Proton NMR and IR study of self-association in pyridylalkanols: Open or cyclic dimers? Higher polymers?

Article abstract of DOI:10.1002/poc.1056

¹H NMR measurements indicate that (X-pyridyl)alkanols of the general formula (C₅H₄N)(CH₂)_nOH, where n = 1, 2 or 3, self-associate as open dimers, cyclic dimers, trimers and tetramers, with considerable variations depending on the position of the alkyl chain and its length. (X-Pyridyl)propan-2-ols behave like the corresponding pyridylmethanols with, however, somewhat lower association constants. The IR spectra of 3-(X-pyridyl)-2,2,4,4-tetramethylpentan-3-ols (X = 3 or 4) in carbon tetrachloride suggest weak association, while the 2-pyridyl derivative occurs mainly as the intramolecularly hydrogen-bonded rotamer. The OH NMR shifts for the 3- and 4-pyridyl derivatives in benzene are concentration-dependent, but neither the equilibrium constants nor the degree of association can be evaluated. Benzyl alcohol in benzene associates as an open dimer and a cyclic tetramer, as does 2phenylpropan-2-ol, only more weakly. Rotation barriers for 3-(X-pyridyl)-2,2,4,4-tetramethylpentan-3-ols (X = 2, 3 or 4) in DMSO or nitrobenzene are 20-21 kcal mol^-1. Copyright

Full text of DOI:10.1002/poc.1056

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2006; 19: 295–307
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.1056
Proton NMR and IR study of self-association in
pyridylalkanols: open or cyclic dimers? higher
polymers?
*
John S. Lomas, Alain Adenier and Christine Cordier
Interfaces, Traitements, Organisation et Dynamique des Syste`mes, Universite´ de Paris 7, CNRS UMR 7086, 1 rue Guy de la Brosse,
75005 Paris, France
Received 24 October 2005; revised 12 January 2006; accepted 2 February 2006
1
ABSTRACT: H NMR measurements indicate that (X-pyridyl)alkanols of the general formula (C5H4N)(CH2)nOH,
where n ¼ 1, 2 or 3, self-associate as open dimers, cyclic dimers, trimers and tetramers, with considerable variations
depending on the position of the alkyl chain and its length. 2-(X-Pyridyl)propan-2-ols behave like the corresponding
pyridylmethanols with, however, somewhat lower association constants. The IR spectra of 3-(X-pyridyl)-2,2,4,4-
tetramethylpentan-3-ols (X ¼ 3 or 4) in carbon tetrachloride suggest weak association, while the 2-pyridyl derivative
occurs mainly as the intramolecularly hydrogen-bonded rotamer. The OH NMR shifts for the 3- and 4-pyridyl
derivatives in benzene are concentration-dependent, but neither the equilibrium constants nor the degree of association
can be evaluated. Benzyl alcohol in benzene associates as an open dimer and a cyclic tetramer, as does 2-
phenylpropan-2-ol, only more weakly. Rotation barriers for 3-(X-pyridyl)-2,2,4,4-tetramethylpentan-3-ols (X ¼ 2,
3 or 4) in DMSO or nitrobenzene are 20–21 kcal molꢀ1. Copyright # 2006 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894–3230/suppmat/
KEYWORDS: pyridine; alcohols; hydrogen bonds; NMR; IR; self-association constants; dimers; trimers; tetramers;
rotamers
INTRODUCTION
associated: thus 2,2,4,4-tetramethylpentan-3-ol, otherwise
known as di(tert-butyl)methanol, dimerizes weakly,31–33,36
and tertiary alcohols derived from this alcohol have very
low self-association constants.30,31,34,35b,37 Tri(tert-butyl)-
methanol is a monomer even in the solid state.38
Whether the hydrogen bond in water is classified as weak,
moderate, or strong appears to be largely a matter of where
the limits are placed. The calculated value,1 5 kcal molꢀ1
,
puts it just on the ‘‘strong’’ side of Desiraju and Steiner’s
‘‘weak-strong’’ classification.2 What really distinguishes
the water molecule is the number of hydrogen bonds in
which it can participate, both as a donor and as an acceptor.
It is this feature which makes self-association between
water molecules such a highly important phenomenon.
When it comes to organic derivatives, in which one
hydrogen has been replaced by a hydrocarbon group, the
possibilities for extensive hydrogen-bonded networks are
much reduced, but low-molecular-weight alcohols such as
methanol, ethanol, and other 1-alkanols, for example, self-
associate as dimers, trimers, tetramers, and even higher n-
mers,3–24 phenols as dimers, trimers and tetramers.23a,24–29
However, when the hydrocarbon group is bulky,30–37 steric
hindrance to the approach of like molecules offsets the
advantage of hydrogen bonding, and not only does the
extent of association fall but also the number of molecules
In simple alcohols the OH group is both the acceptor
and the donor, but more interesting are species in which
there is a chemically distinct acceptor. The biologically
most important hydrogen bonds involve hydrogen atoms
covalently bound to oxygen or nitrogen, and the acceptor
atoms are commonly nitrogen or oxygen. In this study we
shall consider the particular case of O—H ꢁ ꢁ ꢁ N bonding
in pyridine-substituted alcohols. Previous work appears to
be limited to three studies.39–41 The NMR chemical shift
of the OH hydrogen in (2-pyridyl)alkanols in chloroform
increases with concentration, indicating intermolecular
hydrogen bonding, despite the proximity of the OH group
and the nitrogen atom.39 In contrast, (2-pyridyl)di(1-
adamantyl)methanol was isolated as the syn rotamer with
an intramolecular hydrogen bond.40 Intramolecular
hydrogen bonding in (2-pyridyl)alkanols was also
investigated by IR spectroscopy.41
The aim of this work is to determine as far as possible by
NMR and IR spectroscopies the nature and degree of the
apparent association in (2-pyridyl)alkanols and to extend
this study to 3- and 4-substituted derivatives. Steric effects
*Correspondence to: J. S. Lomas, Interfaces, Traitements, Organis-
`
´
ation et Dynamique des Systemes, Universite de Paris 7, 1 rue Guy de la
Brosse, 75005 Paris, France.
E-mail: lomas@itodys.jussieu.fr
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296
J. S. LOMAS, A. ADENIER AND C. CORDIER
on association will be investigated by replacing the CH2
hydrogens of the (X-pyridyl)methanols by, firstly, methyl
groups [2-(X-pyridyl)propan-2-ols] and then by tert-butyls
[3-(X-pyridyl)-2,2,4,4-tetramethylpentan-3-ols]. Though
the latter are somewhat less hindered than the
di(1-adamantyl) derivative previously studied,40 they prove
to be difficult to study, because of their low solubility and
the presence, in the 2- and 3-pyridyl derivatives, of syn and
anti rotamers in equilibrium. Results concerning the
rotational isomerism of these compounds are included in
this paper.
