2910
J. Phys. Chem. 1993,97, 2910-2913
A Proton NMR Investigation of Rotation about the C(0)-N Bonds of Ureafpl Yiming Zhao, Mary Katherine Raymond, Helen Tsai, and John D. Roberts’ Division of Chemistry and Chemical Engineering, California Institute of Technology,$ Pasadena, California 91 125 Received: October 19, 1992 The rates and activation energies have been determined by proton N M R for H2I5N(C0)I4NH21and hydrogenexchange equilibrated mixturesof 1and H2I5N(CO)”NH2 2 with D2NC(O)ND2 3. Synthesis of 1was achieved by the classic Wdhler procedure from I5NH4 C = - ’ 4 N 4 with no detectable formation of H215N(C0)’5NH2. In the slow-rotation regime, the chemical-shift difference between the protons cis and trans to the carbonyl oxygen decreases rather rapidly with increasing temperature (0.0063 ppm/”). Coupling parameters were extracted from the rather complex six-spin system afforded by H2I5NC(O)I5NH2. The activation parameters for the rotation in dimethylformamide-dimethylsulfoxide solution were AG* (245 K) = 11.2 f 0.3 kcal/mol and Ea = 13.5 f 0.25 kcal/mol. Significant changes in the sensitivity of the variations of the proton shifts with temperature were found with substitution of deuterium for hydrogen and addition of water to the solvent. The overall results are in accord with the resonance interpretation of the barrier to rotation about the C(0)-N bonds of amides and ureas.
The rates and activation parameters for rotation about the C(0)-N bonds of simple amides have been extensively studied by NMR,2 and after some false starts, it is now clear that, in the absence of compelling steric hindrance, the activation energy is about 20 kcal/mol. This value is usually accounted for by partial double-bond character of the C(0)-N bond resulting from electron delocalization of the unshared pair of electrons on the nitrogen to the carbonyl group. If one assumes that, in the transition state, the hydrogens on nitrogen and the nitrogen determine a plane 90° to the plane of the carbonyl group and the atom attached to it, then the delocalizationshould be effectively zero because the unshared pair of electronson nitrogen is expected to be in an orbital orthogonal to the 7 orbital of the carbonyl group. Thesimpleexpectationthen is that theactivation enthalpy would be close to the amide resonance energy, and indeed, the formamide resonance energy calculated from heat of combustion is about 21-22 kcal.ja The resonance energy of urea estimated from thermochemical data is 30-33 k ~ a l , and ~ , this suggests that the rotational barrier around its C(0)-N bonds should be in the range 8-13 kcal because, in the transition state, one C(0)-N bond could retain the 21-22 kcal of amide resonance energy, while the rotating bond would lose 8-13 kcal of resonance energy. This is quite reasonable because, as will be discussed in more detail below, the free energies of activation for rotation about the C(0)-N bonds of urea are known to be much smaller than 20 kcal. To complete the argument, it was desirable to get a fix on E, for the rotational barrier of urea using well-established NMR techniques. Stilbs and Forstn? recognizing the potential difficulties resulting from I4N quadrupole broadening effects on the NMR proton resonances of urea, undertook to study the CO-N bond rotation with the aid of H21SN(C10)1sNH2(2) but found the proton spectrum to be too complex to be usefully resolved at the low temperatures (-220 K at 60 MHz) required for study of the line shapes. We have found the same to be true for the 15N spectrum of 2, which is also complex (Figure 1) and for which we find excellent agreement with the reported5 couplings and shifts. Stilbs and Fors6n4 determined a AG*of 1 1.5 kcal from the proton line-shape changes of unlabeled urea 4 in a dimethyl sulfoxidedimethylformamidesolvent in the range 220-229 K. Dedicated with great appreciation to Professor Harden M. McConnell on the occasion of his 65th birthday. Contribution No. 875 I from the Gatesand Crellin Laboratories,California Institute of Technology. Pasadena, CA 91 125.
