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Stereodynamics of N-Isopropyl-N-methylpropargylamine. Dynamic NMR Studies. Molecular Mechanics Calculations Jay H. Brown* Science Department/Chemistry Program, Southwest State University, Marshall, Minnesota 56258
C. Hackett Bushweller Chemistry Department, University of Vermont, Burlington, Vermont 05405
[email protected] Received September 19, 2000
N-Isopropyl-N-methylpropargylamine (N-isopropyl-N-methyl-2-propyn-1-amine; IMPA) is chiral at the pyramidal nitrogen. Racemization occurs via an inversion-rotation process. Both 13C{1H} and 1H dynamic NMR (DNMR) spectra decoalesce in response to slowing inversion-rotation (∆G q ) 7.7 ( 0.1 kcal/mol). While aspects of the DNMR spectra suggest the presence of minor conformations, the spectrum at 100 K shows a strong preference for one conformation. The NMR data suggest that the preferred conformation has both the isopropyl methine proton and the ethynyl group anti to the lone pair. Both isopropyl methyl groups are gauche to the lone pair. This conformational preference is in significant contrast to N-ethyl-N-methyl-2-aminopropane in which the population of that conformation having the ethyl methyl group and the isopropyl methine proton both anti to the lone pair is only 5% at 95 K. The NMR data, supported by molecular mechanics (MMX) calculations, suggest a special stabilization for the ethynyl group being oriented anti to the lone pair. Introduction Amines constitute a very important class of organic compounds. Any successful attempt to ascertain the stereodynamics of an aliphatic amine must involve consideration of both pyramidal inversion and isolated rotation.1-3 The inversion process is complex, involving both inversion at the pyramidal nitrogen in concert with, or accompanied by, rotation about carbon-nitrogen bonds.1-4 The overall process is best described as inversion-rotation. For simple aliphatic amines, barriers to isolated rotation (rotation without inversion) are generally lower than barriers to inversion-rotation.1 Raman, infrared, microwave, and molecular orbital theory have been useful for studying the stereodynamics of several simple amines, including the following: methylamine,5 dimethylamine,5 trimethylamine,5 ethylamine,6 ethylmethylamine,7 dimethylethylamine,8 and isopropylamine.9 (1) For a recent review, see: Bushweller, C. H. In Acyclic Organonitrogen Stereodynamics; Lambert, J. B., Takeuchi, Y., Eds.; VCH Publishers: New York, 1992. (2) For previous reviews, see: Lambert, J. B. Top. Stereochem. 1971, 6, 19. Lehn, J. M. Fortschr. Chem. Forsch. 1970, 15, 311. Payne, P. W.; Allen, L. C. In Applications of Electronic Structure Theory; Schaefer, H. F., Ed.; Plenum Press: New York, 1977; Vol. 4. Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 400. (3) Orville-Thomas, W. J., Ed. Internal Rotation in Molecules; J. Wiley and Sons: New York, 1974. (4) Bushweller, C. H.; Anderson, W. G.; Stevenson, P. E.; Burkey, D. L.; O’Neil, J. W. J. Am. Chem. Soc. 1974, 96, 3892.Bushweller, C. H.; Anderson, W. G.; Stevenson, P. E.; O’Neil, J. W. J. Am. Chem. Soc. 1975, 97, 4338. Anderson, J. E.; Tocher, D. A.; Casarini, D.; Lunazzi, L. J. Org. Chem. 1991, 56, 1731. (5) (a) Tsuboi, M.; Hirakawa, A. Y.; Tamagake, K. J. J. Mol. Spectrosc. 1967, 22, 272. (b) Nishikawa, T.; Itoh, T.; Shimoda, K. J. Am. Chem. Soc. 1977, 99, 5570. (c) Wollrab, J. W.; Laurie, V. W. J. Chem. Phys. 1968, 48, 5058. (d) Erlandson, G.; Gurdy, W. Phys. Rev. 1957, 10, 513. (e) Lide, D. R.; Mann, D. E. J. Chem. Phys. 1958, 28, 572.
