6352
J. Org. Chem. 1991,56, 6352-6357
Preferred Geometry of Unusual Nitrones. A Facile E - 2 Isomerization of a C-Alkoxynitrone David E. Gallis,' James A. Warshaw, Bruce J. Acken, and DeLanson R. Crist* Department of Chemistry, Georgetown University, Washington, DC 20057
Received April 10, 1991 A detailed structural study was carried out on C-methoxy-C-aryl-N-tert-butylnitronee(l),members of a relatively new class of compounds (acyclic imidate N-oxides). By 'H NMFt chemical shifta it was shown that 1 exist exclusively as the E isomers in DCCIBand the 2 isomers in acetone-& NOE difference spectra confirm these assignments and indicate a preferred conformation in which 0-methyl and C-phenyl are more syn periplanar than anti in (PBN), both cases. Configurations and conformations were similarly determined for C-phenyl-N-tert-butylnitrone as well as several nitrone salts. Rates of E to 2 isomerization of the phenyl, p-methoxyphenyl,and p-nitrophenyl derivatives of 1 were measured in acetone from 266 to 280 K giving AH* values of 14.1,16.9,and 14.2 kcal/mol and AS*values of -24.3,-14.5,and -25.5 eu, respectively. The unusually low values of AH*are interpreted in terms of ground-state destabilization due to steric repulsions that are relieved in going to the transition state by rotation about the C-N bond. The large negative AS* values suggest solvent reorganization to stabilize the charge-separated character of the transition state. Geometry-optimized MNDO calculations are in agreement with conformation results from NOE experiments and predict a large dipole moment difference between E and 2 isomers.
Interest in nitrone chemistry has increased markedly in recent years due to their applications in organic synthesis2 and as spin trapping agentsq3 Although certain examples of cyclic alkoxynitrones have found use in the synthesis of spin labels: reactions of acyclic C-alkoxynitrones have only recently been investigated and include cycloaddition,6 electrophilic and nucleophilic substitutions: hydrolysis: redox reactions: and radical additions.' In the only reported mention of configuration assignment of an acyclic C-alkoxynitrone, Ashburn and Coates6 concluded that C-ethoxy-C-phenyl-N-methylnitrone existed as a 5 2 mixture of E / Z isomers, assuming that the more upfield methyl was one shielded by phenyl in the Z configuration. An X-ray structure determination on a sulfur analogue supports this approach.8 The configuration of one example of the recently reported, analogous C-vinylnitrone~~ was confirmed by NOE. We have shown for imidates that nuclear Overhauser effect difference spectroscopy can be used not only for configuration assignments but also for indicating preferred conformations.10 We now report configuration assignment and conformational preference for a series of C-methoxy-N-tert-butylnitrones by chemical shift data and NOE difference spectra. A more detailed study of the C-aryl nitrones revealed a striking solvent effect on configuration and an unusually facile E to 2 isomerization in acetone. (1) Taken, in part, from the Ph.D. thesis of D. E. Gallis, present Environmental Resources Management, Inc., Exton, PA 19341.
ad&
(2) (a) Breuer, E. Nitrones, Nitronates, and Nitroxides; Breuer, E., Aunch, H.G., Nielaen, A., Ma.;Wiley New York,1989; pp 13.9-312. (b) Torssell, K.B. G.Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH Publishers: New York, 1988. (c) For a recent example, nee: DeShong, P.; Li, W.; Kennington, J. W.,Jr.; Ammon, H. L. J. Org. Chem. 1991,56, 1364-1373. (3) (a) Janzen, E. G. Methods in Enzymology; Academic Press: Orlando, FL, 1984; Vol. 105, pp 188-198. (b) Perkins, M. J. Adv. Phys. Org. Chem. 1980,17,1-64. (4) Keana, J. F. W. Chem. Reu. 1978,3744. (5) Aahbum, S. P.; Coates, R. M. J. Ora. Chem. 1985,50,3076-3081. (6) Warshaw, J. A.; Gallis, D. E.; Acken, B. J.; Conzalez, 0. J.; Crist, D. R. J. Org. Chem. 1989,54,1736-1743. (7) Acken, B. J.; Warshaw, J. A.; Callis, D. E.; Crist, D. R. J . Org. Chem. 1989,54, 1743-1745. (8) Coates, R. M.; Firsan, S. J. J. Org. Chem. 1986, 51, 5198-5209. (9) Bartoli, C.; Marcantoni, E.; Petrini, M.; Dalpozzo, R. J.Org. Chem. 1990,55,4456-4459. (10) Gallis, D. E.; Crist, D. R. Magn. Reson. Chem. 1987, 480-483.
