Research article Received: 15 May 2013
Revised: 1 August 2013
Accepted: 3 August 2013
Published online in Wiley Online Library: 23 September 2013
(wileyonlinelibrary.com) DOI 10.1002/mrc.4003
Conformational analysis of N,N,N-Trimethyl(3,3-dimethylbutyl)ammonium iodide by NMR spectroscopy: a sterically hindered transstandard Albert Tianxiang Liu, Mrinmoy Nag, William R. Carroll and John D. Roberts* A predominantly trans-1,2-disubstituted ethane system – N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide – is of particular interest for conformational analysis, because it contains both an organic and a highly polar substituent, making it soluble and thus applicable to study in a large variety of solvents. The fraction of the trans conformer of this molecule in a wide range of protic and aprotic solvents was determined by the nuclear magnetic resonance proton couplings to be approximately 90%, in contrast to the previously assumed 100%. The consistently strong preference of the trans conformation should establish N, N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide as a possibly useful ‘trans-standard’ in conformational analysis, much more so than 1,2-ditert-butylethane, which has a poor solubility in many solvents. Copyright © 2013 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article. Keywords: NMR; 1H; N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide; conformational analysis; trans-standard
Introduction
Magn. Reson. Chem. 2013, 51, 701–704
* Correspondence to: John D. Roberts, Gates and Crellin Laboratories of Chemistry, California Institute of Technology, Pasadena, California 91125. E-mail: [email protected] Gates and Crellin Laboratories of Chemistry, California Institute of Technology, Pasadena, California, 91125
Copyright © 2013 John Wiley & Sons, Ltd.
701
Since Hassel’s early work on cyclohexane and its derivatives, which laid out the fundamentals of conformational analysis,[1] physical organic chemists have attempted to develop procedures for analysis of the conformational preferences of various molecules.[2] One common model system that has been extensively studied are the 1,2-disubstituted ethanes,[3,4] where much experimental nuclear magnetic resonance (NMR) and theoretical work has been performed on measuring their gauche and trans preferences.[5,6] We have placed emphasis on the conformations of such molecules, particularly dicarboxylic acids and their salts, with varying solvent polarities of both protic and aprotic media. Conformational analysis of such small molecule model systems is significant, because it provides interesting comparisons of the preferences observed in water, nonaqueous protic solvent, and aprotic solvent. Aprotic solvents are of particular interest as they can mimic, and so shed light on, the interactions between polar, ionized, and hydrogen-bonded groups in the interiors of folded biomolecules.[2] One area of interest in the study of these small molecules is to experimentally determine their dihedral angles. Very few experimental measurements of rotational dihedral angles for conformers in solution are available.[7] The few solution-phase measurements of these angles were determined by using dipolar couplings determined in ordered media using small-molecule model systems. Consequently, the gauche dihedral angle of the succinic acid monoanion dissolved in the nematic phase of a mixture of aprotic liquid-crystal media was determined to be 74° ± 4°.[8] A similar determination of the dihedral angles of trans conformers seems to be a logical step forward, and such attempt would be simplified by employing a ‘trans-standard’, which by definition gives predominately trans conformation in a variety
of environments. Designing such a molecule can be more challenging than expected as previous research showed significant gauche preferences even in dianionic compounds,[9] in which charge repulsion suggests trans should be highly favored. Disuccinate, for example, showed a surprisingly high (40%) gauche preference in D2O, while the fraction gauche found in the aprotic DMSO were similar (37%) and THF reported to be higher (65%).[7] This may be, in part, due to the presence of small amounts of the monoanion as one might expect a higher trans preference for the dianion because of electrostatic repulsion between the two carboxylate substituents. Instead of seeking to maximize electrostatic repulsion between two substituents here, we employ steric hindrance to induce our trans preference using N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide (TMDMBA). Unlike other compounds with bulky groups, this 1,2-disubstituted ethane system is of particular interest because it contains tetrahedral end groups with both an organic (tert-butyl) and a highly polar substituent (trimethylammonium) making it soluble and thus useful for study in a large variety of solvent systems.[10] Altona’s modification of the Karplus equation, which relates vicinal proton coupling constants (3JHH) to the X―CH2―CH2―Y dihedral angles (θtrans and θgauche) and empirical electronegativity variables (λX and λY), was used in determination of the conformational preferences.[11,12]
A. T. Liu et al. In a previous report,[13] TMDMBA was used as a trans-standard and assumed to be 99.9% trans in all solvents, which corresponds to a free energy difference between gauche and trans conformers of 4.50 kcal/mol. However, an observation of TMDMBA dissolved in water shows that this may not be the case, in which the measured fraction of trans was instead determined to be 91.4%, vide infra, corresponding to a significantly smaller free energy difference of 1.76 kcal/mol. These incongruous measurements led us to question the previous assumption, and TMDMBA was further investigated in a variety of solvents and temperatures. We herein report our findings about this nearly trans-standard.