In addition, barriers to pyramidal inversion have been measured in ammonia,10 methylamine,5a,11 dimethylamine,5c and trimethylamine.12 Dynamic NMR (DNMR) spectroscopy,13 complemented with molecular mechanics calculations,14 have been useful in studying the stereodynamics of more complex amines including: diethylmethylamine,15 triethylamine,15,16 dibenzylmethylamine1, tribenzylamine,17 isopropyldimethylamine,18 isopropylethylmethylamine,19 2-butylethylmethylamine,20 diethylisopropylamine,21 2-(dibenzyl)(6) Durig, J. R.; Li, Y. S. J. Chem. Phys. 1975, 63, 4110. Tsuboi, M.; Tamagake, K. J.; Hirakawa, A. Y.; Yamaguchi, J.; Nakagava, H.; Manocha, A. S.; Tuazon, E. C.; Fateley, W. G. J. Chem. Phys. 1975, 63, 5177. (7) Durig, J. R.; Compton, D. A. C. J. Phys. Chem. 1979, 83, 2873. (8) Durig, J. R.; Cox, F. O. J. Mol. Struct. 1982, 95, 85. (9) Krueger, P. J.; Jan, J. Can. J. Chem. 1970, 48, 3229. (10) Swalen, J. D.; Ibers, J. A. Chem. Phys. 1962, 36, 1914. (11) Tsuboi, M.; Hirakawa, A. Y.; Takamitsu, I.; Sasaki, T.; Tamagake, K. J. J. Chem. Phys. 1964, 41, 2721. (12) Weston, R. E., Jr. J. Am. Chem. Soc. 1954, 76, 2645. (13) Oki, M. In Applications of Dynamic NMR Spectroscopy to Organic Chemistry; VCH Publishers: New York, 1985. Sandstrom, J. In Dynamic NMR Spectroscopy; Academic Press: New York, 1982. Cotton, F. A. In Dynamic Nuclear Magnetic Resonance Spectroscopy; Academic Press: New York, 1975. (14) Burkert, U.; Allinger, N. L. In Molecular Mechanics; American Chemical Society: Washington, DC, 1984. Allinger, N. L. Adv. Phys. Org. Chem. 1976, 13, 1. (15) Bushweller, C. H.; Fleischman, S. H.; Grady, G. L.; McGoff, P.; Rithner, C. D.; Whalon, M. R.; Brennan, J. G.; Marcantonio, R. P.; Domingue, R. P. J. Am. Chem. Soc. 1982, 104, 6224. (16) Fleischman, S. H.; Weltin, E. E.; Bushweller, C. H. J. Comput. Chem. 1985, 6, 249. (17) Fleischman, S. H.; Whalon, M. R.; Rithner, C. D.; Grady, G. L.; Bushweller, C. H. Tetrahedron Lett. 1982, 4233. (18) Brown, J. H.; Bushweller, C. H. J. Am. Chem. Soc. 1992, 114, 8153. (19) Brown, J. H.; Bushweller, C. H. J. Phys. Chem. 1994, 98, 11411. (20) Danehey, C. T., Jr.; Grady, G. L.; Bonneau, P. R.; Bushweller, C. H. J. Am. Chem. Soc. 1988, 110, 7269.
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aminopropane,21 N-allyl-N-methyl-2-aminopropane,22 several N,N-diisopropylalkylamines,23 and several tertbutyldialkylamines.4 For the highly encumbered tertbutyldialkylamines, the isolated tert-butyl rotation barrier is greater than the inversion-rotation barrier. As a result, the preferred conformational exchange pathway involves concomitant nitrogen inversion and tert-butyl rotation.4 For triisopropylamine, steric constraints impose an equilibrium geometry that has essentially C3h symmetry with an almost trigonal planar nitrogen and all three methine C-H bonds in the trigonal plane.24 Inversion at this essentially trigonal planar nitrogen is irrelevant.24 Both steric and electronic factors must be considered when discussing preferred equilibrium conformations of alkylamines.1,2 For example, ethylamine exists as three equilibrium rotamers including two forms with the methyl group gauche to the lone pair and another with the methyl group anti to the lone pair.6 Ethylamine shows a clear preference for the anti conformation.6 From a steric standpoint, the two gauche rotamers should be more stable. However, electronic factors appear to favor the more crowded anti form.6 This is in contrast to several more sterically crowed N-ethyl-N,N-dialkylamines in which the ethyl methyl groups prefer the less crowded positions gauche to the lone pair.15,16,19-21 Propargylamine (2-propyn-1-amine) shows an essentially exclusive preference for the anti conformation in a manner analogous to ethylamine.6,25 While the conformational preferences of propargylamine have been ascertained using Raman, infrared and microwave spectroscopy,25 the conformational