 2, are found for the isomeric [2.2.2] ketones. The results indicate that the incipient enolate of 1 is stabilized by a polar effect of the P carbonyl group at C5, not by homoconjugation. The source of the surprising low reactivity of 2 is unknown at this stage. The small diastereoselectivities, exo (1.2) for 1 and erzdo (2.1) for 2, correlate with relative energies of the diastereomeric pyramidal enolates calculated with AM I. Key words: enolization, bicyclo[2.2.2loctane-2,5-dione, bicyclo[2.2.2]octane-2.6-dione, AM I, thermodynamic acidities. Resume : Optrant ?I 25,0°C, dans des solutions 60 : 40 (vlv) de dioxane-DzO, on a CtudiC la cinCtique de I'Cchange (tnolisation) HID, catalysC par le NaOD, au niveau du C3 en a du groupe carbonyle de la bicy- clo[2.2.2]octane-2,5-dione ( I ) et de la bicyclo[2.2.2]octane-2,6-dione (2). Les constantes de vitesse d'tchange du deuxittme ordre sont de (9.7 + 1,5) x lo-' et (3,4 t 1,2) x lo-" mol-' s-' respectivement pour 1 et 2. Le composC 1 s'tchange donc 76 fois plus rapidement que la bicyclo[2.2.2]octan-2-one (3) (k = (1,27 + 0,02) x L mol-' s-I; toutefois, la 2,6-dione (2) est beaucoup moins reactive (2,7 x 10-"ois moins reactif) que la monocCtone. Par opposition ?I la forte stlectivitt de 658 observCe dans 1e cas de la bicyclo[2.2. Ilheptan-'--one, on a observe de faibles sClectivitCs opposCes, exo (1.2) pour 1 et endo (2.1) pour 2, pour les cCtones [2.2.2] isomttres. Les rtsultats indiquent que I'Cnolate qui se forme dans le composC 1 est stabilist par un effet polaire du groupe carbonyle Pen C5 et non pas par homoconjugaison. La cause de cette faible rCactivitC surprenante du composC 2 est pour l'instant inconnue. Les faibles diastCrCostlectivitts, ex0 (1.2) pour 1 et endo (2,l) pour 2, I Received August 29, 1994. N.H. Werstiuk' and C.D. Roy. Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada. I Author to whom correspondence may be addressed. Telephone: (905) 525-9 140. Fax: (905) 522-2509. Can. J. Chem. 73: 460463 (1995). Printed in Canada 1 Imprime au Canada Can. J. Chem. Downloaded from www.nrcresearchpress.com by SUNY AT STONY BROOK on 11/12/14 For personal use only.

Transcript of Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione...

Page 1: Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione and bicyclo[2.2.2]octane-2,6-dione: a study of homoconjugation, inductive, and steric

Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione and bicyclo[2.2.2]octane-2,6-dione: a study of homoconjugation, inductive, and steric effects on the rates and diastereo- selectivities of a enolization

Nick Henry Werstiuk and Chandra Deo Roy

Abstract: The kinetics of NaOD-catalyzed HID exchange (enolization) at C3 u to the carbonyl group of bicyclo[2.2.2loctane-2,5-dione ( I ) and bicyclo[2.2.2]octane-2.6-dione (2) have been studied in 60:40 (v/v) dioxane-D,O at 25.0°C. The second-order rate constants for exchange are (9.7 + 1.5) x lo-' and (3.4 t 1.2) x lo-' L mol-' s-I for 1 and 2, respectively. Thus, 1, exchanges 76 times faster than bicyclo[2.2.2]octan-2-one (3) ( k = (1.27 + 0.02) x L mol-I s ' ) , but the 2,6-dione 2 unexpectedly is much less reactive (2.7 x lo-') than the monoketone. Unlike the large ex0 selectivity of 658 observed in the case of bicyclo[2.2.1]heptan-2- one, small and opposite selectivities, exo (1.2) for 1 and erzdo (2.1) for 2, are found for the isomeric [2.2.2] ketones. The results indicate that the incipient enolate of 1 is stabilized by a polar effect of the P carbonyl group at C5, not by homoconjugation. The source of the surprising low reactivity of 2 is unknown at this stage. The small diastereoselectivities, exo (1.2) for 1 and erzdo (2.1) for 2, correlate with relative energies of the diastereomeric pyramidal enolates calculated with AM I .

Key words: enolization, bicyclo[2.2.2loctane-2,5-dione, bicyclo[2.2.2]octane-2.6-dione, AM I, thermodynamic acidities.