Results and Discussion In order to fully explore TMDMBA as a trans-standard, we first determined the trans preference of this ethane system in a single solvent (D2O). TMDMBA was prepared as previously described[14] and was found to be readily soluble in a variety of solvents. The fraction of TMDMBA in the trans conformer was determined as previously described for disubstituted ethanes using the Altona–Hassnoot equations.[11] This method requires experimentally determined couplings constants (J13 and J14), empirically determined electronegativity parameters for the substituents (λX and λY), and expected dihedral angles (θgauche and θtrans). The experimentally obtained coupling constants were determined from the proton spectrum using an iterative fitting program gNMR4.[15] The empirically determined electronegativity parameters for the substituents were determined as previously described using the corresponding monosubstituted ethanes.[11] Dihedral angles were computed using density functional theory quantum mechanical calculations upon the optimization of both gauche and trans conformers. Using each of these parameters, the fraction trans in D2O was determined to be 91.4 ± 2%. This indicated that in a single set of conditions, this system showed a marked trans preference. We then set out to test how susceptible to change this trans preference is with a variety of solvent and temperature conditions. We investigated the effects of solvent on the trans preference in TMDMBA. The coupling constants (Table 1), electronegativity parameters (λt-butyl and λ(CH3)3N+, Table 1), and dihedral angles (θgauche = 89.2° and θtrans = 179.8°, Fig. 1) were determined as previously described (vide supra). In all solvents studied, TMDMBA
Figure 1. Ball and stick models of (a) trans and (b) gauche conformers of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide optimized in water force field at m06-2x/cc-pVTZ( f)++.
shows a marked trans preference that is insensitive to solvent environment with 90 ± 3.4% trans in each case (Fig. 2). Not only does TMDMBA enjoy a considerably higher trans preference than any other charged molecules investigated so far[10] but it also shows an exceptionally low sensitivity to solvent polarity (91.4–89.6%). It should be noted that there is a slight downturn in the fraction trans of TMDMBA in nonaqueous solvent systems with the increasing solvent dielectric constants (Fig. 2). However, the downturn of fraction trans is seen to be clearly not statistically significant, unless the error bars reflect systematic rather than statistical deviations. If so, it could suggest a possible solvent effect, which reduces the trans preference with increasing solvent polarity. Nevertheless, the error on these measurements makes the fraction trans of TMDMBA statistically indistinguishable across all solvents studied. We further explored the effects of solvent on the trans preference by comparing the potential energies calculated at different dihedral angles in water and in vacuum. Potential energy surface scans of TMDMBA in the gas phase and in water show no significant difference in relative stability (Fig. 3). This insignificant
Table 1. Semiempirical λ values of tert-butyl and trimethylammonium groups, and the J13 and J14 values of N,N,N-trimethyl-(3,3-dimethylbutyl) ammonium iodide in different solvent systems at room temperature 3
Solvents JH-H t-butyl λt-butyl (Hz) D 2O MeOD EtOD iPrOD DMSO CD3CN DMF Me2CO CDCl3
7.55 * 7.55 7.55 7.55 7.53 7.52 7.52 7.52 7.54
0.39 0.39 0.39 0.39 0.43 0.42 0.42 0.42 0.41
3
JH-H
3N+
(CH3)
λ(CH3)3N+
J13 (Hz)
J14 (Hz)
0.82 0.82 0.84 0.88 0.84 0.80 0.84 0.90 0.80
4.60 4.63 4.62 4.6 4.69 4.61 4.60 4.60 4.57
13.00 12.77 12.74 12.62 12.64 12.84 12.74 12.75 12.83
(Hz)
7.32 7.32 7.31 7.29 7.31 7.23 7.31 7.28 7.33
702
* This measurement was achieved in 1 : 1 D2O MeOD solution, because of the poor solubility of 1,1-dimethylbutane in D2O.