RESULTS AND DISCUSSION
2-(X-Pyridyl)propan-2-ols and
(X-pyridyl)alkanols
Figure 1. Concentration dependence in the OH stretching
region of the IR spectrum of (2-pyridyl)methanol, 1a, in
carbon tetrachloride: (a) 0.016 M; (b) 0.16 M; (c) 0.31 M
About 35 years ago a series of (2-pyridyl)alkanols, 1a–c,
was investigated by IR41 and NMR39 spectroscopies. In
the first part of this study we seek, by means of IR
spectroscopy, qualitative information concerning both
intra- and intermolecular hydrogen bonding in 1a–c and
some 3- and 4-pyridyl derivatives, 2a, 2c, and 3. The
related 2-(X-pyridyl)propan-2-ols, 4–6, are also con-
sidered.42 In the second part we shall attempt to determine
association constants for the formation of the various
possible n-mers by NMR spectroscopy.
Alcohols 2a, 2c, and 3 show free OH absorptions at 3617/
3629, 3639, and 3618/3635 cmꢀ1, respectively, and broad
association bands at 3280, 3315, and 3245 cmꢀ1
,
respectively, all these latter with ill-defined shoulders
to higher wavenumbers (3395, 3420, and 3400 cmꢀ1
,
respectively). Since the relative heights of the principal
and secondary absorptions seem to vary little with change
in concentration, it is not possible to attribute them to
specific types of association. It seems more likely that
(i) IR spectroscopy
they are due to different conformations of the association
complexes.41
Dilute solutions of alcohols 1 in carbon tetrachloride show
free and intramolecularly H-bonded OH absorptions close
to those previously reported.41 At higher concentration
alcohol 1a has a clear association band at 3270 cmꢀ1
which increases relative to the bands for the free (3622/
3641 cmꢀ1) and intramolecularly bonded (3440 cmꢀ1
forms as the concentration is raised (Fig. 1). Further
details of the IR spectra are given in Supplementary
Material Table S1.
Alcohol 1b shows only a relatively weak association
band at about 3300 cmꢀ1, while the presence of a second
low-wavenumber band for 1c at all concentrations
suggests a higher degree of association. For 1c the
relative intensities of the two bands, already observed in
dilute solution at about 3275 and 3380 cmꢀ1, change
slightly, the latter increasing with the concentration.
Alcohols 4–6 were synthesized by the reaction of
methyl-lithium with the appropriate acetylpyridine.
Certain aspects of their IR (in carbon tetrachloride)
and NMR (in benzene) spectra differ from what was
previously reported in chloroform.42 Whereas the OH
vibration wavenumbers in the IR spectrum are stated to be
3450 (neat), 3200, and 3200 cmꢀ1 for 4, 5, and 6,
respectively, we find for 4 in carbon tetrachloride a broad
band at 3430 cmꢀ1 and a weak absorption at 3612/
3621 cmꢀ1, not previously mentioned. This latter
obviously corresponds to the anti rotamer, with a free
OH group. For 5 there are moderately strong free OH
absorptions at 3606/3618 cmꢀ1 and two association bands
at 3400 and 3250 cmꢀ1. The free OH absorptions are
relatively stronger when the solution is diluted. For 6,
,
)
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PROTON NMR AND IR STUDY OF SELF-ASSOCIATION IN PYRIDYLALKANOLS
297
which is very poorly soluble in CCl4, the free OH
absorptions are at the same wavenumbers and there is a
moves, whereas H6 goes slightly upfield. Proton H4
moves downfield and H5 is little affected (Supplementary
Material Fig. S1). The situation in 1a is somewhat
anomalous: proton H6, though close to nitrogen, goes
downfield (Supplementary Material Fig. S2). However,
since intramolecular hydrogen bonding is replaced by
intermolecular bonding, the overall effect on the electron
density is less predictable.
very weak, broad association band at about 3290 cmꢀ1
.
Reinvestigation of 5 and 6 in chloroform reveals that the
strongest absorption at low concentration is in fact that of
free OH at about 3600 cmꢀ1, while the 3200 cmꢀ1 band is
clearly due to association.
(ii) NMR spectroscopy
(b) Association constants. The NMR data for the
variation of the OH proton shift with concentration were
analyzed in terms of several models by means of
WinEQNMR,44 the R-factor (see Experimental section)
being taken as the criterion of goodness-of-fit. Generally a
cyclic trimer or tetramer appears to be accompanied by a
dimer which is usually cyclic, though in some cases the fit
was not disimproved by assuming it to be open. In Table 1
are listed association constants for the best models for
each compound studied. In Supplementary Material
Table S2 the R-factors and the chemical shifts of the
free and hydrogen-bonded OH protons are listed. An
example of the application of several models to a single
data set is given in Supplementary Material Table S3.
For (2-pyridyl)methanol, 1a, three models describe the
data almost equally well: cyclic dimer-trimer; cyclic dimer-
tetramer; open dimer-tetramer. For the corresponding 2-(2-
pyridyl)ethanol, 1b, and 3-(2-pyridyl)propan-1-ol,1c, there
are four possibilities which all satisfy the data very well:
cyclic dimer-trimer; open dimer-trimer; open dimer-
tetramer; cyclic dimer-tetramer. The major difference
between these compounds is that 1b has much lower
association constants, whatever the model. For 2a, 2c, and
3, in each case there are at least three possibilities, but
generally the best fit is with an open dimer-tetramer model.
Free and intramolecularly hydrogen-bonded monomer
are not distinguished. The value of dP, the chemical shift of
the hydrogen-bonded OH hydrogen in the polymer,
whatever it is, refers to intermolecular hydrogen bonding
only (mean values for 2a, 2c, and 3 are 7.24, 6.65, and
7.45 ppm, respectively). The value of the chemical shift of
the monomer, dM, on the other hand, represents both free
and intramolecularly hydrogen-bonded monomer and is
therefore high for the 2-pyridyl derivatives, 1a–c, 3.62,
4.07, and 2.95ppm, respectively. The highest value of dM,
for 1b, is associated with a very small constant for the
formation of polymers. If association constants in the same
models are compared for 1a and 1c, it is seen that they are
always greater for 1c, which has the lowest value of dM of
this series. If dM can be taken as a measure of the hydrogen
bond strength, this means that the formation of association
complexes is modulated by the strength of the intramo-
lecular hydrogen bond. For the other pyridylalkanols, 2 and
3, where the side-chain is in the 3 or 4 position, and
intramolecular hydrogen bonding is absent or very weak,
the values of dM are much smaller (mean values for 2a, 2c,
and 3 are 0.66, 0.36, and 0.64 ppm, respectively) and the
association constants considerably higher.
The 1H NMR chemical shift of a NH or OH proton which
is hydrogen-bonded in an associated form is higher than
that of the same hydrogen in the non-associated form.
