Conformational analysis of N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide by NMR spectroscopy: A sterically hindered trans-standard

Article abstract of DOI:10.1002/mrc.4003

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. 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 is 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. Copyright

Full text of DOI:10.1002/mrc.4003

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 trans-
standard
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 partic-
ular 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.
1
Keywords: NMR; H; N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide; conformational analysis; trans-standard
of environments. Designing such a molecule can be more chal-
Introduction
lenging than expected as previous research showed significant
[
9]
Since Hassel’s early work on cyclohexane and its derivatives, which
laid out the fundamentals of conformational analysis, physical or-
ganic chemists have attempted to develop procedures for analysis
of the conformational preferences of various molecules. One
common model system that has been extensively studied are the
gauche preferences even in dianionic compounds, in which
charge repulsion suggests trans should be highly favored.
Disuccinate, for example, showed a surprisingly high (40%)
[
1]
[
2]
gauche preference in D O, while the fraction gauche found in
2
the aprotic DMSO were similar (37%) and THF reported to be
[
3,4]
[7]
1,2-disubstituted ethanes,
where much experimental nuclear
higher (65%). This may be, in part, due to the presence of small
magnetic resonance (NMR) and theoretical work has been
performed on measuring their gauche and trans preferences.
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 tetrahe-
dral end groups with both an organic (tert-butyl) and a highly po-
[
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 sol-
vents are of particular interest as they can mimic, and so shed light
on, the interactions between polar, ionized, and hydrogen-bonded
lar substituent (trimethylammonium) making it soluble and thus
[
2]
[10]
groups in the interiors of folded biomolecules.
useful for study in a large variety of solvent systems.
Altona’s
One area of interest in the study of these small molecules is to
experimentally determine their dihedral angles. Very few experi-
mental measurements of rotational dihedral angles for con-
modification of the Karplus equation, which relates vicinal pro-
3
ton coupling constants ( J ) to the X―CH ―CH ―Y dihedral
HH
2
2
angles (θtrans and θgauche) and empirical electronegativity vari-
ables (λ and λ ), was used in determination of the conforma-
[
7]
formers in solution are available. 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
X
Y
[
11,12]
tional preferences.
* Correspondence to: John D. Roberts, Gates and Crellin Laboratories of Chemistry,
California Institute of Technology, Pasadena, California 91125. E-mail:
robertsj@caltech.edu
[8]
7
4° ± 4°. 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
Gates and Crellin Laboratories of Chemistry, California Institute of Technology,
Pasadena, California, 91125
Magn. Reson. Chem. 2013, 51, 701–704
Copyright © 2013 John Wiley & Sons, Ltd.