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Figure 2. Fractions of trans conformer of N,N,N-trimethyl-(3,3dimethylbutyl)ammonium iodide plotted against solvent polarity, as suggested by dielectric constant. The error bars shown represent the fraction range of uncertainty for the calculated percentage of gauche conformation.[16] The dihedral angles θgauche and θtrans were calculated to be 89.2° and 179.8°, respectively.
Copyright © 2013 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2013, 51, 701–704
N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide: a sterically hindered trans-standard
Conclusions In the present work, variable solvent and variable temperature studies were performed to TMDMBA. The fraction trans was determined in water indicating a high (90%) but not 100% trans preference. The solvent sensitivity of this high trans preference was investigated and was found to be low in a large variety of solvents. There was a statistically insignificant downturn in the fraction trans with nonaqueous solvents. Variable temperature studies also suggest a relatively steady trans preference and over a wide temperature range (5–90 °C). Together, these results suggested the molecule’s potential to serve as a useful transstandard to test in other solvents. Figure 3. Quantum theoretical calculation of the potential energy surface of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide (TMDMBA) in both gas phase (solid circle) and water (hollow circle) (B3LYP/cc-pvdz ( d)++).
difference of energy further substantiates that solvation probably has very little or no effect on the conformational preferences of TMDMBA. Both the observed fraction trans (90.5 ± 0.9%) and the calculated energy difference (6.77 kcal/mol) between its gauche and trans conformers suggest that TMDMBA could be a useful trans-standard in future mixed-solvent conformational analyses for its strong preference of trans conformer in both protic and aprotic solvents. Next, we investigated the temperature sensitivity of the trans preference in this system. The proportions of trans conformers of TMDMBA in isotropic D2O solution were estimated from the J13 and J14 coupling constants summarized in the supporting information and were plotted against a function of temperatures (Fig. 4). The fraction trans is fairly insensitive to temperature, suggesting that it is mostly an enthalpic process that drives the TMDMBA molecule to its trans conformation, because of steric interactions. A Van’t Hoff analysis suggested a ΔH of 0.690 kcal/mol and a ΔS of 3.584 cal/mol for the conformational change from trans to gauche. The energy difference from trans to gauche conformer (θgauche = 89.2° and θtrans = 179.8°) was therefore calculated to be 1.759 kcal/mol. The fraction trans varied from 91.3% to 87.9% over the 85 °C temperature range in D2O. The relatively stable 89.6 ± 1.7% trans preference suggests TMDMBA as a trans-standard in not only different solvents but also different temperatures.
Experimental Computational details All density functional theory quantum mechanical calculations were carried out with JAGUAR version 7.5, release 207 software package from Schrödinger, Inc. (Portland, OR, USA). For solutionphase calculations, the Poisson–Boltzmann continuum model was used. Potential-energy surface scans, from 180° to 0° at the intervals of 5°, were performed for the gas phase and water by constraining the central C―C―C―N dihedral angle, followed by optimization of all other degrees of freedom using either B3LYP with Dunning’s cc-pVDZ( f)++[17–19] basis set. Fully unconstrained geometry optimizations on the minima of the potential energy scans were performed using m06-2X/cc-pVTZ ( f)++.[19,20] Free energies of the compounds were calculated by performing frequency calculations on the optimized structures using the same functional and basis sets. The frequencies were scaled by 0.9721.[19] Preparation of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide was synthesized following a literature procedure.[14] 3,3-Dimethylbutylamine (1.34 ml, 1.0 g, 9.88 mmol) and iodomethane (2.47 ml, 5.96 g, 41.99 mmol) were stirred with 20 ml anhydrous methanol and 8.24 g potassium carbonate at room temperature for 24 h. The product was isolated by filtration through Celite followed by rotary evaporation. TMDMBA (2.34 g, 87.4% yield) was collected. 1H NMR (500 MHz, D2O): δ 4.79 (s), 3.40–3.37 (m, 2H), 3.11 (s, 9H), 1.72–1.69 (m, 2H), 0.97 (s, 9H). 13C NMR (126 MHz, D2O): δ 64.02 (s), 53.30– 51.98 (m), 35.12 (s), 29.05 (s), 28.27 (s). Preparation of ethyltrimethylammonium iodide Ethylamine (1 ml, 0.69 g, 15.31 mmol) and iodomethane (3.81 ml, 8.68 g, 61.15 mmol) were stirred with 20 ml anhydrous methanol and 7.29 g potassium carbonate in an ice bath for 24 h. The product was isolated by filtration through Celite followed by rotary evaporation. Ethyltrimethylammonium iodide (2.77 g, 84.3% yield) was collected. 1H NMR (600 MHz, D2O): δ 4.79 (s), 3.43–3.39 (q, 2H), 3.10 (s, 9H), 1.39–1.37 (m, 3H).