One signal is observed for a proton in fast exchange
between the two (or more) species, its shift being the
weighted average of the shifts of these species. Con-
sequently, the observed shift is concentration-dependent
and, from the so-called NMR titration curve, association
constants can be determined. This approach has been
much used in a wide variety of fields to determine
association constants and stoichiometries, particularly
those concerned with biologically important species or
their analogs, and in supramolecular chemistry in
general.43
(a) Concentration dependence of NMR shifts. All
alcohols were studied in benzene. Although attention is
normally focused on the OH proton shift, the other proton
shifts are also concentration-dependent, though to a lesser
extent. A particularly clear example is provided by 3,
where the H3/5 and CH2 protons move downfield as the
concentration increases, while H2/6 move upfield
(Fig. 2).
These variations correspond to changes in the electron
density: decrease at sites close to the OH group; increase
at sites close to nitrogen. In 2a H2 is sandwiched between
nitrogen and the CH2OH group and therefore hardly
Figure 2. Concentration dependence of proton shifts in (4-
pyridyl)methanol, 3, in benzene at 298 K
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J. S. LOMAS, A. ADENIER AND C. CORDIER
Table 1. Association constants (Mꢀ1, Mꢀ2 or Mꢀ3) for pyridylalkanols and benzyl alcohols in benzene at 298 K, calculated
according to various dimer, trimer, and/or tetramer models
Cpd.
Open dimer K/Mꢀ1
Cyclic dimer K/Mꢀ1
Cyclic trimer K/Mꢀ2
0.82 ꢂ 0.10
Cyclic tetramer K/Mꢀ3
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
2a
2a
2a
2c
2c
2c
3
3
3
4
4
5
5
5
6
0.18 ꢂ 0.04
0.36 ꢂ 0.01
1.61 ꢂ 0.09
3.55 ꢂ 0.15
0.68 ꢂ 0.04
0.34 ꢂ 0.02
0.64 ꢂ 0.03
1.52 ꢂ 0.01
2.90 ꢂ 0.16
0.22 ꢂ 0.01
0.32 ꢂ 0.01
0.99 ꢂ 0.03
1.30 ꢂ 0.03
0.20 ꢂ 0.03
0.30 ꢂ 0.04
0.35 ꢂ 0.06
1.03 ꢂ 0.11
1.45 ꢂ 0.18
3.93 ꢂ 0.22
5.16 ꢂ 0.67
37.8 ꢂ 1.0
1.26 ꢂ 0.15
2.46 ꢂ 0.10
20.6 ꢂ 1.4
9.31 ꢂ 1.30
25.0 ꢂ 1.9
155 ꢂ 10
536 ꢂ 17
4.67 ꢂ 0.21
4.30 ꢂ 0.32
1.21 ꢂ 0.21
2.11 ꢂ 0.11
53.4 ꢂ 5.2
235 ꢂ 17
1.70 ꢂ 0.18
3.08 ꢂ 0.16
231 ꢂ 20
866 ꢂ 36
6.00 ꢂ 0.37
0.14 ꢂ 0.07
0.066 ꢂ 0.027
1.35 ꢂ 0.17
10.4 ꢂ 1.5
18.0 ꢂ 1.1
1.85 ꢂ 0.27
4.45 ꢂ 0.41
287 ꢂ 22
1.26 ꢂ 0.66
1.46 ꢂ 0.19
5.71 ꢂ 13.3
6
6
9
9
10
10
11
11
46.1 ꢂ 18.2
159 ꢂ 222
3.22 ꢂ 1.44
1.08 ꢂ 2.11
1.20 ꢂ 1.72
0.60 ꢂ 5.16
2.25 ꢂ 12.4
1.26 ꢂ 0.03
2.16 ꢂ 0.04
0.31 ꢂ 0.01
0.53 ꢂ 0.01
0.25 ꢂ 0.01
0.17 ꢂ 0.01
0.46 ꢂ 0.01
0.32 ꢂ 0.01
2-(3-Pyridyl)propan-2-ol, 5, behaves very much like 2a
(dM ¼ 0.89 ppm; dP ¼ 6.96 or 7.42 ppm). However, alco-
hols 4 and 6 are poorly soluble in benzene, and
measurements could be made over only a very limited
concentration range. The OH proton shift of alcohol 4 in
benzene at 298 K increases only slightly and almost
linearly with concentration, by about 0.1 ppm on going
from near-zero to 0.3 M. If we assume that the value of dP
is 7.5 ppm, this would indicate a dimerization constant of
0.14 or 0.066 Mꢀ1, depending on whether the dimer is
taken as open or cyclic, and that intramolecular hydrogen
bonding prevails over association (dM ¼ 4.91 ppm).
Trimer and tetramer species were rejected by the
optimization procedure. For alcohol 6, with the same
assumption, the data are well described by three models,
albeit with very high standard deviations, particularly on
the higher n-mer association constants. Models with an
open or cyclic dimer accompanied by a tetramer are the
best (dM ¼ 0.90 ppm).
5, and 6, respectively.42 While the limiting value, dM, for 4
in benzene, 4.91 ppm, is similar to that quoted, the much
smaller values for 5 and 6, both about 0.9 ppm, indicate
that there is considerable self-association at the pre-
sumably higher concentrations used for the early
measurements.
(c) OH NMR shifts in almost neat alcohols. Curve-
fitting gives not only association constants but also the
related shifts of the monomer and polymer species, dM
and dP, respectively (Table S2). While the former is
relatively well defined by measurements made at low
concentration and varies little with the model, the latter
shows considerable fluctuations. It is therefore important
to consider whether these values correspond in any way to
the shift of the OH proton in the neat compound, bearing
in mind however that even this will not be completely
associated. Several compounds [1a–c, 2a, 2c, and 10 (see
below)] were therefore examined in the presence of the
minimum amount (5%) of deuteriated benzene for
locking.
1
The OH proton signal in the H NMR spectrum in
chloroform is reported to be at 5.0, 6.1, and 4.1 ppm for 4,
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PROTON NMR AND IR STUDY OF SELF-ASSOCIATION IN PYRIDYLALKANOLS
299
Equation (1) was solved numerically:
the temperature is raised, the variation being approxi-
mately linear with temperature and depending on the
solvent and the nature of the group.45 Hydrogen-bonded
protons are associated with higher negative values of the
temperature coefficient, in the ppb Kꢀ1 range, than those
which are not hydrogen-bonded.
Our data on the association of 2a, 3, and 5
(Supplementary Material Tables S5 and S6) confirm that
dM varies little with temperature.37 The temperature
coefficients for dP, on the other hand, are model- and
alcohol-dependent, ranging from 22.5 (5, open dimer-
trimer) to ꢀ19 (3, open dimer-tetramer) ppb Kꢀ1. The
latter figure is of the same order of magnitude as values
for the hetero-association of pyridine with hindered
alcohols.37 For low-molecular-weight alcohols in cyclo-
hexane, values based on a 1-2-n association model range
2
½alcoholꢃ ¼ ½monomerꢃ þ 2K2½monomerꢃ
n
þ nKn½monomerꢃ
(1)
where n ¼ 3 or 4, and K2 and Kn are the association
constants for formation of dimer and n-mer, respectively.