preference of a propargyl group in a more crowded N-isopropyl-N-alkylpropargylamine has not yet been determined. In this paper, we report a DNMR study of N-isopropylN-methylpropargylamine (N-isopropyl-N-methyl-2-propyn-1-amine; IMPA) that reveals a strong preference for one conformation at 100 K in which the ethynyl group adopts the position anti to the nitrogen lone pair. Indirect evidence suggests the existence of minor conformation(s). Molecular mechanics (MMX) calculations are in agreement with the NMR evidence and provide additional insight into the conformational preference of this propargylamine derivative.30 (21) Brown, J. H.; Bushweller, C. H. J. Am. Chem. Soc. 1995, 117, 12567. (22) Brown, J. H.; Bushweller, C. H. J. Phys. Chem. A. 1997, 101(31), 5700. (23) Anderson, J. E.; Casarini, D.; Lunazzi, L. J. Chem. Soc., Perkin Trans. 2 1990, 1791. (24) Bock, H.; Coebel, I.; Havlas, Z.; Liedle, S.; Oberhammer, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 187. (25) Verma, A. L.; Bernstein, H. J. J. Chem. Soc., Faraday Trans. 2 1973, 69, 1586. Cervellati, R.; Caminati, W.; Degli Esposti, C.; Mirri, A. M. Mol. Spectrosc. 1977, 66(3), 389. Palmieri, P.; Mirri, A. M. J. Mol. Struct. 1977, 37(1), 164. Hamada, Y.; Tsuboi, M.; Nakata, M.; Tasumi, M. J. Mol. Spectrosc. 1984, 107(2), 269. Riggs, N. V. Aust. J. Chem. 1987, 40(3), 435. (26) Brown, J. H.; Bushweller, C. H. QCPE 1993, Program no. 633. For a PC-based program to plot DNMR spectra, see: Brown, J. H. QCPC 1993, Program no. QCMP 123. (27) A two-letter designation will be used to name conformations. The first letter defines the orientation of the propargyl quaternary carbon (G denotes gauche to the lone pair and to the N-methyl group; G′ denotes gauche to the lone pair and to the isopropyl group; A denotes anti to the lone pair). The second letter defines the orientation of the isopropyl methine proton (G denotes gauche to the lone pair and to the N-methyl group; G′ denotes gauche to the lone pair and to the propargyl group; A denotes anti to the lone pair). (28) Hamlow, H. P.; Okuda, S. Tetrahedron Lett. 1964, 37, 2553. Lambert, J. B.; Keske, R. G.; Carhart, R. E.; Jovanovich, A. P. J. Am. Chem. Soc. 1967, 89, 3761.
Brown and Bushweller
Figure 1. Experimental 13C{1H} DNMR spectra (62.898 MHz) of N-isopropyl-N-methylpropargylamine (IMPA; 3% v/v in CBrF3) in the left column and theoretical line shape simulations in the right column. The rate constant (ki) is for inversion-rotation at the pyramidal nitrogen.
DNMR Studies. The 13C{1H} DNMR spectra (62.898 MHz) of IMPA (3% v/v in CBrF3) are shown in Figure 1. At 180 K, the spectrum shows six singlets at 20.83 (isopropyl methyl carbons), 39.75 (N-methyl carbon), 44.52 (propargyl methylene carbon), 53.10 (isopropyl methine carbon), 73.77 (propargyl methine carbon), and 79.18 ppm (propargyl quaternary carbon). Integration of the peak areas is unreliable due to different logitudinal relaxation (T1) values and different nuclear Overhauser effect (NOE) enhancements of the carbon nuclei in the 13C{1H} spectra.31 Differences in the peak heights may also be due to missing data points that correspond to peak maximasa common problem for narrow lines. At 155 K, the signal due to the isopropyl methyl carbons is decoalesed into two signals in response to slowing inversionrotation on the NMR chemical exchange time scale (Figure 1).1,19 At 155 K, all other resonances remain (29) Fleischman, S. H. In On the Stereodynamics of Tertiary Amines. PhD. Dissertation, University of Vermont, 1986, 80, 148, 260. (30) Serena Software, Box 3076, Bloomington, IN 47402-3076. (31) Friebolin, H. In Basic One- and Two-Dimensional NMR Spectroscopy, 3rd ed.; Wiley-CVH Publishers: Weinheim, 1998; p 146, 168. Wehrli, F.; Wirthlin, T. In Interpretation of Carbon-13 NMR Spectra; Heyden & Son Publishers: London, 1980; p 7.
Stereodynamics of N-Isopropyl-N-methylpropargylamine Table 1.