Magn. Reson. Chem. 2013, 51, 701–704
Nuclear magnetic resonance samples preparation and analysis N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide (15 mg, c.a.) and ethyltrimethylammonium iodide (15 mg, c.a.) were dissolved
Copyright © 2013 John Wiley & Sons, Ltd.
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Figure 4. Estimated gauche fractions of N,N,N-trimethyl-(3,3-dimethylbutyl) ammonium iodide (isotropic D2O solution) plotted against the temperature measured. The error bars shown represent the fraction range of uncertainty for the calculated percentage of gauche conformation.[16] The angles θgauche and θtrans were taken as 89.2° and 179.8°, respectively.
A. T. Liu et al. in a variety of solutions (D2O, methanol-D4, ethanol-D6, 2-propanolD8, DMSO-D6, acetonitrile-D3, DMF-D7, acetone-D6, and CDCl3). NMR spectra were recorded with an NMR spectrometer using the default pulse sequence in the software. All experiments were performed on a 600 MHz NMR spectrometer. Typical spectra parameters for 1H spectra: 16 scans, spectral width 9600 Hz, relaxation delay of 1 s, and acquisition time of 4 s. Specific parameters used are also reported on the spectra shown in the Supporting Information. J13 and J14 coupling constants, shown in Table 1 and the Supporting Information, were extracted using an iterative spectral fitting program gNMR4.[15] Quantum mechanical computation was used to estimate the optimal θtrans (78°) and θgauche (180°) of TMDMBA. λt-butyl values in different solvents were collected from previous unpublished results, whereas that of λ(CH3)3N+ were derived from the 3JH-H coupling constants for the ethyltrimethylammonium iodide obtained (Table 1).[11]
Supporting Information Characterization, computational data, and Altona equations used for the calculations of percent gauche of TMDMBA in all solvents are given in the supporting document.
Acknowledgements This research was supported by the National Science Foundation under grant CHE0543620, the Petroleum Research Fund of the American Chemical Society, the Senior Mentor Grant of the Camille and Henry Dreyfus Foundation, the McCloskey NORAC Fund, and the Summer Undergraduate Research Fellowship Program (SURF) at California Institute of Technology.
References [1] O. Hassel, Nobel Lectures. 1970. Chemistry 1930–1970, Elsevier Publishing Company, Amsterdam, 1972. [2] D. H. R. Barton. Cell. Mol. Life Sci. 1950, 6, 316–320. doi:10.1007/ BF02170915. [3] E. L. Eliel, Conformational Analysis, Interscience, New York, 1965, pp. 351–432. [4] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley & Sons, New York, 1994, pp. 606–615. [5] M. D. Drake, A. K. Harsha, S. Terterov, J. D. Roberts. Magn. Reson. Chem. 2006, 44, 210–219. doi:10.1002/mrc.1758. [6] D. R. Kent IV, K. A. Petterson, F. Gregoire, E. Snyder-Frey, L. J. Hanely, R. P. Muller, W. A. Goddard III, J. D. Roberts. J. Am. Chem. Soc. 2002, 124, 4481–4486. doi:10.1021/ja012016a. [7] J. D. Roberts. Acc. Chem. Res. 2006, 39, 889–896. doi:10.1021/ar050229p. [8] A. A. Smith, M. D. Drake, J. D. Roberts. J. Phys. Chem. A 2008, 112, 12367–12371. doi:10.1021/jp801644a. [9] E. Lit, F. Mallon, H. Tsai, J. D. Roberts. J. Am. Chem. Soc. 