The OH shift was then calculated from Eqn (2) or (3):
2
½alcoholꢃdcalc ¼ ½monomerꢃdM þ 2K2dP½monomerꢃ
n
(2)
þ nKndP½monomerꢃ
or:
2
½alcoholꢃdcalc ¼ ½monomerꢃdM þ K2ðdM þ dPÞ½monomerꢃ
n
þ nKndP½monomerꢃ
(3)
from ꢀ4 to ꢀ8 ppb Kꢀ1 23
.
Large positive values are,
when the dimer is open (Supplementary Material Table S4).
For the pyridylalkanols the calculated shifts are in all
but one case (2c in the cyclic dimer-trimer model) lower
than observed, by an average for all models and
compounds of 0.09 ppm. In all cases the calculated shift
is within 0.2 ppm of that observed, the greatest deviations
concerning the cyclic dimer-tetramer model. The ques-
tion arises as to whether results based on relatively low
concentrations of alcohols in benzene are compatible with
those where the ‘‘solvent’’ represents only 5% of the
solution. In previous work it was found that alcohol
hetero-association behaved consistently from low con-
centrations of pyridine in benzene right up to neat
pyridine.37 In the present case it is reassuring to find that
there is good agreement between the calculated and
observed shifts, but this can hardly be used as a test to
determine which of the models is the most appropriate. At
the high concentrations of these experiments it is possible
that higher n-mers are present, or that the trimer and
tetramer shifts are greater than that of dimer.
therefore, anomalous. However, since the data for alcohol
5 are more scattered than for 2a and 3 (R-factors >1%),
the results are less reliable. It may simply be that the open
dimer-trimer model is incorrect, although the R-factors
are as good as for cyclic dimer-trimer and open dimer-
tetramer.
(e) Thermodynamic parameters and molecular me-
chanics calculations. In the three cases where we have
determined the dimer and n-mer association constants at a
range of temperatures (Supplementary Material Table
S5), the van’t Hoff plots show a significant difference in
the reaction enthalpies and entropies (Table 2). Dimers,
whether they be open or cyclic, are associated with small
values of reaction enthalpies, ranging from ꢀ2 to
ꢀ5 kcal molꢀ1 (1 cal ¼ 4.184 J). Trimers and tetramers
have much greater DH8, from ꢀ10 to ꢀ15 kcal molꢀ1
,
tetramers being associated with slightly higher values
than trimers. The dimerization enthalpies are less than
would be expected for even one O—H ꢁ ꢁ ꢁ N hydrogen
bond, which suggests that hydrogen bonding is partially
offset by the increase in steric energy caused by bringing
the two systems together. Dimer reaction entropies
(d) Temperature coefficients of OH NMR shifts. The
signal of an OH or NH proton usually goes upfield when
Table 2. Reaction enthalpies (kcal molꢀ1) and entropies (cal molꢀ1 Kꢀ1) for selected pyridylalkanols in benzene, calculated
according to various dimer, trimer, and/or tetramer models
Open dimer
DH8 DS8
Cyclic dimer
DH8 DS8
Cyclic trimer
DH8 DS8
Cyclic tetramer
DH8 DS8
Cpd.
Model
2a
2a
2a
3
3
3
5
5
5
Cyclic dimer-trimer
Cyclic dimer-tetramer
ꢀ3.8 ꢂ 1.6 ꢀ12.1 ꢂ 5.2 ꢀ10.4 ꢂ 0.8 ꢀ28.9 ꢂ 2.5
ꢀ4.8 ꢂ 0.8 ꢀ14.1 ꢂ 2.5
ꢀ13.8 ꢂ 0.9 ꢀ36.4 ꢂ 3.0
ꢀ14.3 ꢂ 1.2 ꢀ35.4 ꢂ 3.7
Open dimer-tetramer ꢀ4.6 ꢂ 1.0 ꢀ12.2 ꢂ 3.2
Cyclic dimer-trimer
Cyclic dimer-tetramer
ꢀ2.5 ꢂ 0.4 ꢀ7.3 ꢂ 1.4 ꢀ10.3 ꢂ 0.9 ꢀ27.9 ꢂ 2.7
ꢀ3.7 ꢂ 0.2 ꢀ10.3 ꢂ 0.8
ꢀ13.1 ꢂ 0.8 ꢀ33.0 ꢂ 2.7
ꢀ12.4 ꢂ 0.2 ꢀ28.1 ꢂ 0.7
Open dimer-tetramer ꢀ3.4 ꢂ 0.3 ꢀ7.9 ꢂ 1.0
Cyclic dimer-trimer
Open dimer-trimer
Open dimer-tetramer ꢀ4.2 ꢂ 0.1 ꢀ11.1 ꢂ 0.4
ꢀ3.1 ꢂ 0.2 ꢀ10.0 ꢂ 0.5 ꢀ14.6 ꢂ 0.5 ꢀ44.2 ꢂ 1.6
ꢀ2.2 ꢂ 0.2 ꢀ6.2 ꢂ 0.7 ꢀ12.8 ꢂ 0.4 ꢀ37.3 ꢂ 1.1
ꢀ15.4 ꢂ 0.1 ꢀ40.6 ꢂ 0.4
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J. S. LOMAS, A. ADENIER AND C. CORDIER
average about ꢀ10 cal molꢀ1 Kꢀ1 as against ꢀ35 cal
molꢀ1 Kꢀ1 for the higher polymers. These differences,
though perfectly reasonable, do not allow us to
discriminate between the various models. Neither do
our results provide any information about the coopera-
tivity effect.
Molecular mechanics calculations (MMFF94 in Sybyl
7.0 from Tripos, St. Louis, MO)46 were run on all the
monomers and on some of the possible polymers, from
open dimers to cyclic tetramers (Table 3, further details in
Supplementary Material Table S7). In almost all cases
there is a reduction in steric energy on going from n
monomer molecules to one n-mer species (DSE). The
calculations find open dimers to be several kcal molꢀ1
more strained than the cyclic equivalents. Schematic
representations of the dimer, trimer and tetramer of
alcohol 2a are shown above.
where DH8 has been measured (2a, 3 and 5), DSE values
for formation of the open dimer, cyclic dimer, trimer, and
tetramer exceed the corresponding reaction enthalpies,
DH8, by an average of 4.4, 9.0, 11.7, and 21.3 kcal molꢀ1
,
respectively. If these figures are divided by the number of
hydrogen bonds in the various species, we find excess
energies of 4.4, 4.5, 3.9, and 5.3 kcal molꢀ1, respectively,
which indicates that MM overestimates the strength of
one hydrogen bond by about 4.5 kcal molꢀ1. This means
that the cyclic dimers for compounds 1–6 are no less
strained than the open dimers. Of the force fields available
in Sybyl, the only other one which accepts these
molecules is Tripos, and this gives even higher values
of DSE.