*
0022-3654/93/2097-2910$04.00/0
Figure 1. Observed and calculated partial nitrogen-1 5 spectrum of 99% urca-15N2 dissolved in deutericdimethyl sulfoxide at room temperature at 50.7 MHz. Only the downfield and the center group of rmnanca are shown. There is also an upfield resonance that is the mirror image of the downfield peak. The major peah are separated by about 86 Hz. The calculated spectral groupings were obtained with the aid of the LACON3 programI3 extensively rewritten in True BASIC to run on Macintosh or IBM peraonal computers. The coupling constants extracted from this spectrum agree with those reported from analysis of the proton rcsonanca by Stilbs and For&n5 to within 0.05 Hz, except for ’5” for which we obtained 4.6 Hz rather than the 5.1 Hz.
Walter, Schaumann, and Rose6 found AG* = 1 1.O kcal at 225
K in dimethylformamideacetone. To diminish the potential quadrupolebroadening problem with 4 and the spectral complexity problem with 2, we opted to study H2l5N(C=0)l4NH2 (1). with which we could expect that the spectral complexity of 2 arising from the N-N coupling would
bemostly obliterated by the 14Nquadrupolerelaxation. Although we expected there would be sufficient 1 for our use in commercial samples of 33%-enriched urea-ISN, the NMR spectra showed this material to be a 1:2 mixture of 2 and 4. However, 1 was easily prepared by the classic Wdhler synthesis’ through heating 15NH4C14N0.The NMR spectra of 1 indicated no trace of 2, which was unexpected because the cyanateurea reaction is known to be reversible. However, numerical integration of the known rate constantss for the reaction conditions and reaction time confirmed that a negligible amount of 2 would be found. 63 1993 American Chemical Society
The Journal of Physical Chemistry, Vol. 97, No. 12, 1993 2911
Rotation about the C(0)-N Bonds of Urea
3 0 H ~__f Figure 2. I3Cspectrum at 125.7 MHz of a solution of 31% urea-I5N2and 69% urea-14N2in 10%dimethyl-& sulfoxide-90% water that was heated at 100 "C for 40 h. The integral of this spectrum shows the presence of + ,
44% of urea-I4N2(center peak), 45% of urea-15Nl(broadened doublet), and 10%of urea-I5N2(sharptriplet). The 14N/15Nisotope effect on the IT chemical shift amounts to 2.5 Hz (0.020 ppm).
db
261'
251'
2
0.0010s
0.0018 s
4
f--
3
200Hz
0
0.0070 s
I_t
Figure 3. Illustrative changes in the proton spectra of urea-l5N1 as a function of temperaturein dimethylformamidc-deuteriodimethylsulfoxide solution with derived T values.
Furthermore, when a sample of 31% 2 and 69% 4 was heated in water at 100 "C for 40 h, the I3C spectrum (Figure 2) indicated the presence of 41, and 2 in the proportions of 4.3:4.4:1, not far from the calculated equilibrium proportions for this starting mixture of 5.05:4.49:1. We investigated the rotational barrier parameters for 0.05 M 1 in the same dimethylformamide-dimethyl sulfoxide solvent mixture used previously4 and also in the presence of different amounts of water. An advantage to using 1 was that the rate constants could be derived from the line-shape changes of the protons attached to both the I5N and I4N as a function of temperature. Interestingly, the I4N/ISN isotope effect on the proton shifts was 1 Hz or less. Some illustrative 500-MHz spectra are shown in Figure 3. As previously noted,6in the slow-rotation regime, the chemical-shift difference between the protons decreases rather rapidly with temperature, as do also the shifts relative to the resonance of the formyl proton of the dimethylformamide. The intramolecular shift-difference changes have been attributed to differential and temperature-variable hydrogen bonding to solvent? We believe it more likely that the intramolecular shift changes result from torsional oscillations at the C-N bond that increase in amplitude as the temperature increases. During such oscillations, if harmonic, the protons will spend more of the time out-of-plane than in-plane and hence become more nearly equivalent. The