1993, 115, 9563–9567. doi:10.1021/ja00074a022. [10] F. Gregoire, S. H. Wei, E. W. Streed, K. A. Brameld, D. Fort, L. J. Hanely, J. D. Walls, W. A. Goddard, J. D. Roberts. J. Am. Chem. Soc. 1998, 120, 7537–7543. doi:10.1021/ja974311u. [11] C. Altona, R. Francke, R. D. Haan, J. H. J. Ippel, G. Daalmans, A. J. A. W. Hoekzema, J. V. Wijk. Magn. Reson. Chem. 1994, 32, 670–678. doi:10.1002/mrc.1260321107. [12] M. Karplus. J. Chem. Phys. 1959, 30, 11–15. doi:10.1063/1.1729860. [13] R. J. Abraham, G. Gatti. J. Chem. Soc. (B). 1969, 0, 961–968. doi:10.1039/J29690000961. [14] P. A. S. Smith, S. Frank. J. Am. Chem. Soc. 1952, 74, 509–512. doi:10.1021/ja01122a067. [15] GNMR 4.1, I., Adept scientific: litchworth, herbs, 1999 [16] K. A. Petterson, R. S. Stein, M. D. Drake, J. D. Roberts. Magn. Reson. Chem. 2005, 43, 225–230. doi:10.1002/mrc.1512. [17] T. H. Dunning Jr.. J. Chem. Phys. 1989, 90, 1007–1023. doi:10.1063/1.456153. [18] R. A. Kendall, T. H. Dunning Jr.. J. Chem. Phys. 1992, 96, 6796–6806. doi:10.1063/1.462569. [19] D. E. Woon, T. H. Dunning Jr.. J. Chem. Phys. 1993, 98, 1358–1371. doi:10.1063/1.464303. [20] Y. Zhao, D. G. Truhlar. Theor. Chem. Acc. 2008, 120, 215–241. doi:10.1007/s00214-007-0310-x.
704 wileyonlinelibrary.com/journal/mrc
Copyright © 2013 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2013, 51, 701–704
Revised: 1 August 2013
Accepted: 3 August 2013
Published online in Wiley Online Library: 23 September 2013
(wileyonlinelibrary.com) DOI 10.1002/mrc.4003
Conformational analysis of N,N,N-Trimethyl(3,3-dimethylbutyl)ammonium iodide by NMR spectroscopy: a sterically hindered transstandard Albert Tianxiang Liu, Mrinmoy Nag, William R. Carroll and John D. Roberts* A predominantly trans-1,2-disubstituted ethane system – N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide – is of particular interest for conformational analysis, because it contains both an organic and a highly polar substituent, making it soluble and thus applicable to study in a large variety of solvents. The fraction of the trans conformer of this molecule in a wide range of protic and aprotic solvents was determined by the nuclear magnetic resonance proton couplings to be approximately 90%, in contrast to the previously assumed 100%. The consistently strong preference of the trans conformation should establish N, N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide as a possibly useful ‘trans-standard’ in conformational analysis, much more so than 1,2-ditert-butylethane, which has a poor solubility in many solvents. Copyright © 2013 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article. Keywords: NMR; 1H; N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide; conformational analysis; trans-standard
Introduction
Magn. Reson. Chem. 2013, 51, 701–704
* Correspondence to: John D. Roberts, Gates and Crellin Laboratories of Chemistry, California Institute of Technology, Pasadena, California 91125. E-mail: [email protected] Gates and Crellin Laboratories of Chemistry, California Institute of Technology, Pasadena, California, 91125
Copyright © 2013 John Wiley & Sons, Ltd.