For alcohols 2a, 3, 5 and 6, dimers, trimers, and
tetramers should be formed with increasing ease: the
larger the ring, the greater the strain relief. Values for 1a
follow the same order but are much smaller. If these
values were correct, and if there were no compensatory
reaction entropy changes,47 only tetramers would be
found in solutions of these alcohols. In fact, in the cases
3-(X-Pyridyl)-2,2,4,4-tetramethylpentan-3-ols
The three previously unreported 3-(X-pyridyl)-2,2,4,4-
tetramethylpentan-3-ols, 7–9, were synthesized by reac-
tion of the appropriate X-pyridyl-lithium with 2,2,4,4-
tetramethylpentan-3-one in diethyl ether at ꢀ758C, and
were purified by column chromatography.
Table 3. Molecular mechanics calculations on selected pyridylalkanols and benzyl alcohols (MMFF94, steric energy differences
in kcal molꢀ1
)
˚
Cpd.
DSE open d.
DSE cyc. d.
DSE tri.
DSE tetra.
N ꢁ ꢁ ꢁ O/A (a)
N ꢁ ꢁ ꢁ H–O/8 (a)
1a
1b
1c
2a
2c
3
4
5
6
7-syn
8-anti
8-syn
9
10
11
ꢀ1.06
2.63
1.54
8.08
4.62
7.33
ꢀ1.09
8.33
8.20
3.79
6.79
9.79
16.03
16.19
2.646
2.799
2.810
123.9
138.3
158.8
13.51
7.06
11.50
2.10
11.35
12.58
24.44
34.90
35.29
22.83
3.42
25.02
22.68
2.605
2.518
125.4
128.5
35.92
36.98
8.66
8.29
8.24
18.58
10.15
4.04
7.01
32.46
20.65
22.59
37.37
(a) Dimensions for 2-pyridyl-substituted alcohols.
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PROTON NMR AND IR STUDY OF SELF-ASSOCIATION IN PYRIDYLALKANOLS
301
(i) Rotation barriers
attributed by XHCORR and the rotamers identified by
2D-NOESY experiments (Supplementary Material Fig.
S3). The anti and syn rotamers are characterized by the
presence of strong cross-peaks for correlations between
the tert-butyl groups and H2 and H4, respectively.
Nevertheless, the tert-butyl groups are so voluminous that
there are clear correlations, albeit weaker, with H4 and
H2, respectively. Very weak correlations between the anti
and syn OH groups and H4 and H2, respectively, are also
observed.
Alcohol 8 occurs as a mixture of anti and syn forms in a
ratio of 1.41:1 in benzene at 298 K. Molecular mechanics
calculations give steric energies of 77.0 and 77.4 kcal molꢀ1
for the anti and syn rotamers, respectively (Table S7), the
difference of 0.4 kcal molꢀ1 being in good agreement with
the free energy difference of 0.2 kcal molꢀ1. Values for
chloroform, pyridine, and DMSO are (based on the
assumption that relative peak positions are not solvent-
dependent; NOE experiments were not performed in
these solvents) slightly lower, at 0.15, 0.00, and
ꢀ0.05 kcal molꢀ1, respectively, the anti isomer being
slightly less favored as solvent basicity increases.
It has been known since the early 1970s that a —C(t-
Bu)2OH group attached to a benzene ring rotates slowly
on the NMR time-scale with a barrier of about
20 kcal molꢀ1 48,49
.
Barriers to rotation of the same rotor
attached to hetero-aromatic groups vary from about 14 to
22 kcal molꢀ1 50
Replacing the tert-butyl groups by the
.
more rigid 1-adamantyl substituent raises the rotation
barrier by 5–10 kcal molꢀ1, depending on the group to
which the rotor is attached.51 This makes it possible to
isolate both members of a rotamer pair on the bench,52
whereas the tert-butyl derivatives can only be distin-
guished in solution, most conveniently by NMR
spectroscopy.
(a) 3-(2-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol, 7. In
chloroform or benzene, alcohol 7 occurs very predomi-
nantly (ca. 95%, estimated from the magnitude of a
second peak in the tert-butyl region and, in benzene, of
peaks in the aromatic region) as the intramolecularly
hydrogen-bonded syn isomer. Molecular mechanics
calculations give steric energies of 89.5 and
85.8 kcal molꢀ1 for the anti and syn rotamers, respect-
ively (Table S7), the difference of 3.7 kcal molꢀ1 being
rather greater than the free energy difference of about
1.8 kcal molꢀ1 at 298 K. In pyridine and DMSO the anti/
syn ratio rises to 0.24 and 0.57, respectively. This
corresponds to the familiar situation where the equi-
librium between two rotamers, one with an intramolecular
hydrogen bond and the other without, is strongly affected
by the hydrogen bond basicity of the solvent.53 The slope
of a plot of log(K) for a set of seven solvents against the
corresponding hydrogen bond basicity parameters54 is
1.49 ꢂ 0.09, which is similar to values found in other
systems.53
Mean rotation barriers measured in DMSO at 343–
388 K are 20.6 kcal molꢀ1 for both the syn ! anti and
anti ! syn rotations, the temperature dependence being
very low for both reactions, that is, the activation
entropies are again close to zero.
(c) 3-(4-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol, 9.
Since there is no dissymmetric element this derivative
exists as a single species, that is, there are no rotamers.
The NMR spectra clearly distinguish four CH groups in
the pyridine ring, and the mean rotation barrier in DMSO
at 363–408 K is 20.7 kcal molꢀ1 and in nitrobenzene at
368–393 K is 20.9 kcal molꢀ1
.
Mean rotation barriers measured in DMSO at 348–
378 K are 20.2 and 19.7 kcal molꢀ1 for syn ! anti and
anti ! syn, respectively, the temperature dependence
being very low for both reactions, that is, the activation
entropies are close to zero. Small, mainly negative,
activation entropies have been reported for other rotations
of this type.53,55
The rotation barriers found here for the X-pyridyl
derivatives are similar to that reported by Baas et al.49 for
the corresponding 3,4,5-trimethoxybenzene derivative in
DMSO at
a coalescence temperature of 421 K
(21.4 kcal molꢀ1), which agrees with that calculated
from the data of Gall et al.48 Values for the 2-, 3- and 4-
pyridyl derivatives at 421 K would be 19.5/20.2, 20.7, and
20.8 kcal molꢀ1, respectively.