13C{1H}
NMR Chemical Shifts for the Major Conformation of IMPA at 95 Ka
carbon(s)b CH(C*H3)2 C*H(CH3)2 NC*H3 NC*H2 ≡C*H -C*≡ c
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chemical shift (letter designation), ppmc 21.70 (F)d 21.51 (G)d 52.15 (C) 41.22 (E) 44.28 (D) 75.12 (B) 79.41 (A)
a Spectra referenced to TMS at 0 ppm. b Indicated by asterisk. See Figure 1. d Gauche to nitrogen lone pair.
sharp. At 150 K, the lower frequency isopropyl methyl carbon resonance is differentially broadened (Figure 1). Slow inversion with rapid isolated rotation on the NMR time scale would result in two resonances of equal intensity.1,19 At 130 K, the N-methyl carbon resonance is also broadened (Figure 1). This behavior may be due to the onset of slowing isolated rotational processes that have barriers comparable to that for inversionrotation.1,4,15-22 Below 150 K, no further decoalescence is observed. The 13C spectrum at 95 K, and especially the low-noise 1H spectrum at 100 K (vide infra) are both consistent with the presence of one dominant molecular conformation. While no minor sub-spectra are directly detected at 95 K, differential broadening at higher temperatures (vide supra) suggest the existence of minor conformation(s).19,22 Below 130 K, the concentration(s) of any minor form(s) could decrease to amount(s) below the NMR detection limit, especially for the high-noise 13C spectrum at 95 K.32 Acquisition of a higher quality 13C spectrum at 95 K was precluded by solubility constraints and the danger in keeping the NMR probe at such a low temperature for an extended period of time. To obtain a barrier for inversion, the 13C spectrum at 150 K was simulated as accurately as possible. This required adjusting of the peak areas in the simulation. Slight changes in the peak areas greatly effected the relative heights of the narrow lines at 150 K. Iterations between 130, 150, 155, 160 (not shown), and 180 K gave the first-order rate constants seen in Figure 1. The rate constants used in the 95 and 180 K simulations were obtained through extrapolation of an Eyring plot. The simulations employed a two-site F to G exchange of magnetization (ki; Figure 1; Table 1) for the isopropyl methyl carbon atoms. At 150 K, there is a divergence between the theoretical simulations and the experimental spectrum for the isopropyl methyl carbon resonances, suggesting again the presence of minor conformation(s).19,22 The N-methyl carbon resonance also shows broadening at 130 K. Below 150 K, efficient transverse relaxation (T2) obscures the small chemical shift difference between the two diastereotopic isopropyl methyl carbon resonances. Except for the isopropyl methyl carbon resonances (vide infra), no changes are noted in the chemical shifts throughout the entire temperature range. This is consistent with the preference for one dominant molecular conformation. From the line shape simulation at 155 K, the free energy of activation (∆G q) for inversion-rotation is 7.7 ( 0.1 kcal/mol. In an attempt to determine the concentration(s) of any minor subspectra which may be responsible for the (32) Concepcion, R. V.; Breeyear, J. J.; Jewett, J. G.; Bushweller, C. H. J. Phys. Org. Chem. 1998, 11, 84.
Figure 2. Experimental 13C{1H} DNMR spectra (62.898 MHz) of N-isopropyl-N-methylpropargylamine (isopropyl methyl region) in the left column and theoretical line shape simulations in the right column. The rate constant ki is for inversionrotation at the pyramidal nitrogen. The rate constant k1 is for isolated N-C bond rotation.
Figure 3. Deconvolution of the theoretical simulation of the 13C{1H} NMR spectrum (62.898 MHz) of the isopropyl methyl region of N-isopropyl-N-methylpropargylamine (IMPA) at 150 K. The rate constant ki is for inversion-rotation at the pyramidal nitrogen. The rate constant k1 is for isolated N-C rotation.
observed differential broadening of the lower frequency isopropyl methyl resonance at 155 and 150 K, additional simulations were carried out (Figure 2). While one must remain cautious in evaluating the results of simulations that involve unresolved sub-spectra, this exchange model does provide reasonable fits throughout this short temperature range (Figure 2). At 150 K, the population of the minor subspectrum was 10% (Figure 3, Table 2). The ki process involves AB to BA and DC to CD exchanges in magnetization. The k1 process involves AB to DC and BA to CD exchanges in magnetization. With the ki process assigned to inversion-rotation (vide supra), the k1 process can be assigned to isolated N-C bond rotation. The population of the minor subspectrum had to be reduced to 1% to obtain reasonable fits at 130 and 95 K (not
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Table 2. 13C{1H} NMR Parameters Used To Estimate the Concentration(s) for the Minor Subspectra of IMPA at 150 Ka
Table 3.
major subspectrum minor subspectrum (90%) chemical shift (10%) chemical shift (letter designation) ppmc (letter designation) ppmc
protons(s)b
carbon(s)b CH(C*H3)2
22.18 (A)d 21.51 (B)d
21.51 (C)d 11.84 (D)e
a Spectra referenced to TMS at 0 ppm. b Indicated by asterisk. See Figure 3. d Gauche to nitrogen lone pair. e Anti to nitrogen lone pair.