701
Since Hassel’s early work on cyclohexane and its derivatives, which laid out the fundamentals of conformational analysis,[1] physical organic chemists have attempted to develop procedures for analysis of the conformational preferences of various molecules.[2] One common model system that has been extensively studied are the 1,2-disubstituted ethanes,[3,4] where much experimental nuclear magnetic resonance (NMR) and theoretical work has been performed on measuring their gauche and trans preferences.[5,6] We have placed emphasis on the conformations of such molecules, particularly dicarboxylic acids and their salts, with varying solvent polarities of both protic and aprotic media. Conformational analysis of such small molecule model systems is significant, because it provides interesting comparisons of the preferences observed in water, nonaqueous protic solvent, and aprotic solvent. Aprotic solvents are of particular interest as they can mimic, and so shed light on, the interactions between polar, ionized, and hydrogen-bonded groups in the interiors of folded biomolecules.[2] One area of interest in the study of these small molecules is to experimentally determine their dihedral angles. Very few experimental measurements of rotational dihedral angles for conformers in solution are available.[7] The few solution-phase measurements of these angles were determined by using dipolar couplings determined in ordered media using small-molecule model systems. Consequently, the gauche dihedral angle of the succinic acid monoanion dissolved in the nematic phase of a mixture of aprotic liquid-crystal media was determined to be 74° ± 4°.[8] A similar determination of the dihedral angles of trans conformers seems to be a logical step forward, and such attempt would be simplified by employing a ‘trans-standard’, which by definition gives predominately trans conformation in a variety
of environments. Designing such a molecule can be more challenging than expected as previous research showed significant gauche preferences even in dianionic compounds,[9] in which charge repulsion suggests trans should be highly favored. Disuccinate, for example, showed a surprisingly high (40%) gauche preference in D2O, while the fraction gauche found in the aprotic DMSO were similar (37%) and THF reported to be higher (65%).[7] This may be, in part, due to the presence of small amounts of the monoanion as one might expect a higher trans preference for the dianion because of electrostatic repulsion between the two carboxylate substituents. Instead of seeking to maximize electrostatic repulsion between two substituents here, we employ steric hindrance to induce our trans preference using N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide (TMDMBA). Unlike other compounds with bulky groups, this 1,2-disubstituted ethane system is of particular interest because it contains tetrahedral end groups with both an organic (tert-butyl) and a highly polar substituent (trimethylammonium) making it soluble and thus useful for study in a large variety of solvent systems.[10] Altona’s modification of the Karplus equation, which relates vicinal proton coupling constants (3JHH) to the X―CH2―CH2―Y dihedral angles (θtrans and θgauche) and empirical electronegativity variables (λX and λY), was used in determination of the conformational preferences.[11,12]
A. T. Liu et al. In a previous report,[13] TMDMBA was used as a trans-standard and assumed to be 99.9% trans in all solvents, which corresponds to a free energy difference between gauche and trans conformers of 4.50 kcal/mol. However, an observation of TMDMBA dissolved in water shows that this may not be the case, in which the measured fraction of trans was instead determined to be 91.4%, vide infra, corresponding to a significantly smaller free energy difference of 1.76 kcal/mol. These incongruous measurements led us to question the previous assumption, and TMDMBA was further investigated in a variety of solvents and temperatures. We herein report our findings about this nearly trans-standard.
Results and Discussion In order to fully explore TMDMBA as a trans-standard, we first determined the trans preference of this ethane system in a single solvent (D2O). TMDMBA was prepared as previously described[14] and was found to be readily soluble in a variety of solvents. The fraction of TMDMBA in the trans conformer was determined as previously described for disubstituted ethanes using the Altona–Hassnoot equations.[11] This method requires experimentally determined couplings constants (J13 and J14), empirically determined electronegativity parameters for the substituents (λX and λY), and expected dihedral angles (θgauche and θtrans). The experimentally obtained coupling constants were determined from the proton spectrum using an iterative fitting program gNMR4.[15] The empirically determined electronegativity parameters for the substituents were determined as previously described using the corresponding monosubstituted ethanes.[11] Dihedral angles were computed using density functional theory quantum mechanical calculations upon the optimization of both gauche and trans conformers. Using each of these parameters, the fraction trans in D2O was determined to be 91.4 ± 2%. This indicated that in a single set of conditions, this system showed a marked trans preference. We then set out to test how susceptible to change this trans preference is with a variety of solvent and temperature conditions. We investigated the effects of solvent on the trans preference in TMDMBA. The coupling constants (Table 1), electronegativity parameters (λt-butyl and λ(CH3)3N+, Table 1), and dihedral angles (θgauche = 89.2° and θtrans = 179.8°, Fig. 1) were determined as previously described (vide supra). In all solvents studied, TMDMBA
Figure 1. Ball and stick models of (a) trans and (b) gauche conformers of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide optimized in water force field at m06-2x/cc-pVTZ( f)++.