Resume : Optrant ?I 25,0°C, dans des solutions 60 : 40 (vlv) de dioxane-DzO, on a CtudiC la cinCtique de I'Cchange (tnolisation) HID, catalysC par le NaOD, au niveau du C3 en a du groupe carbonyle de la bicy- clo[2.2.2]octane-2,5-dione ( I ) et de la bicyclo[2.2.2]octane-2,6-dione (2). Les constantes de vitesse d'tchange du deuxittme ordre sont de (9.7 + 1,5) x lo-' et (3,4 t 1,2) x lo-" mol-' s-' respectivement pour 1 et 2. Le composC 1 s'tchange donc 76 fois plus rapidement que la bicyclo[2.2.2]octan-2-one (3) (k = (1,27 + 0,02) x

L mol-' s-I; toutefois, la 2,6-dione (2) est beaucoup moins reactive (2,7 x 10-"ois moins reactif) que la monocCtone. Par opposition ?I la forte stlectivitt de 658 observCe dans 1e cas de la bicyclo[2.2. Ilheptan-'--one, on a observe de faibles sClectivitCs opposCes, exo (1.2) pour 1 et endo (2.1) pour 2, pour les cCtones [2.2.2] isomttres. Les rtsultats indiquent que I'Cnolate qui se forme dans le composC 1 est stabilist par un effet polaire du groupe carbonyle Pen C5 et non pas par homoconjugaison. La cause de cette faible rCactivitC surprenante du composC 2 est pour l'instant inconnue. Les faibles diastCrCostlectivitts, ex0 (1.2) pour 1 et endo (2,l) pour 2,

I Received August 29, 1994.

N.H. Werstiuk' and C.D. Roy. Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada.

I Author to whom correspondence may be addressed. Telephone: (905) 525-9 140. Fax: (905) 522-2509.

Can. J. Chem. 73: 460463 (1995). Printed in Canada 1 Imprime au Canada

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Page 2: Experimental and AM1 calculational studies of the deprotonation of bicyclo[2.2.2]octane-2,5-dione and bicyclo[2.2.2]octane-2,6-dione: a study of homoconjugation, inductive, and steric

Communication

offrent une bonne corrClation avec les Cnergies relatives calculCes par AM1 pour les Cnolates pyramidaux diastCrComkres.

Mots cle's : Cnolisation, bicyclo[2.2.2]octane-2.5-dione, bicyclo[2.2.2]octane-2,6-dione, AM 1, aciditCs thermo- dynamiques.

[Traduit par la ridaction]

Over the past two decades a great deal of research has been carried out on the a and p (homoenolization) enolization of ketones (1-4) to determine the role of various factors such as orbital alignment, steric effects, homoconjugation, and hyper- conjugation in determining the kinetic and thermodynamic acidities of this very important class of compounds. Our long- standing interest in this field (5,6), specifically in establishing how remote polar groups stabilize enolates, and our develop- ing interest in using semiempirical calculations with AM I to predict and rationalize variations in the kinetic and thermody- namic acidities of carbon and oxygen acids (6-9) motivated us to undertake experimental and computational studies on the isomeric diones bicyclo[2.2.2]octane-2,5-dione (1) and bicy- clo[2.2.2]octane-2,6-dione (2). Because the C3 methylene hydrogens of 1 and 2 are diastereotopic2 and exhibit distinct 'H nmr resonances (6), which is not the case for bicy- clo[2.2.2]octan-2-one, the diastereoselectivities of exchange can be determined in the absence of differential steric effects for exo and endo approach of the base at C3. This is an impor- tant point because it is possible that a differential steric effect between the methano and ethano bridges gives rise to the large exo selectivity of 658 found for enolization at C3 of bicy- clo[2.2.l]heptan-2-one (5). Our goal was to use the diastereo- selectivities of WD exchange and AM1 calculations to establish the importance of homoconjugative stabilization of an incipient enolate by a carbonyl group located P to the eno- lizable center as in [2.2.2] ketones. If a enolization at C3 of 1 is assisted by homoconjugation, then the exo/endo rate ratio should be substantially greater than 1, a consequence of the fact that exo deprotonation leads to development of the back- lobe of ap-orbital syn to the T-system of the carbonyl group at C5; this is not the case for endo deprotonation. On the other hand, if the incipient enolate is stabilized solely by a polar effect and differential steric effects are small or negligible (this also holds for the enolization of 2) the exo/endo diastereo- selectivity should be near 1. A study of 1 and 2 also provided us with an opportunity to establish whether AM1 is useful for predicting the relative rates and diastereoselectivities of eno- lization reactions in solution. In this communication we report