shift change with temperature is substantially larger for the downfield resonance than the upfield resonance. This fact has been utilized6 in the hydrogen-bonding argument to assign the downfield resonances to the "outer* urea protons (cis to the oxygen); although, with formamide, the outer protons are surely the upfield amide proton^.^ If our argument is correct and the decrease in shift with temperature is mostly the result of increased amplitude of torsional motions around the C(0)-N bond, it need not be necessary for the nonequivalent protons to have equal changes in shift for a particular torsional amplitude, because the stereoelectronic and shielding situations of the outer and inner protons are not likely to be the same. In fact, the shift of the downfield protons changes more rapidly with temperature than that of the upfield protons (Figure 4). In determining the rotation rates, we applied corrections to the line-shape calculations based on extrapolation of the shift differences into the region where extensive overlap of the resonancesoccur.4 As noted quadrupole broadening of the proton resonances is not very important at the lower temperatures, but viscous broadening is and also requires some correction. The curves shown in Figure 3 were matched by computer-generated line shapes based on the classic equations derived by McConnell.Io From this data, we obtained AG'(245 K) = 11.1 f 0.3 kcal and E, = 13.2 f 0.5 kcal. The change of chemical-shift difference with temperature of the nonequivalent protons in the slow-rotation regime of 1 was approximatelylinear (Figure 5) and, when extrapolated, indicated that the shift difference would be zero around room temperature. It seems reasonable that, at room temperature, the rate of rotation would be too fast to measure by currently available NMR techniques. It does not seem likely that extrapolation to still higher temperatures would lead to a change in sign of the shift difference, so what is the state of the urea molecule at room temperature or above? This and other questions made investigation of the deuterium isotope effect on the urea rotation rates of special interest. The principal difficulty with studying C-N bond rotation of partially deuteriated urea by proton NMR is to know precisely which species of molecule is giving the proton signal, because proton-deuterium exchanges, while not fast enough to obscure the NMR signals, will lead to a statistical mixture of protondeuterium isotopomers. In one trial, we used a 1:l mixture of 1and 3. The derived rotation rates seemed internally consistent, but they were the composite rates from the six possible isote pomers, all with equal statistical probabilities, although those with NHD groups gave half as intense proton signals in the intermediate range as those with NHz groups. We were particularly interested in isotope effects produced by deuterium substitution at the nitrogen not undergoing rotation. To make this the principal influence on the rates, we used a mixtureof 18% of 2 and 82% of 3. On the assumption of statistical equilibrium, 55% of the proton signal would arise from C(O)NHD*(NDz), 67% would come from species with two deuteriums on the nonrotating nitrogen, and 97% would be observed from species with at least one deuterium on the nonrotating side. This deuteriated mixture gave AG'(245 K) = 11.1 f 0.3 kcal and E. = 13.4 & 0.25 kcal. The rate at 245 K and activation parameters were not much affected by deuterium substitution. However, there were rather dramatic changes in the proton chemical-shift differences in the slow-rotation regime and the slope of the average shift with temperature in the fast-rotation regime, as can be seen in Figures 4 and 5, respectively. While the decrease in the differences between the separate proton shifts may be the result of a simple isotope effect, the temperature dependences of the shifts appear to be more complicated. We suggest that they are related to the deuterium isotope effect on the torsional oscillations around the C-N bonds." In the extreme, these oscillations lead to the
2912 The Journal of Physical Chemistry, Vol. 97, No. 12, 1993 6.2
6.0
Proton shifts, ppm
5.8
5.6
5.4
'
200
I
I
I
I
225
250
215
300
Temperature, OK Figure 4. Variation of the separate and rotational-averaged 500-MHz chemicalshifts for urea samplesas a function of temperature: (H) 1,0.01 M water; ( 0 ) 18%2 and 82% j; (0)1, 0.2 M water.