c
CH(CH*3)2 CH*(CH3)2 ≡CH* NCH*2 NCH*3
1H
Chemical Shifts for the Conformation of IMPA Observed at 100 Ka
chemical shifts (letter designation) ppm 1.16 (F)d 1.14 (G)d 2.54 (C)e 2.09 (E) 3.70 (A) 3.18 (B) 2.34 (D)
coupling constants (Hz)c 3J CF
) 3JCG ) 7.0 Hz
3J CF 4J AE 4J AE 2J AB
) 3JCG ) 7.0 Hz ) 4JBE ) 2.2 Hz ) 4JBE ) 2.2 Hz ) -18 Hz
a Spectra referenced to TMS at 0 ppm. b Indicated by asterisk. See Figure 4. d Gauche to nitrogen lone pair. e Anti to nitrogen lone pair.
c
Figure 4. Experimental 1H DNMR spectra (250.136 MHz) of N-isopropyl-N-methylpropargylamine (IMPA; 3% v/v in CBrF3) in the left column and theoretical line shape simulations in the right column. The rate constant (ki) is for inversionrotation at the pyramidal nitrogen.
shown). We are hesitant to perform Van't Hoff calculations due to the limited temperature range and the uncertainties associated with the unresolved minor subspectral population(s). We are also hesitant to report a barrier for the k1 exchange process due to uncertainties associated with the unresolved minor subspectral population(s). To provide additional insight, 1H DNMR spectra (250.136 MHz) of IMPA (3% v/v in CBrF3) were acquired. At 190 K, the spectrum of IMPA (Figure 4) shows a doublet at 1.08 ppm (3JHCCH ) 7.0 Hz; isopropyl methyl protons), a triplet at 2.20 ppm (4JHCCCH ) 4JHCCCH ) 4.5 Hz; propargyl methine proton), a singlet at 2.27 ppm (Nmethyl protons), a septet at 2.62 ppm (3JHCCH ) 7.0 Hz;
isopropyl methine proton), and a doublet at 3.36 ppm (4JHCCCH ) 4.5 Hz; propargyl methylene protons). At 150 K, the signal due to the propargyl methylene protons is decoalesed into two mirror-image multiplets of equal intensity (Figure 4). This is consistent with the slowing of inversion-rotation while isolated rotation remains fast on the NMR time scale.1,4,15-22 Throughout the temperature range, the diastereotopic isopropyl methyl groups are not resolved. Apparently the anisotropy associated with the propargyl group is not enough to decoalese the resonances of the diastereotopic isopropyl methyl groups. The differential broadening observed in the 13C spectrum at 150 K is not present in the 1H spectrum, presumably due to the smaller 1H chemical shift dispersion. Both the isopropyl methyl and propargyl methylene proton resonances move to higher frequency (∼0.2 ppm) from 190 to 100 K. This slight chemical shift dependence on temperature may be the result of exchange with minor conformation(s) or poorly understood solvent effects.31 From the line shape simulation at 160 K, the ∆G q value for inversion-rotation is 7.7 ( 0.1 kcal/mol. One intriguing aspect of the 100 K spectrum is that the propargyl methylene protons show two asymmetric resonances (Figure 4). The observed asymmetry is not the result of different couplings between the propargyl methylene protons and the propargyl methine proton since the propargyl methine proton resonance is a perfect triplet at 100 K, revealing identical coupling to both propargyl methylene protons (Figure 4, Table 3). The asymmetry could be due to differential transverse relaxation, differential long-range coupling to protons other than the propargyl methine proton, or the onset of slowing a lowbarrier isolated rotational process 1,4,15-22,32 In any event, the spectrum at 100 K is consistent with the strong preference for one molecular conformation. If any minor species are present, the populations are small. Chemical shifts due to those conformations cannot be determined. The 13C{1H} DNMR spectrum at 95 K can be used in conjunction with the 1H DNMR spectrum at 100 K to identify the major IMPA conformation.27 To accurately simulate the 13C{1H} spectrum at 95 K, two closely spaced peaks at 21.70 and 21.51 ppm are used for the isopropyl methyl carbon resonances (Figure 1; Table 1). These chemical shifts are consistent with isopropyl methyl carbons that are both oriented gauche to the nitrogen lone pair.18,19,21,22 To accurately simulate the 1H NMR spectrum at 100 K, two closely spaced isopropyl methyl resonances at 1.16 and 1.14 ppm (Figure 4, Table 3) are used. These chemical shifts are also consistent with isopropyl methyl groups that are both oriented gauche to the lone pair.18,19,21,22 The isopropyl methine proton must be anti to the lone pair (i.e., in the A orientation).27