Results Nitrones l a d were prepared as previously described by alkylation of the hydroxamic acids with methyl trifluoromethanesulfonate (triflate, or O T f ) followed by deprotonation.* CH3-0
CH3-
RbC
).(
E
1 a, R b, R 0,
=
t-eu
z
CgHg
= P-CHaOCgHq
R =P-OzNCgHq
d, R = H
Preferred Geometry. C-Alkoxy-C-arylnitrones. The parent nitrone la in chloroform has 'H chemical shifta in the first entry of Table I (deuterated solvents used throughout). When this solvent is evaporated and replaced with acetone, the shifts undergo slight changes due to a small solvent effect (second entry), but then these signals decrease with time as new signals (third entry) appear and grow in intensity until they are essentially the only signals present. From integrals the process involved is a simple isomerization. When the acetone is evaporated and replaced with chloroform, again there is a small solvent effect on chemical shifts (fourth entry), but the signals are replaced with time by the original ones, thereby demonstrating that the isomerization is reversible but with a striking solvent effect on isomer preference. The preferred isomer in each solvent was assigned on the basis of chemical shift differences. In acetone, a more upfield tert-butyl signal (by 0.60 ppm) indicates the 2 configuration in which these hydrogens are in the shielding cone of phenyl. This is in keeping with results for aldoand ketonitrones," N-tert-butyloxaziridines,'2benzimidates,1° and C-ethoxy-C-phenyl-N-methylnitrone.6In support of this assignment, the ortho hydrogens of this (11) Bjorgo, J.; Boyd, D. R.; Neill, D. C.; Jenninge, W. B. J. Chem. SOC.,Perkin Trans. 1 1977, 254-259. (12) Gonzalez, 0. J.; Gallis, D. E.; Crist, D. R. J. Org. Chem. 1986,51, 3266-3270.
OO22-3263/91/1956-6352$02.50/0 0 1991 American Chemical Society
J. Org. Chem., Vol. 56, No. 22, 1991 6363
Preferred Geometry of Unusual Nitrones
Table I. 'H Chemical Shifts of C-Methoxy-C-arylnitrones 6. oDm solvent OCH3 N-t-Bu 0-Ph I
structure
" Preferred isomer in that solvent.
_
.
CDCl3 acetone-d, acetone-d, CDCl3
3.64 3.69 3.47 3.49
1.63 1.58 1.03 1.03
7.91 8.04 7.64 7.61
7.41b 7.44b 7.35b 7.31b
CDC13 acetone-de acetone-d, CDCl,
3.64 3.68 3.43 3.47
1.63 1.51 1.02 1.04
7.96 8.04 7.52 7.52
6.93 6.99 6.91 6.84
CDCl3 acetone-d6 acetone-de CDCl,
3.76 3.79 3.54 3.53
1.67 1.61 1.05 1.03
8.17 8.32 7.93 7.81
8.32 8.33 8.25 8.18
la-B
la-#
p-OCH3
3.85 3.87 3.80 3.81
Also p-Ph hydrogens.