Shift difference, HZ
175
200
225
250
275
300
Temperature, OK
Figure 5. Changes of 500-MHz proton chemical-shift differences of various urea samples in the slow-rotation regime. The points are well fitted by linear relationships, and the correlation lines are extrapolated to zero shift. The linearity of the averaged shifts in Figure 4 offers 1,0.01 M water; support for the extrapolations shown in this figure: (0) ( 0 ) 18% 2 and 82% j; (H) 1, 0.2 M water; (0)1, 0.6 M water.
rotational transition state. Decreases in the amplitude of such torsional motions associated with deuterium substitution would be expected to increase the resonance stabilization and to give less of an increase in amplitude with increases in temperature. That there is some, but not a large, increase in E, could be the result of increased stabilization of the nonrotating C-N bond in the transition state as the result of the same stiffening process. Addition of 0.2 M water to the solvent (before the addition the water concentration as judged by integration of the NMR peaks was 0.01 M in water) caused sizable decreases in the proton-shift difference, but not much change in the slope of the change of the average shift difference with temperature; see Figure 4. With 0.2 M water, the rate of rotation about the C(O)-NH2 bonds was about 50%less than in the absence of water. Slowing of the rate by water could be the result of hydrogen bonding to the carbonyl oxygen of urea and the expected concomitant increase in the resonance energy of the ground state relative to the transition state. Large reductions in the rotation rates of amides and substituted ureas by substances that complex with the carbonyl oxygen are well-known.2 The reasons for the diminishment of the chemical-shift difference in the slow-rotation regime by addition of water are less clear. With 0.6 M water, the chemicalshift difference is quite small and rapidly decreases with temperature (see Figure 5 ) . This phenomenon makes it difficult to measure the rotation rate, because the shift difference seems
Zhao et al. to go to zero well before there is substantial line broadening. However, no line-shape changes were observed indicating that the chemical-shiftdifferencechanged sign, and coalescencearising from rapid rotation occurred, possibly at around 245 K, as was obtained with 0.2 M water (but now with the proton resonances having opposite shifts). On the whole, the results obtained from the NMR studies support the general resonance interpretation for the source of the barrier for rotation around amide bonds. To see whether detailed quantum mechanical calculations would indicate a different way of looking at the results, as has been suggested for formamide,3b Dr. Robert Kumpf and Professor Dennis A. Dougherty have used a 6-31G* basis set and the Gaussian 90 program to calculate the properties of urea and the rotational transition state. Their preliminary results indicate that the rotational barrier is comparable to that calculated for f ~ r m a m i d equite , ~ ~ a bit higher than the observed value of about 13 kcal. There is extensivedata indicatingthat urea molecules are planar in the crystalline state, but the most stable configuration for the gaseous state appears from the dipole moment obtained by microwave spectra to be nonplanar. Such a configuration is supported by recent calculations reported by Meier and Coussens.12 The highest level (MP2/61G*) calculations by these workers suggest that both nitrogens are somewhat pyramidal and, furthermore, that there are different torsional angles about the C-N bonds, withonebeing twisted 13.4O and theother 145.8O away from the plane defined by the N-C-N group. That the microwave spectrum should show a smaller dipole moment than expected for an average planar urea is not surprising, provided that there is substantial harmonic torsional motion about the C-N bonds and, as suggested earlier, the hydrogens are on the average out-of-plane much more of the time than they are inplane. Because trivalent nitrogen prefers a pyramidal configuration, it would not be surprising that, even with important resonance contributions, there would still be some degree of nonplanarity of the nitrogens. Further, because urea is crossconjugated, it is also not wholly surprising that onenitrogen might be twisted out of the plane more than the other, because that would lessen the cross conjugation. However, that the twist of the less-conjugated nitrogen would be as much as 145.8' seems less easily understood. Certainly, it would not be expected that the C-N bonds in the asymmetricallytwisted nonplanar structure would be calculated to have exactly the same length to within 0.001 A. It is interesting that the planar and nonplanar states are calculated to only differ in energy by 2.6 kcal. Professor W. A. Goddard and his colleagues are planning to reinvestigate the theoretical situation using a somewhat different basis set.