Stereodynamics of N-Isopropyl-N-methylpropargylamine
This precludes the G′A conformation in which the ethynyl group adopts a position that is gauche to the nitrogen lone pair and the isopropyl group (i.e., the G′ orientation) causing destabilizing syn-1,3 repulsions with a proximate isopropyl methyl group. This leaves the G and A positions as possible orientations for the ethynyl group. In the G orientation, the triple bond is gauche to the lone pair and the N-methyl group. In the A orientation, the triple bond is anti to the lone pair. The 1H NMR spectrum at 100 K shows two closely spaced resonances at 3.70 and 3.18 ppm (Figure 4; Table 3) for the propargyl methylene protons. If the propargyl methylene protons were oriented anti and gauche respectively to the nitrogen lone pair, we would expect to see a chemical shift difference of about 1 ppm.1,15,19,21,22,28 A chemical shift difference of only 0.52 ppm indicates that either an exchange process is still fast at 100 K, or that these two protons are oriented in positions other than anti and gauche respectively to the nitrogen lone pair.1,15,19,21,22,28 The only conformational exchange process that would average the environments of the propargyl methylene protons is interconversion between AA and GA forms. This process involves isolated rotation about a N-C bond and eclipsing of the ethynyl group with the N-methyl group. The barrier for this process in dipropargylmethylamine (5.6 ( 0.3 kcal/mol) is well above the lower limit for detection in our laboratory (4.5 kcal/mol).18,29 This process will be slow on the NMR time scale at 100 K and is unlikely to be the cause of the closely spaced methylene resonances observed at this temperature. Thus, the dominant conformation responsible for the observed 13C{1H} and 1H NMR spectra at 95 and 100 K, respectively, is either the AA form (Figure 5; S configuration at nitrogen) or the GA conformation. In the GA form, the propargyl group may be twisted away from the perfectly staggered G position leading to the small chemical shift difference for the methylene protons. The small chemical shift difference observed for the methylene protons does seem to favor the AA conformation.1,15,19,21,22,28 Molecular mechanics (MMX) calculations support this assignment (vide infra).30 Since one major conformation dominates the 1H NMR spectrum at slow exchange, signals due to any minor conformations could not be directly detected. Therefore, the approach in simulating the exchange-broadened DNMR spectra, to obtain a barrier for inversion-rotation, was to use only the NMR parameters for the dominant conformation observed at 95 K. For the 1H DNMR spectra, simulation of the methylene protons' decoalescence involved an AB to BA exchange of magnetization (ki; Figure 4, Table 3). Extrapolation from higher temperatures provided the inversion rate at 100 K. Accurate simulations are achieved from 190 to 150 K (Figure 4). Below 150 K, there is a divergence between the theoretical simulations and the experimental spectra, presumably due to the presence of unresolved sub-spectra due to minor conformation(s). From the simulation at 160 K, the free energy of activation (∆G q) is 7.7 ( 0.1 kcal/mol. To obtain accurate fits of the isopropyl methyl region of the 13C{1H} spectra between 155 and 150, two subspectra were necessary (Figures 2 and 3, Table 2). The minor subspectrum (10% at 150 K) has chemical shifts that are consistent with gauche (21.51 ppm) and anti (11.84 ppm) isopropyl methyl groups.18,19,21,22 Conformation(s) which are consistent with this minor sub-spectrum are the G′G′, GG′, and GG forms (Figure 5).
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Figure 5. AA, GA, G′G′, GG′, and GG conformations of N-isopropyl-N-methylpropargylamine (IMPA). S configuration at nitrogen. Relative energies are found in Table 4. Select dihedral angles, bond angles, and bond lengths are found in Table 5. Nitrogen is indicated by an asterisk.