shows a marked trans preference that is insensitive to solvent environment with 90 ± 3.4% trans in each case (Fig. 2). Not only does TMDMBA enjoy a considerably higher trans preference than any other charged molecules investigated so far[10] but it also shows an exceptionally low sensitivity to solvent polarity (91.4–89.6%). It should be noted that there is a slight downturn in the fraction trans of TMDMBA in nonaqueous solvent systems with the increasing solvent dielectric constants (Fig. 2). However, the downturn of fraction trans is seen to be clearly not statistically significant, unless the error bars reflect systematic rather than statistical deviations. If so, it could suggest a possible solvent effect, which reduces the trans preference with increasing solvent polarity. Nevertheless, the error on these measurements makes the fraction trans of TMDMBA statistically indistinguishable across all solvents studied. We further explored the effects of solvent on the trans preference by comparing the potential energies calculated at different dihedral angles in water and in vacuum. Potential energy surface scans of TMDMBA in the gas phase and in water show no significant difference in relative stability (Fig. 3). This insignificant
Table 1. Semiempirical λ values of tert-butyl and trimethylammonium groups, and the J13 and J14 values of N,N,N-trimethyl-(3,3-dimethylbutyl) ammonium iodide in different solvent systems at room temperature 3
Solvents JH-H t-butyl λt-butyl (Hz) D 2O MeOD EtOD iPrOD DMSO CD3CN DMF Me2CO CDCl3
7.55 * 7.55 7.55 7.55 7.53 7.52 7.52 7.52 7.54
0.39 0.39 0.39 0.39 0.43 0.42 0.42 0.42 0.41
3
JH-H
3N+
(CH3)
λ(CH3)3N+
J13 (Hz)
J14 (Hz)
0.82 0.82 0.84 0.88 0.84 0.80 0.84 0.90 0.80
4.60 4.63 4.62 4.6 4.69 4.61 4.60 4.60 4.57
13.00 12.77 12.74 12.62 12.64 12.84 12.74 12.75 12.83
(Hz)
7.32 7.32 7.31 7.29 7.31 7.23 7.31 7.28 7.33
702
* This measurement was achieved in 1 : 1 D2O MeOD solution, because of the poor solubility of 1,1-dimethylbutane in D2O.
wileyonlinelibrary.com/journal/mrc
Figure 2. Fractions of trans conformer of N,N,N-trimethyl-(3,3dimethylbutyl)ammonium iodide plotted against solvent polarity, as suggested by dielectric constant. The error bars shown represent the fraction range of uncertainty for the calculated percentage of gauche conformation.[16] The dihedral angles θgauche and θtrans were calculated to be 89.2° and 179.8°, respectively.
Copyright © 2013 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2013, 51, 701–704
N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide: a sterically hindered trans-standard
Conclusions In the present work, variable solvent and variable temperature studies were performed to TMDMBA. The fraction trans was determined in water indicating a high (90%) but not 100% trans preference. The solvent sensitivity of this high trans preference was investigated and was found to be low in a large variety of solvents. There was a statistically insignificant downturn in the fraction trans with nonaqueous solvents. Variable temperature studies also suggest a relatively steady trans preference and over a wide temperature range (5–90 °C). Together, these results suggested the molecule’s potential to serve as a useful transstandard to test in other solvents. Figure 3. Quantum theoretical calculation of the potential energy surface of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide (TMDMBA) in both gas phase (solid circle) and water (hollow circle) (B3LYP/cc-pvdz ( d)++).
difference of energy further substantiates that solvation probably has very little or no effect on the conformational preferences of TMDMBA. Both the observed fraction trans (90.5 ± 0.9%) and the calculated energy difference (6.77 kcal/mol) between its gauche and trans conformers suggest that TMDMBA could be a useful trans-standard in future mixed-solvent conformational analyses for its strong preference of trans conformer in both protic and aprotic solvents. Next, we investigated the temperature sensitivity of the trans preference in this system. The proportions of trans conformers of TMDMBA in isotropic D2O solution were estimated from the J13 and J14 coupling constants summarized in the supporting information and were plotted against a function of temperatures (Fig. 4). The fraction trans is fairly insensitive to temperature, suggesting that it is mostly an enthalpic process that drives the TMDMBA molecule to its trans conformation, because of steric interactions. A Van’t Hoff analysis suggested a ΔH of 0.690 kcal/mol and a ΔS of 3.584 cal/mol for the conformational change from trans to gauche. The energy difference from trans to gauche conformer (θgauche = 89.2° and θtrans = 179.8°) was therefore calculated to be 1.759 kcal/mol. The fraction trans varied from 91.3% to 87.9% over the 85 °C temperature range in D2O. The relatively stable 89.6 ± 1.7% trans preference suggests TMDMBA as a trans-standard in not only different solvents but also different temperatures.