(b) 3-(3-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol, 8. The
1H NMR spectrum of 8 in benzene was resolved, that is,
the various signals were associated with the H2, H4, H5,
and H6 protons in the major and minor isomers, by gNMR
simulation of the two sets of peaks, the 13C NMR peaks
(ii) Association studies
IR spectra of near-saturated solutions of 8 and 9 in carbon
tetrachloride show broad bands for the OH stretching
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302
J. S. LOMAS, A. ADENIER AND C. CORDIER
modes around 3370 cmꢀ1, consistent with self-associ-
ation. Alcohol 7 already absorbs in this region (3330
cmꢀ1) even at low concentration, due to intramolecular
hydrogen bonding; no further absorption is detected at
high concentration.
The self-association of alcohols 7–9 was further
investigated by determining the concentration dependence
of the NMR shift of the OH protons in benzene (Table 4). In
the case of the 2-pyridyl derivative, 7, the chemical shift of
neither the syn nor the anti OH proton changes significantly.
The syn OH proton is hydrogen-bonded intramolecularly,
as shown by its high NMR shift and the low OH stretching
wavenumber. The fact that the anti rotamer is at very low
concentration argues against self-association.
In view of the results for the less hindered pyridylalk-
anols, the data for 9 (Table 4) were tentatively interpreted
on the assumption that an open dimer and a larger cyclic
polymer are formed. The choice of an open dimer was
motivated by MM calculations, which indicate greater
DSE than for a cyclic dimer. Again a value of dP
(¼7.5 ppm) was assumed. With these assumptions either
a tetramer or, even better, a trimer completes the model
adequately, but with very large uncertainties on the values
of the association constants (Table 1). Both the K values
for dimers of 9 (1.20 and 1.08 Mꢀ1, respectively) appear
to be higher than what was found for 2,2,4,4-tetra-
methylpentan-3-ol in carbon tetrachloride (0.15 Mꢀ1), a
solvent in which self-association constants are at least 5
times higher than in benzene.37
In the 3-pyridyl derivative, 8, both OH protons move
downfield as the concentration increases, that for 8-anti
less than that for 8-syn, while the anti/syn ratio is
unchanged. If for the sake of simplicity we consider only
open dimers, then we have potentially two homo-dimers
(anti-anti and syn-syn), and two hetero-dimers (anti-syn
and syn-anti). Systems where homo-association is
accompanied by hetero-association can be handled if
the homo-association constants can be determined
separately,56 but this is not possible for alcohol 8, which
could, moreover, form homo- and hetero-polymers as
well. Nevertheless, qualitative comparison of the con-
centration dependence of the OH NMR shifts for 8-anti
and 8-syn with that for 9 (Table 4) suggests a similar
degree of association at the same overall concentration.
In conclusion, the concentration dependence of the OH
proton NMR shift indicates that the highly sterically
hindered alcohols 8 and 9 associate at least as dimers.
However, the situation is too complex to analyze in 8, and
the low solubility of 9 means that only very tentative
values of the association constants can be given.
Calculations on the 2-pyridyl derivatives show clearly
the steric effect of replacing hydrogen by methyl and by
tert-butyl in the series 1a, 4, and 7. As the substituent
becomes more space-demanding the OH oxygen is forced
closer to the nitrogen, and the N ꢁ ꢁ ꢁ H—O angle opens
slightly (Table 3). This is mirrored by a progressive
increase in the OH proton shift and a decrease in the
degree of self-association. For the series comprising 1a–c,
where the chain-length increases, there is a rough
correlation between the N ꢁ ꢁ ꢁ O distance and the
N ꢁ ꢁ ꢁ H—O angle, but none with the shift of the OH
proton, dM.
Despite the fact that we have not been able to analyze
fully the data for 8 and 9, it is instructive to compare series
of molecules with decreasing substituent size: 2-
substituted: 7, 4, 1a; 3-substituted: 8, 5, 2a. In alcohol
7 neither the syn nor the anti rotamer shows any tendency
to associate, whereas 4, though largely syn, associates
slightly. The weaker intramolecular bond in 1a allows
both a dimer and a trimer or tetramer. The raw data for the
two rotamers of alcohol 8 suggest a much greater degree
of association than for 7, somewhat less than that of 5,
which in turn differs from 2a essentially in the magnitude
of the trimer or tetramer association constant. It is difficult
to be affirmative about the 4-substituted series: 9, 6, 3,
since association constants for alcohols 6 and 9 are so ill-
defined. Alcohol 9, with two tert-butyl substituents,
appears to have a dimerization constant about a third of
that of 6 and a fifth of that of 3, where both bulky
substituents have been replaced by hydrogens. Nothing
can be said about the association constants for higher n-
mers, except that they appear to fall rapidly with
increasing substituent size.
Table 4. Concentration dependence of OH NMR shifts
(ppm) for 3-pyridyl-2,2,4,4-tetramethylpentan-3-ols, 7–9,
in benzene at 298 K
Cpd.
[M]
dobs
Cpd.
[M]
dobs
7-anti
0.0019
0.0111
1.688
1.715
7-syn
0.0355
0.2101
6.929
6.918
8-anti
0.0013
0.0064
0.0318
0.0596
0.1192
1.466
1.508
1.704
1.895
2.233
8-syn
0.0009
0.0045
0.0226
0.0423
0.0845
1.487
1.543
1.789
2.020
2.390
Benzyl alcohol and 2-phenylpropan-2-ol
Benzyl alcohol, 10, has been the subject of several
investigations,25,29,57–59 mainly by IR spectroscopy,
various authors reaching quite different conclusions.
According to early work25 there are dimeric and high-
order complexes in carbon tetrachloride, but another
author reports that tetramers are the major species,58
while multivariate resolution methods indicate open-
9
0.0053
0.0159
0.0524
0.0987
0.2094
1.477
1.537
1.739
1.963
2.353
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PROTON NMR AND IR STUDY OF SELF-ASSOCIATION IN PYRIDYLALKANOLS
303
chain aggregates and cyclic aggregates involving 4 and 7
monomers, respectively,59 though the monomer is the
major component throughout the range studied
(<0.2 mol kgꢀ1). According to heat capacity measure-
ments in n-heptane, tetramers are the predominant species
for 1-alkanols,29 whereas for other alcohols (including 10
and 2-phenylpropan-2-ol, 11) as the steric hindrance
increases, the tetramer population is severely reduced.
10 (Table 3), in contradiction with what is observed. Again,
these calculations overestimate the H-bond strength.
The analysis of the NMR titration curves for 1–3 and 5
in terms of a monomer-dimer-higher n-mer model gives
no structural information about the associated species.