Table 11. NOE Enhancements for C-Methoxy-C-arylnitronesO lH observed, % (error) 'H saturated a-OCH3 o-phenylb N-t-Bu 2.5 (0.7) 0.0 (0.4) a-OCH3 4.5 (0.4) N-t-Bu 0.9 (0.1) 12.0 (0.1) a-OCH3 4.3 (0.1)
nitrone
m-Ph
other hydrogens
m-phenyl 2.0 (0.1) 0.0 (0.1) 5.9 (0.1) 0.0 (0.1) -2.1 (0.1) 14.4 (0.1) 0.0 (0.1) lb-ZI' 1.5 (0.2) 9.6 (0.2) 0.0 (0.3) 5.1 (0.2) 0.0 (0.3) 0.0 (0.2) 0.0 (0.2) 14.9 (0.3) IC-Et 4.4 (0.3) 0.0 (0.2) 5.8 (0.2) IC-zd 0.0 (0.1) 11.0 (0.1) 4.2 (0.1) "NOE data on samples deoxygenated prior to analysis at various temperatures: la-E, 7.0 "C; la-2,25 "C; lb-E, -5 "C;lb-2,7 "C; IC-E, 2 "C; IC-2, 25 "C; Id-2,0 "C. bWith respect to the a carbon. 'In CDCl,. acetone-ds. lb-Et
N-t-Bu a-OCH3 p-OCH3 N-t-Bu a-OCH3 p-OCH3 N-t-Bu a-OCH3 N-t-Bu a-OCH3
3.3 (0.1)
-13.75,
I
-14.25-
-c
1
\
-14.75
-15.254 3.55
3.60
3.65
3.70
3.75
I
3.80
(lm x 10 exp 3, 1/K
saturation of N-tert-butyl causes a 2.5% enhancement of the 0-methoxy signal and, as expected for the E configuration, no enhancement for ortho hydrogens. For the isomer in acetone (la-2) saturation of N-tert-butyl gives a very large enhancement of 12.0% for ortho hydrogens (indicating that phenyl and tert-butyl are cis) but has little effect (N\!-B~ 1d - 2 CH30
H*h23 they may be comparable for the two isomers, as is the degree of phenyl conjugation. To the extent that a tert-butyllphenyl steric interaction is similar to that of tert-butyl/O-methyl, the main difference between I-E and 1-27 is their dipole moment. (22) (a) Bj0rg0, J.; Boyd, D.R.; Watson, C. G.; Jennings, W. B.; Jerina, D. M. J. Chem. SOC.,Perkin Tram. 2 1974, 1081-1084. (b) For an
alternative explanation to the imine results of ref 23, see: Kyba, E. P. Tetrahedron Lett. 1973, 5117-5120. (c) Bakke, J. M.; Ronneberg, H.; Chadwick, D. J. Magn.Reson. Chem. 1987,25,251-254. (23) Epiotis, N. D.; Bjorkquist, D.; Bjorkquiet, L.; Sarkanen, S . J. Am. Chem. SOC.1973,95, 7558-7562.
MNDO-calculated heats of formation, which refer, of course, to the gas phase, are relatively close for the two isomers, in agreement with the observation that the solvent can influence isomer preference so markedly. The lower energy isomer, by 2.8 kcal/mol, is for the less polar E configuration, which exists in the less polar chloroform. The rather large calculated dipole moment difference of 1.33 D helps explain the striking solvent effect in which the exclusive isomer is E in chloroform and the more polar 2 in the more polar acetone. Less pronounced solvent effects on isomer preference were reported for aldonitronesZ4and for nitrones 1LZ6 Changing the solvent from chloroform to the more polar DMSO increased the relative amount of the more polar 11-2from 14% to 60%. CHsOCO cw30c0\
llf
11-27
Interestingly, the a-hydrogen of 11-Ein chloroform occurred at a lower field than 11-Zdue to deshielding by the N-oxide but at a higher field in DMSO. It was suggested= that the dipole of DMSO aligned with that of the N-oxide to cause an increased deshielding of this hydrogen in the Z isomer. A specific dipole-dipole interaction of the same sort may account for further stabilization of 1-2. It is clear that 1, with AH*values