another study (lo), with the difference possibly arising from the fact that slightly different dioxane/D20 ratios were used in the two studies. Under identical conditions, the 2,5-dione 1 (k = (9.7 f 1.5) x lo-'), which we synthesized recently (6), underwent exchange 76 times faster3 than 3 and 2.8 x lo4 times faster than 2 (k = (3.4 f 1.2) x lo-'), which was pre- pared by the method described by Gerlach and Muller (1 1). Analysis of several incompletely exchanged (30%) samples of 1 with 'H nmr established that exchange of the e.ro hydrogen is preferred by a factor of 1.2. Because the differential steric effect for approach of hydroxide ion exo or endo at C3 is expected to be small, the results establish that the incipient enolate anion at C3 is stabilized through a polar effect, not by homoconjugation. Unlike 1, the 2,6-dione 2 is much less reac- tive (2.7 x lo-,) than 3. The low rate of exchange of 2 is not due to a hydroxide ion-depleting ring-opening reaction; 2 was recovered in 80% yield (there was 5.03% H/D exchange at C3(C5)) from a 4 h reaction in 0.04 M NaOD - dioxane-D20 at 25°C. Some time ago Bartlett and Forrest Woods found that 2 did not give the positive FeC1, test that is exhibited by eno- lizable 1,3-diketones, but they did not carry out base-catalyzed HID exchange studies (12). Our work shows that H/D exchange at the bridgehead carbon C1 does not occur at a detectable rate in a medium that induces rapid WD exchange of acyclic and monocyclic 1,3-diketones; there is no detect- able signal with the chemical shift expected for the bridgehead deuteron in the 2~ spectrum of 2, which was isolated from a 4 h exchange reaction. Under identical conditions, the hydro- gens at C3 and C6 of the 2,5-dione 1 are equilibrated with the deuterium pool (97% exchange) within 1 min. The reason for the low reactivity of 2 relative to monoketone 3 is presently unknown. That this low reactivity is not due to the formation of a cyclic hydrate involving the carbonyl groups at C2 and C6 was established by 'H nmr spectroscopy. The exchange solu- tion of 2 exhibits only signals that exactly match the nmr spec- trum obtained in CDCI,. Possibly, a through-space interaction of the carbonyl T-systems at C2 and C6, a decrease in the elec- trophilicity of carbonyl groups, and angle strain resulting from the introduction of a second carbonyl group at C6 combine to

the rates and the exo/endo preferences for NaOD-catalyzed HI D exchange of 1 and 2 along with the results of an AM1 cal- culational study.

To check our experimental method, the H/D exchange of bicyclo[2.2.2]octan-2-one (3) was studied in 0.04 M NaOD - 60:40 dioxane-D20 at 25.0°C. The second-order rate constant ((1.27 t 0.02) x L mol-' s-I) compares reasonably well with the rate constant (3.03 x lo-' L mol-' s-I) obtained in

"he exchange solutions (60:40 dioxane-D20) were 0.12 M in ketone and 0.02 or 0.04 M in NaOD. Uptake of deuterium was monitored with 200 MHz 'H nmr spectroscopy by integrating the appropriate resonances and using the bridgehead protons as inter- nal standards. In some cases the results were checked mass spec- trometrically. Because 1 and 2 exhibited significant variations in the rates of HID exchange as the base concentration was decreased, we used a ~ n i - ~ o i n t kinetic method to obtain the rate constants, which are the mean of three determinations. That the variability in the rate was not due to the intrusion of an acid-base

The exo hydrogens are syn to the ethano bridges of 1 and 2; the equilibrium involving 1 and its enolate was established by obtain- endo hydrogens are anti to the ethano bridges. As in the case of 1 ing a 200 MHz 'H nmr spectrum of the exchange solution; within (6), nuclear Overhauser difference spectroscopy was used to the detection limits of nmr, no signals other than those due to 1 assign the resonances of the C3 exo and endo hydrogens of 2. were found in the spectrum.

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Can. J . Chern. Vol. 73, 1995

Table 1. AMI-calculated enthalpies of formation and ionization.

AH; AHf AH,. Relative Ketone ketone Cl-enolate C3-enolate AH, Cl AHi C3 A M i C3 rate

1 -85.75 -68.03 -94.96 38 1.9 355.1 -8.1 7 6 2 -85.34 -67.94 -93.99 38 1.6 355.6 -0.5 0.0027 3 -61.51 -33.14 -60.47 392.6 363.2 0.0 1

"The values are in kcallmol. "AH, = (AHAenolate) - AHAketone)) - AHAH'); AH,(H+) taken as 365.4 kcallmol.

Table 2. AMI-calculated enthalpies of formation of pyramidal enolates and experimentally observed diastereoselectivities.

AH; AHf exo/endo Ketone exo enolate endo enolate AHpxo - AHpndo Diastereoelectivity

"The values in kcallmol.

reduce the kinetic acidity of 2. Additional experimental and computational studies are needed to determine the source(s) of the unexpected low reactivity of 2. Analysis of partially labelled 2 (6%) with 'H nmr established that deprotonation at C3 occurs with an endo diastereoselectivity of 2.1.