Our mathematical model only requires that, except when
the dimer is open, there be as many equivalent hydrogen
bonds as there are monomers in the n-mer, but does not
specify which atoms are involved in these bonds. It is
important to note, however, that the degree of association
of 10 and 11 is very much smaller than that of the 3- and
4-pyridyl analogs, 2a, 3, 5, and 6. This indicates that the
pyridine nitrogen atom is directly implicated in the
association of these latter, and of all the other
pyridylalkanols investigated. While the pyridine nitrogen
has an electron-withdrawing effect which makes the OH
hydrogen more acidic, that is, a better donor, it must at the
same time make the oxygen atom a weaker acceptor. The
overall substituent effect of a pyridine nitrogen on
association should therefore be small. The conclusion that
we are dealing with O—H ꢁ ꢁ ꢁ N bonding is corroborated
by the much lower wavenumbers for IR stretching
associated with this as compared to O—H ꢁ ꢁ ꢁ O bonding,
which is characterized by values of the order of
Attempts to model cyclic dimers by molecular
mechanics calculations failed, any preliminary closed
structure opening automatically, whereas symmetrical
cyclic trimer and tetramer species are well defined. For all
three species, there is a considerable reduction in steric
energy as compared to that of two, three or four
monomers, respectively (Table 3). Schematic representa-
tions of the open dimer, closed dimer, cyclic trimer and
cyclic tetramer of alcohol 10 are shown below.
3500 cmꢀ1 12,14,15,30,31,32b,33,36,58–60
.
The NMR data on 10 and 11 in benzene at 298 K at
concentrations up to 1.5 M are well satisfied by a dimer-
tetramer model, regardless of whether the dimer is
assumed to be open or cyclic (Table 1). Note, however,
that the agreement between the OH shift observed for neat
benzyl alcohol and that calculated according to the cyclic
dimer-tetramer model is the worst of all (Supplementary
Material Table S4). For 10, tetramers predominate except
below about 0.55 M, where the open dimer and tetramer
levels are very similar. For 11, which is more crowded than
10 in the vicinity of the OH group, the dimer constant is
very similar and the tetramer constant about one quarter
that of 10. The association complex is predominantly
tetramer above a concentration of about 0.9 M. The MM
calculations suggest that 11 should be more associated than
CONCLUSION
NMR titration curves for pyridylalkanols in benzene are in
most cases somewhat equivocal about the exact character
of the self-association. The data can be interpreted in terms
of models based on open or cyclic dimers coexisting
with cyclic trimers or tetramers. The relative magnitudes
of the association constants depend on the length and
the position, with respect to the pyridyl nitrogen, of the
alkanol chain. In particular, for (2-pyridyl)alkanols
the extent of association is inversely proportional to the
strength of the intramolecular hydrogen bond, as judged by
the OH NMR shift in the alcohol monomer. Molecular
mechanics calculations with the MMFF94 force field
appear to exaggerate the enthalpic advantage of associ-
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304
J. S. LOMAS, A. ADENIER AND C. CORDIER
ations in pyridylalkanols by 4–5kcal molꢀ1 per hydrogen
bond. Sterically hindered pyridylalkanols clearly self-
associate but the mode and extent of association cannot be
determined by NMR studies, particularly when associ-
ations between different rotamers are possible.
of two peaks separated by 5–20 cmꢀ1. Further details
on the IR spectra are given in Supplementary Material
Table S1.
The literature on alcohol self-association reports
studies by a multitude of techniques on a wide variety
of alcohols in a considerable number of solvents at
concentrations ranging from dilute to neat. It should be
noted, moreover, that there are two schools of thought
concerning the modelling of hydrogen bonding: chemical
theory, which we have used here, where hydrogen bond
formation is treated as a chemical reaction, and physical
theory, in which hydrogen bonds are considered as strong
physical interactions.23 The latter approach tends to gloss
over the differences between open and cyclic polymers
and also between polymers of different sizes. The ‘‘best’’
model approach selects a few equilibria from a multitude
of possible exchange processes between species, while
the NMR data are the weighted averages of all the
exchange processes. Each model treats only a part of a
complex system of equilibria in solution, in such a way
that the NMR data are compatible with several
descriptions: all may therefore be valid. Other exper-
imental approaches and high-level quantum mechanical
calculations would no doubt help to overcome the
intrinsic ambiguity of the NMR study.
Materials
Compounds 1–3, 10, and 11 were commercial materials
(>99%) used as received. 2-(X-Pyridyl)propan-2-ols, 4–
6, were synthesized by the reaction of the appropriate
acetylpyridine with methyl-lithium in ether at room
temperature.42 NMR and IR spectra of these compounds
are listed in the Supplementary Material section of this
paper.
3-(2-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol,
7. To 2-bromopyridine in diethyl ether at ꢀ758C was
added an equivalent of n-butyl-lithium in hexane. After
stirring for 30 min, a 10% excess of 2,2,4,4-tetramethyl-
pentan-3-one was added and the mixture allowed to warm
slowly to room temperature. Conventional work-up,
followed by column chromatography on alumina in light
petroleum (b. range 35–608C)/diethyl ether mixtures gave
the alcohol (mp 438C; 15% yield), eluted in 1–2% diethyl
ether. 7-syn: IR (CCl4)/cmꢀ1: 3330; dH (benzene,
0.0355 M) 1.159 (s, 2 t-Bu), 6.542 (H5, J 1.0, 4.9,
7.4), 6.929 (s, OH), 6.956 (H4, J 1.8, 7.4, 8.2), 7.285 (H3,
J 1.0, 1.1, 8.2), and 8.131 (H6, J 1.1, 1.8, 4.9); dC
(chloroform) 29.4 (t-Bu), 41.4 (Cq), 81.8 (COH), 121.7
(C5), 123.2 (C3), 134.9 (C4), 145.8 (C6), and 162.3 (C2).
7-anti: IR (CCl4)/cmꢀ1: 3643; dH (benzene, 0.0019 M)
1.18 (s, 2 t-Bu), 1.69 (s, OH), 6.62 (H5), 7.17 (H4), 7.70
(H3), and 8.40 (H6). (Found: C, 75.8; H, 10.1; N,
6.0. C14H23NO requires C, 75.97; H, 10.47; N,
6.33%).
EXPERIMENTAL
General methods
1H NMR 1D spectra were recorded in deuteriated
benzene at 298 K on a Bruker AC 200 spectrometer
with a spectral resolution of 0.001 ppm/pt, 13C NMR
spectra in deuteriochloroform at 298 K. Shifts (in ppm)
are referenced to TMS at 0.000 ppm (1H) or to solvent
peak at 77.0 ppm (13C). Aromatic proton signals of the
various alkanols at convenient concentrations were
assigned by spectrum simulation using the gNMR
program (version 4.1 from Adept Scientific, Letchworth,
UK); coupling constants (J in Hz) are not signed. IR
transmission spectra were recorded in carbon tetrachlor-
ide at 298 K on a Nicolet Magna 860 FTIR spectrometer
with 4 cmꢀ1 resolution. Generally experiments were
performed at a range of concentrations. The association
bands are broad and concentration-dependent, both in
intensity and in wavenumber, this latter tending to fall as
the concentration increases. Values given are rounded to
the nearest 5 or 10 cmꢀ1. In some cases, spectra were
decomposed by curve-fitting with Voigt functions for the
individual association bands, using the Origin program
(Microcal Software, Inc., now OriginLab Corporation,
MA), but we have not attempted to be exhaustive in
decomposing these or the free OH bands. These latter
are sharp, Lorentzian and constant, but generally consist
3-(3-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol,
8. Synthesized by reaction of 3-pyridyl-lithium with
2,2,4,4-tetramethylpentan-3-one as for 7. The alcohol
(mp 1088C; 29% yield) was eluted in 100% diethyl ether.