Experimental Computational details All density functional theory quantum mechanical calculations were carried out with JAGUAR version 7.5, release 207 software package from Schrödinger, Inc. (Portland, OR, USA). For solutionphase calculations, the Poisson–Boltzmann continuum model was used. Potential-energy surface scans, from 180° to 0° at the intervals of 5°, were performed for the gas phase and water by constraining the central C―C―C―N dihedral angle, followed by optimization of all other degrees of freedom using either B3LYP with Dunning’s cc-pVDZ( f)++[17–19] basis set. Fully unconstrained geometry optimizations on the minima of the potential energy scans were performed using m06-2X/cc-pVTZ ( f)++.[19,20] Free energies of the compounds were calculated by performing frequency calculations on the optimized structures using the same functional and basis sets. The frequencies were scaled by 0.9721.[19] Preparation of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide was synthesized following a literature procedure.[14] 3,3-Dimethylbutylamine (1.34 ml, 1.0 g, 9.88 mmol) and iodomethane (2.47 ml, 5.96 g, 41.99 mmol) were stirred with 20 ml anhydrous methanol and 8.24 g potassium carbonate at room temperature for 24 h. The product was isolated by filtration through Celite followed by rotary evaporation. TMDMBA (2.34 g, 87.4% yield) was collected. 1H NMR (500 MHz, D2O): δ 4.79 (s), 3.40–3.37 (m, 2H), 3.11 (s, 9H), 1.72–1.69 (m, 2H), 0.97 (s, 9H). 13C NMR (126 MHz, D2O): δ 64.02 (s), 53.30– 51.98 (m), 35.12 (s), 29.05 (s), 28.27 (s). Preparation of ethyltrimethylammonium iodide Ethylamine (1 ml, 0.69 g, 15.31 mmol) and iodomethane (3.81 ml, 8.68 g, 61.15 mmol) were stirred with 20 ml anhydrous methanol and 7.29 g potassium carbonate in an ice bath for 24 h. The product was isolated by filtration through Celite followed by rotary evaporation. Ethyltrimethylammonium iodide (2.77 g, 84.3% yield) was collected. 1H NMR (600 MHz, D2O): δ 4.79 (s), 3.43–3.39 (q, 2H), 3.10 (s, 9H), 1.39–1.37 (m, 3H).
Magn. Reson. Chem. 2013, 51, 701–704
Nuclear magnetic resonance samples preparation and analysis N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide (15 mg, c.a.) and ethyltrimethylammonium iodide (15 mg, c.a.) were dissolved
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Figure 4. Estimated gauche fractions of N,N,N-trimethyl-(3,3-dimethylbutyl) ammonium iodide (isotropic D2O solution) plotted against the temperature measured. The error bars shown represent the fraction range of uncertainty for the calculated percentage of gauche conformation.[16] The angles θgauche and θtrans were taken as 89.2° and 179.8°, respectively.
A. T. Liu et al. in a variety of solutions (D2O, methanol-D4, ethanol-D6, 2-propanolD8, DMSO-D6, acetonitrile-D3, DMF-D7, acetone-D6, and CDCl3). NMR spectra were recorded with an NMR spectrometer using the default pulse sequence in the software. All experiments were performed on a 600 MHz NMR spectrometer. Typical spectra parameters for 1H spectra: 16 scans, spectral width 9600 Hz, relaxation delay of 1 s, and acquisition time of 4 s. Specific parameters used are also reported on the spectra shown in the Supporting Information. J13 and J14 coupling constants, shown in Table 1 and the Supporting Information, were extracted using an iterative spectral fitting program gNMR4.[15] Quantum mechanical computation was used to estimate the optimal θtrans (78°) and θgauche (180°) of TMDMBA. λt-butyl values in different solvents were collected from previous unpublished results, whereas that of λ(CH3)3N+ were derived from the 3JH-H coupling constants for the ethyltrimethylammonium iodide obtained (Table 1).[11]
Supporting Information Characterization, computational data, and Altona equations used for the calculations of percent gauche of TMDMBA in all solvents are given in the supporting document.
Acknowledgements This research was supported by the National Science Foundation under grant CHE0543620, the Petroleum Research Fund of the American Chemical Society, the Senior Mentor Grant of the Camille and Henry Dreyfus Foundation, the McCloskey NORAC Fund, and the Summer Undergraduate Research Fellowship Program (SURF) at California Institute of Technology.
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