Experimental Part Singly lSN-labeledurea was prepared by the classic WBhler synthesis.' Ammonium-15Ncyanate was prepared by stirring a finelyground equimolar mixtureof silvercyanateand ammoniumISNchloride in water for 2 h. The resulting silver chloride was removed by filtration, and the filtrate containing 15NH,C14N0 was heated in a boiling water bath for an hour. The water was removed under reduced pressure and the residue recrystallized from absolute ethanol and dried in a vacuum desiccator. The yield of l5NH4CI4NOwas 4296, mp 128-130 OC (lit. mp 132.7 "C). The urea-I5Nz was obtained from Isotec. TheNMRspectraweretakenona Bruker FTSOO-MHzNMR spectrometer. The solvent for the low-temperature experiments was 0.65:0.15 (v/v) dimethylformamide and deuteriodimethyl sulfoxide. The latter provided the deuterium field-frequencylock. The urea concentration was uniformly 0.05 M. The reference peak used for the proton spectra was the 7.792 ppm formyl proton resonance of the dimethylformamide. The proton-shift change of methanol was used to calibrate the probe temperature. Usually about 12 different temperatures were used to cover the range of spectral changes from 200 K to room temperature.
Rotation about the C(0)-N Bonds of Urea
The Journal of Physical Chemistry, Vol. 97, No. 12, 1993 2913
The rates were obtained by comparing the low-temperature spectra with spectral curves calculated with a True BASIC program that sums simulations of individual proton spectra expected for the 14Nand l5N ends of the singly labeled urea with different line widths and couplings, but with the same chemicalshift difference. Actually, quadrupole relaxation of 14Nwas fast enough so that its couplings to protons and I5N had no influence on the spectra, except for some proton line broadening. Provision was made for inclusion of I4N/I5Nisotope effects on the proton shifts, but these were negligible. The slow-exchange chemicalshift differences in the intermediate range were estimated by plotting and extrapolatingthe shift differencesin the slow-rotation regimeagainst temperatureas in Figure5.. Thelinewidthsbecame increasingly broad as the temperature was decreased in the slowrotation regime, and these were also plotted and extrapolated into the intermediate regime, so as to have appropriate values for the slow-exchange line widths at the various temperatures. Usually, the spectra could be matched to particular T values to about *3%. Calculations of AG*and E, were made in the usual way.
Company, Inc., Eastman Kodak Company and Minnesota Mining and Manufacturing. Additional support was provided by Caltech Summer Undergraduate Research Fellowships (SURF). (2) Oki, M. Applications c$ Dynumic NMR Spectroscopy to Organic Chemistry; VCH Publishas: Deertield, FL, 1985; pp 41-67. (3) (a) Wheland, G.W. Resonance in Organic Chemistry;John Wiley and Sons: New York, 1955; pp 99-100. Note that Wheland backed off from an earlier estimate of 41 kcal for urea; see: Wheland, G. W. The Theory of Resonunce;John Wiley and Sons: New York, 1944; p 70. (b) For a different interpretation based on ab initio calculations, see also: Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987, 109, 5935. (4) Stilbs, P.; FmsCn, S. J. Phys. Chem. 1971, 75, 1901. (5) Stilbs, P.;ForsCn, S. Org. Mugn. Reson. 1976,8, 384. (6) Walter, W.; Schaumann, E.; Rose, H. Tetrahedron 1972,28, 3233. (7) WBhler, F. Ann. Phys. 1825, 3, 177; 1828, 12, 253. (8) Walker, J.; Hambly, F. J. J. Chem. Soc. 1895, 67, 746. (9) Sunners, B.; Piette, L. H.;Schneider, W. G. Can. J . Chem. 1960,38,
References and Notes
LJJ, 4 J .
681.
(IO) McConnell, H. M. J . Chem. Phys. 1958, 28,430. (11) Campos, M.; Diaz, G. Z . Nuturforsch. 1982, 37A, 1289. (12) Meier, R. G.; Coussens, B. J . Mol. Struct. (THEOCHEM) 1992, q . ? ,
(1) This research wassupported by theCaltechConsortiumin Chemistry and Chemical Engineering; founding members E. 1. Du Pont de Nemours and
.IC
(13) Bothner-By, A. A.; Castellano, S. M. In Computer Programs for Chemistry; DeTar, D. F., Ed.; W. A. Benjamin: New York, 1968; Vol. I , Chapter 3.