Molecular Mechanics. Molecular mechanics calculations using the MMX force field (PCMODEL version 6.0) may provide additional insight to the conformational preference of IMPA.30 Calculations suggest that the AA form (Figure 5) should be the dominant conformation at 100 K (Table 4). 27 Four other conformations (GG, G′G′, GG′, and GA) have relative energies (∆Hf) g 0.75 kcal/ mol as compared to the AA form (Table 4). Assuming that the entropy difference between any two conformers of IMPA is small, the GG, G′G′, GG′, and GA forms will be present at concentrations less than 2% at 100 K. At temperatures as low as 100 K, entropy contributions (T∆S°) to the free energy should be small as well (i.e., ∆H° ≈ ∆G°). The relative ∆Hf values listed in Table 4 may be regarded as reasonable estimates of the free energy differences between conformations. A relatively large van der Waals contribution (VdW) to the AA conformational energy (Table 4) indicates that this species is more crowed than conformations containing anti and gauche isopropyl methyl groups, respectively. However, the AA form (Figure 5) has the lowest charge-charge electrostatic interaction (QQ) as a consequence of the anti orientation of the ethynyl group (Table 4). As a result, the AA conformation is predicted to be the preferred species. The GA conformation (Figure
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Table 4. Relative Energy Parameters for the Five Lowest Energy Conformations of IMPA Calculated by the MMX Force Field
conformation
stretching (Str)
bending (Bnd)
stretch-bend cross term (StrBnd)
torsion (Tor)
Van der Waal interactions (VdW)
charge-charge electrostatic interactions (QQ)
MMX energy
∆Hf
AAa G′G′b GG GAc GG′
0.11 0.00 0.01 0.19 0.01
0.06 0.60 0.48 0.00 0.48
0.00 0.01 0.01 0.00 0.01
0.09 0.53 0.63 0.00 0.69
0.63 0.00 0.01 1.01 0.05
0.00 0.48 0.49 0.47 0.50
0.00 0.74 0.77 0.84 0.86
0.00 0.75 0.77 0.85 0.86
a StrBnd ) 0.27 kcal/mol; QQ ) 0.39 kcal/mol; MMX energy ) 10.54 kcal/mol; ∆H ) 40.59 kcal/mol. b Str ) 0.94 kcal/mol; VdW ) 4.93 f kcal/mol. c Bnd ) 2.42 kcal/mol; StrBnd ) 0.28 kcal/mol; Tor ) 0.70 kcal/mol.
Table 5. Selected Dihedral Angles, Bond Angles, and Bond Lengths for the AA, G′G′, GG, GA, and GG′ Conformations of IMPA Calculated with the MMX Force Field dihedral angle (deg)
bond angle (deg)
bond length (A)
1-2-3-4 4-3-2-5 2-3-6-7
AA Conformationa -179.7 2-3-6 113.1 -58.4 2-3-4 112.1 61.3 4-3-6 109.9
2-3 3-6 3-4
1.474 1.464 1.463
1-2-3-4 4-3-2-5 2-3-6-7
-63.5 62.5 -56.6
G′G′ Conformationa 2-3-6 113.1 2-3-4 113.3 4-3-6 109.4
2-3 3-6 3-4
1.472 1.464 1.462
1-2-3-4 4-3-2-5 2-3-6-7
62.7 -171.1 -175.6
GG Conformationa 2-3-6 113.7 2-3-4 111.6 4-3-6 110.6
2-3 3-6 3-4
1.472 1.463 1.462
1-2-3-4 4-3-2-5 2-3-6-7
-178.7 -57.5 177.4
GA Conformationa 2-3-6 112.2 2-3-4 111.6 4-3-6 109.8
2-3 3-6 3-4
1.475 1.465 1.463
1-2-3-4 4-3-2-5 2-3-6-7
-65.1 -60.8 -173.2
GG′ Conformationa 2-3-6 111.9 2-3-4 113.3 4-3-6 110.6
2-3 3-6 3-4
1.472 1.464 1.461
a
The atomic numbering scheme can be found on the conformations in Figure 5.