Two sets of AM 1 calculations (the keyword PRECISE was used to tighten the convergence criteria) were carried out on the 2,5-dione 1, the 2,6-dione 2, 3, and their enolates and the results are given in Tables 1 and 2. The gas phase enthalpies of ionization of 1, 2, and 3 calculated from the AHf's of the ketones and their planar enolates are given in Table 1. The geometrical structures of the optimized geometries of 1 and 2 are given in Fig. 1. The AM1-calculated C(3) AHi7s (AH, (1) - AHi (3) = - 8.1 kcallmol), which are a measure of the rela- tive thermodynamic acidities of 1 and 3, correlate with the kinetic acidities. But 2 is much less reactive kinetically than 3, not what would be expected on the basis of the calculational AH,'s. Yet the calculated AH, of the C1 bridgehead hydrogen of 2 is 18.4 and 26.0 kcallmol higher than the C3 AHils of 3 and 1, respectively, in keeping with the fact that this hydrogen does not undergo H/D exchange under normal enolization conditions (vide supra). Most surprising is the finding that the calculated C1 AHi's of 1 and 2 are virtually identical. That the C 1 AH,'s of 1 and 2 are 10.7 and 11 .O kcallrnol lower than the C1 AH, of 3 establishes two important points: (a) the inductive stabilization of a carbanion by an a carbonyl group is repro- duced in the AM1 calculations, and (b) a and P carbonyl groups evidently stabilize a bridgehead enolate of a 12.2.21 ketone to the same degree.4 To establish whether AM1 calcu- lations are useful for estimating the relative reactivities of diastereotopic hydrogens a to a carbonyl group and to provide new insights into the factors that determine the diastereoselec- tivities, we calculated the AHf's (Table 2) of exo and erzdo pyramidal C3 enolates of 1 (1-exo-enolate and 1-erzdo-enolate)

We plan to determine the rates of bridgehead exchange of 3,3,6,6- tetrarnethylbicyclo[2.2.2]octane-2,5-dione and 3,3,5,5-tetrameth- ylbicyclo[2.2.2]octane-2,6-dione with t-BuOWt-BuOD to test the results of the AM1 calculations.

Fig. 1. Displays of AM I -optimized geometrical structures of ketones and pyramidal enolates.

and 2 (2-exo-enolate and 2-erzdo-enolate). The AM1-opti- mized geometrical structures of the pyramidal enolates obtained by deleting the exo or erzdo hydrogens and fixing the H-C3-C2-0 torsional angle of the remaining hydrogen at the value calculated for the ketone are displayed in Fig. 1. While

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Communication

1-exo-enolate is slightly more stable than 1-endo-enolate, the order of stability is reversed for the pyramidal enolates derived from 2 (Table 2). Because the transition states for OH- induced a enolization undoubtedly have pyramidal character, we expected that the experimental diastereoselectivities would correlate with the AAH,'s of the pyramidal enolates. The data given in Table 2 confirm this expectation. We expect that AAH,'s of the pairs of pyramidal enolates will decrease to bring the values in line with the experimental diastereoselec- tivities as the a carbons approach the triangular planar config- uration of the planar enolates. It is also noteworthy that the relative magnitudes of the AAH,'s correlate with the relative magnitudes of the diastereoselectivities. It is possible that better orbital alignment - the endo H-C3-C=O torsional angle is 2" larger than the exo H-C3-C2-0 angle - and a through-space polar effect differentially stabilize the endo pyramidal enolate of 2 relative to the exo diastereomer. In going from 1 to 1-exo-enolate, C3 bends slightly towards the carbonyl carbon at C5: the C3-C4-C5 angle decreases from 108.6" to 106.9" and the C3,C5 internuclear distance decreases from 2.46 to 2.42 A. And, there is a surprisingly large increase in the C1-C2 bond lengths when the ketones are converted to the pyramidal enolates (1, 1.517 A; 1-exo-enolate, 1.555 A; 1- endo-enolate, 1.555 A; 2, 1.5 18 A; 2-exo-enolate, 1.567 A; 2- endo-enolate, 1.565 A). According to the AM1 calculations (Tables 1 and 2), the pyramidal enolates are 9-10 kcallmol higher in energy than the planar enolates (the exo enolates of 1 and 2 by 9.44 and 9.63 kcallmol, respectively; the endo eno- lates of 1 and 2 by 9.57 and 9.12 kcal/mol, respectively). Even so, there must be a substantial interaction between the anionic carbon and the carbonyl group of the pyramidal enolates because the AM 1 -calculated enolate C2-C3 bond lengths (1- exo-enolate, 1.402 A; 1-endo-enolate, 1.398 A; 2-exo-enolate, 1.399 A; 2-endo-enolate, 1.397 A) are much shorter than the corresponding C-C bonds of 1 and 2 (1.507 and 1.506 A, respectively).

Acknowledgement

We thank the Natural Sciences and Engineering Research Council of Canada for financial support.

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