A. T. Liu et al.
[
13]
In a previous report, 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 mea-
sured fraction of trans was instead determined to be 91.4%, vide
infra, corresponding to a significantly smaller free energy differ-
ence 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 de-
termined the trans preference of this ethane system in a single
solvent (D O). TMDMBA was prepared as previously described
2
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(Àf)++.
[
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
[
11]
Altona–Hassnoot equations. This method requires experimen-
tally determined couplings constants (J13 and J14), empirically
determined electronegativity parameters for the substituents
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
[
10]
(λ
X
and λ
Y
), and expected dihedral angles (θgauche and θtrans).
any other charged molecules investigated so far
but it also
The experimentally obtained coupling constants were deter-
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 ef-
fect, 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 prefer-
ence 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 signif-
icant difference in relative stability (Fig. 3). This insignificant
mined from the proton spectrum using an iterative fitting pro-
[
15]
gram gNMR4.
parameters for the substituents were determined as previously
The empirically determined electronegativity
[
11]
described using the corresponding monosubstituted ethanes.
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 D O was determined to be 91.4 ± 2%. This in-
2
dicated 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 pre-
viously described (vide supra). In all solvents studied, TMDMBA
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
3
Solvents
J
H-H t-butyl
λ
t-butyl
J
H-H (CH3)
λ
(CH3)3N+
J
13
J
14
(Hz)
3N+ (Hz)
(Hz)
(Hz)
D
2
O
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
7.32
7.32
7.31
7.29
7.31
7.23
7.31
7.28
7.33
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
13.00
12.77
12.74
12.62
12.64
12.84
12.74
12.75
12.83
MeOD
EtOD
iPrOD
DMSO
4.69
4.61
4.60
4.60
4.57
CD
DMF
Me CO
CDCl
3
CN
Figure 2. Fractions of trans conformer of N,N,N-trimethyl-(3,3-
dimethylbutyl)ammonium iodide plotted against solvent polarity, as
suggested by dielectric constant. The error bars shown represent the frac-
tion range of uncertainty for the calculated percentage of gauche confor-
2
3
*
This measurement was achieved in 1 : 1 D
because of the poor solubility of 1,1-dimethylbutane in D
2
O MeOD solution,
O.
[16]
mation.
The dihedral angles θgauche and θtrans were calculated to be
2
8
9.2° and 179.8°, respectively.
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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 de-
termined 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 trans-
standard to test in other solvents.
Figure 3. Quantum theoretical calculation of the potential energy sur-
face of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide (TMDMBA)
in both gas phase (solid circle) and water (hollow circle) (B3LYP/cc-pvdz
Experimental
(Àd)++).
Computational details
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.
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 solution-
phase 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
[
17–19]
Next, we investigated the temperature sensitivity of the trans
preference in this system. The proportions of trans conformers
B3LYP with Dunning’s cc-pVDZ(Àf)++
basis set. Fully
unconstrained geometry optimizations on the minima of the
potential energy scans were performed using m06-2X/cc-pVTZ
of TMDMBA in isotropic D O solution were estimated from the
2
[
19,20]
J13 and J14 coupling constants summarized in the supporting in-
formation and were plotted against a function of temperatures
(Àf)++.
Free energies of the compounds were calculated
by performing frequency calculations on the optimized struc-
tures using the same functional and basis sets. The frequencies
(Fig. 4). The fraction trans is fairly insensitive to temperature,
[
19]
suggesting that it is mostly an enthalpic process that drives the
TMDMBA molecule to its trans conformation, because of steric in-
teractions. A Van’t Hoff analysis suggested a ΔH of 0.690 kcal/mol
and a ΔS of À3.584 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 calcu-
lated to be 1.759 kcal/mol. The fraction trans varied from 91.3% to
were scaled by 0.9721.
Preparation of N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium
iodide
N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide was synthe-
[
14]
sized following a literature procedure. 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
8
2
7.9% over the 85 °C temperature range in D O. The relatively
stable 89.6 ± 1.7% trans preference suggests TMDMBA as a
trans-standard in not only different solvents but also different
temperatures.
1
evaporation. TMDMBA (2.34 g, 87.4% yield) was collected. H NMR
(
(
5
500 MHz, D
m, 2H), 0.97 (s, 9H). C NMR (126 MHz, D
1.98 (m), 35.12 (s), 29.05 (s), 28.27 (s).
2
O): δ 4.79 (s), 3.40–3.37 (m, 2H), 3.11 (s, 9H), 1.72–1.69
13
2
O): δ 64.02 (s), 53.30–
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 7.29g potassium carbonate in an ice bath for 24 h. The product
was isolated by filtration through Celite followed by rotary evapora-
tion. Ethyltrimethylammonium iodide (2.77 g, 84.3% yield) was
1
collected. H NMR (600 MHz, D O): δ 4.79 (s), 3.43–3.39 (q, 2H),
2
3.10 (s, 9H), 1.39–1.37 (m, 3H).
Figure 4. Estimated gauche fractions of N,N,N-trimethyl-(3,3-dimethylbutyl)
ammonium iodide (isotropic D
2
O solution) plotted against the temperature
Nuclear magnetic resonance samples preparation and analysis
measured. The error bars shown represent the fraction range of uncertainty
for the calculated percentage of gauche conformation. The angles θgauche
and θtrans were taken as 89.2° and 179.8°, respectively.
[16]
N,N,N-Trimethyl-(3,3-dimethylbutyl)ammonium iodide (15 mg, c.a.)
and ethyltrimethylammonium iodide (15 mg, c.a.) were dissolved
Magn. Reson. Chem. 2013, 51, 701–704
Copyright © 2013 John Wiley & Sons, Ltd.
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A. T. Liu et al.
in a variety of solutions (D O, methanol-D , ethanol-D , 2-propanol-
2
4
6
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6
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Magn. Reson. Chem. 2013, 51, 701–704