5) has the largest relative van der Waals contribution indicating that it’s the most sterically crowded species (Table 4). This, coupled with a relatively large chargecharge electrostatic interaction makes the GA conformation less stable than the AA form. The GG′ conformation (Figure 5) is predicted to be the least stable species (Table 4). While the GG′ conformation has a relatively low van der Waals (VdW) contribution, it has both the highest charge-charge electrostatic (QQ) and torsional (Tor) contributions to the total energy (Table 4). Table 5 contains selected parameters for the five lowest energy conformations of IMPA. The torsion (C2-N3-C6-C7) for the GG′ and GG conformations (Figure 5) are -173.2° and -175.6° respectively (Table 5). The smaller absolute value noted for the GG′ form (-173.2°) indicates increased twisting of the propargyl group so that the ethynyl group moves toward the sterically less crowded region proximate to the nitrogen lone pair. Similar twisting of the isopropyl group is also noted. The torsion angle (C1-C2-N3-LP) for the GG′ conformation and (C5-C2-N3-LP) for the GG form are 52.5° and -54.7°, respectively. The smaller absolute value noted for the analogous torsion angle associated with the GG′ form (52.5°) indicates an increased twisting of the isopropyl group placing the isopropyl methyl carbon that is gauche to the lone pair closer to the less crowded region proximate to the lone pair. Increased twisting of the propargyl and isopropyl groups in the GG′ conformation
would result in increased torsional contributions to the conformational energy (vide supra). Stabilization of the AA conformation is due, in large part, to optimized electrostatic interactions. While symmetry considerations of IMPA and N-ethyl-N-methyl-2-aminopropane are similar, conformational preferences are in sharp contrast. The preferred conformations of N-ethyl-N-methyl-2-aminopropane (93%) have gauche ethyl methyl groups and the methine proton in positions gauche to the lone pair.19 IMPA shows a strong preference (about 98%) for that conformation (AA) that has the ethynyl group and the isopropyl methine proton anti to the lone pair. The isopropyl methyl groups are both gauche to the lone pair. One other factor that would stabilize the AA form of IMPA relative to N-ethyl-N-methyl-2-aminopropane is the fact that the ethynyl group is sterically smaller than a methyl group.33 The A value for the ethynyl group is 0.4 kcal/mol while the A-value for the methyl group is 1.6 kcal/mol.33 The ethynyl group will experience reduced steric repulsions in the A orientation as compared to a methyl group15,16,19-21
Experimental Section NMR Spectra. The DNMR spectra were recorded using a Bruker WM-250 NMR system at the University of Vermont. NMR sample temperature was varied using a custom-built nitrogen gas delivery system in conjunction with a Bruker BVT-1000 temperature control unit. Temperature measurements were accurate to (3 K as determined by calibration experiments involving an independent thermocouple inserted in 5- and 10-mm NMR tubes containing toluene. Thermocouple readings were then compared to the Bruker BVT-1000 temperature control unit. NMR samples were prepared in precision 5- and 10-mm tubes. All spectra were referenced to tetramethylsilane at 0 ppm. N-Isopropyl-N-methylpropargylamine (N-IsopropylN-methyl-2-propyn-1-amine, IMPA). Propargylamine hydrochloride (10 g, 0.11 mol) in methanol (150 mL) was placed in a three-neck round-bottom flask fitted with an efficient condenser. With stirring and cooling, acetone (6.4 g, 0.11 mol) and sodium cyanoborohydride (7 g, 0.11 mol) were added. The mixture was stirred at room temperature for 3 days. With cooling and stirring, concentrated HCl (30 mL) was then added. The bulk of the liquid was removed under vacuum to yield a wet tan solid. The solid was dissolved in water (40 mL) and washed with five 40-mL portions of ether. The aqueous layer was placed in a three-neck round-bottom flask fitted with an efficient condenser. With stirring and cooling, solid KOH (30 g) was added to pH > 10. NaCl (10 g) was then added and the mixture stirred at room temperature for 24 h. The mixture was extracted with four 40-mL portions of ether. The ether layers were combined and placed in a three-neck round-bottom (33) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc. 1969, 91, 344. Schneider, H. J.; Hoppen, V. J. Org. Chem. 1978, 43, 3866. Booth, H.; Everett, J. R. J. Chem. Soc., Perkin Trans. 2 1980, 255.
Stereodynamics of N-Isopropyl-N-methylpropargylamine flask fitted with an efficient condenser. With cooling and stirring, formic acid (97%; 10.4 g, 0.22 mol) was added. The ether was removed by rotary evaporation to yield a yellow oil. The yellow oil was placed in a three-neck round-bottom flask fitted with an efficient condenser. With stirring, aqueous formaldehyde (37%; 17.8 g, 0.22 mol) was added dropwise. The mixture was stirred at room temperature for 24 h and then filtered. The bulk of the liquid was removed under vacuum to yield a wet yellow solid. The solid was placed in a three-neck round-bottom flask fitted with an efficient condenser. With cooling and stirring, the amine salt was neutralized with the addition of an aqueous 40% NaOH solution (35 mL). The resulting top layer was extracted and dried over anhydrous Na2SO4 for 2 h. N-Isopropyl-N-methylpropargylamine was
J. Org. Chem., Vol. 66, No. 3, 2001 909 purified on a 25% SF-96/5% XE-60 on Chromosorb WAW GLC column (20 ft × 3/8 in.) at 423 K. N-Isopropyl-N-methylpropargylamine was confirmed by 1H NMR (see text), 13C{1H} NMR (see text), and mass spectroscopy m/e (M+), 111.
Acknowledgment. J.H.B. would like to thank the Southwest State University Committee for Faculty Improvement Grants (Grant 211610) for the purchase of PCMODEL. C.H.B. is grateful to the National Science Foundation (Grant CHE80-24931) and to the University of Vermont Committee on Research and Scholarship for partial support of this research. JO001389B