The 1H NMR spectrum was resolved by gNMR
simulation of the two sets of peaks, the 13C NMR peaks
attributed by XHCORR and the rotamers identified by
NOESY. 8: IR (CCl4)/cmꢀ1: 3642, 3618, 3370. 8-syn:dH
(benzene, 0.0227 M) 0.911 (s, 2 t-Bu), 1.789 (s, OH),
6.688 (H5, J 0.8, 4.6, 8.2), 7.490 (H4, J 1.6, 2.5, 8.2),
8.547 (H6, J 0.4, 1.6, 4.6) and 9.322 (H2, J 0.4, 0.8, 2.5);
dC (chloroform) 29.4 (t-Bu), 41.7 (Cq), 82.5 (COH), 120.6
(C5), 135.1 (C4), 140.3 (C3), 147.3 (C6) and 150.2 (C2).
8-anti:dH (benzene, 0.0317 M) 0.920 (s, 2 t-Bu), 1.704 (s,
OH), 6.893 (H5, J 0.9, 4.7, 8.1), 7.943 (H4, J 1.7, 2.4,
8.1), 8.490 (H6, J 0.4, 1.7, 4.7) and 9.061 (H2, J 0.4, 0.9,
2.4); dC (chloroform) 29.4 (t-Bu), 41.6 (Cq), 82.2 (COH),
122.8 (C5), 135.4 (C4), 141.4 (C3), 146.6 (C6), and 149.6
(C2). (Found: C, 76.2; H, 10.6; N, 6.1. C14H23NO requires
C, 75.97; H, 10.47; N, 6.33%).
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PROTON NMR AND IR STUDY OF SELF-ASSOCIATION IN PYRIDYLALKANOLS
305
3-(4-Pyridyl)-2,2,4,4-tetramethylpentan-3-ol,
9. Synthesized by reaction of 4-pyridyl-lithium with
2,2,4,4-tetramethylpentan-3-one as for 7. The alcohol
(mp 1528C; 30% yield) was eluted in 100% diethyl ether.
IR (CCl4)/cmꢀ1: 3643, 3625, 3380; dH (benzene, 0.0524
M) 0.904 (s, 2 t-Bu), 1.739 (s, OH), 7.099 (H5, J 0.8, 2.2,
5.5), 7.506 (H3, J 0.7, 2.2, 5.3), 8.477 (H6, J 0.7, 5.5), and
8.668 (H2, J 0.8, 5.3); dC (chloroform) 29.3 (t-Bu), 41.2
(Cq), 82.5 (COH), 123.0 (C3), 123.2 (C5), 146.9 (C6),
149.4 (C2), and 154.7 (C4). (Found: C, 75.8; H, 10.6; N,
6.4. C14H23NO requires C, 75.97; H, 10.47; N, 6.33%).
19.7 kcal molꢀ1); 7, syn ! anti, 20.0 ꢂ 0.2, ꢀ0.5 ꢂ 0.4
(mean value 20.2 kcal molꢀ1
)
(T ¼ 348–378 K); 8,
anti ! syn, 20.0 ꢂ 0.2, ꢀ1.6 ꢂ 0.6 (mean value
20.6 kcal molꢀ1); 8, syn ! anti, 20.2 ꢂ 0.2, ꢀ1.3 ꢂ 0.6
(mean value 20.6 kcal molꢀ1
)
(T ¼ 343–388 K); 9,
ꢀ, 19.2 ꢂ 0.2, ꢀ3.8 ꢂ 0.4 (mean value 20.7 kcal molꢀ1
)
(T ¼ 363-408 K); 9, nitrobenzene, ꢀ, 22.2 ꢂ 0.6, 3.5 ꢂ
1.4 (mean value 20.9 kcal molꢀ1) (T ¼ 368–393 K).
NMR titrations
Solutions of liquids were made up by injecting successive
amounts of the alcohol into deuteriated benzene (0.5 ml)
in an NMR tube. In calculating concentrations, volumes
were taken as additive and the cubical expansion of the
solution with temperature was assumed to be the same as
that of the solvent. To a weighed amount of solid in an
NMR tube was added solvent (0.5 ml); the volume was
corrected by assuming a density of 1 g mlꢀ1 for the solid
and additivity of volumes. 1H NMR spectra were recorded
at 298 K and in some cases at 298–328 K (Table S5).
1H NOESY Experiment on 3-(3-pyridyl)-2,2,4,4-
tetramethylpentan-3-ol, 8
1
For H-1H dipolar contact analysis, a NOESY spectrum
was recorded in deuteriated benzene (degassed by several
pump-freeze-thaw cycles and sealed under vacuum) on a
Bruker DRX-500 spectrometer equipped with a Silicon
Graphics workstation (Supplementary Material Fig. S3).
A 5 mm broad-band probe with a shielded z-gradient was
used. The temperature was monitored with a BCU 05
temperature unit and fixed at 300 K. Data were processed
on a Silicon Graphics workstation with the help of GIFA
(version 4.3).61 The 2D-NOESYexperiment was acquired
in the TPPI mode. It was recorded with 2 K points in t2
over 6 kHz and 620 points in t1. A 2.0 s relaxation delay
and a mixing time of 600 ms were used for the 16 scans of
each FID. Zero-filling was added in F1. Squared-sine
window functions were applied in both dimensions before
Fourier transformation. Baselines were corrected using a
polynomial function.
Reaction enthalpies (kcal molꢀ1
)
and entropies
(cal molꢀ1 Kꢀ1) were determined from van’t Hoff plots
(Table 2). Alcohols 1–3 were studied from about 0.01 to
2 M, 5 to 1.2 M. Highest concentrations of certain
alcohols were severely limited by solubility: 4 to
0.3 M; 6 to 0.08 M; 7–9 to about 0.2 M.
Calculation of association constants
The general-purpose computer program, WinEQNMR,44
optimizes association constants and the chemical shifts of
the monomer, dM, and of the various associated species,
dP. In practice we found that no more than three species
could be handled (two association constants) and that it
was advisable to make the simplifying assumption that all
the hydrogen-bonded OH protons have the same chemical
shift. Trimers and tetramers were assumed to be cyclic
and to have three and four identical hydrogen-bonded OH
protons, respectively. In the case of an open dimer we
assumed that the shift of the free OH proton is the same as
that of the monomer and that the hydrogen-bonded OH
proton has the same shift as in a cyclic trimer or tetramer.
The pertinence of the various models tested for each data
set was judged according to the R-factor (defined in
Supplementary Material Table S3), which was below 1%
for the results quoted, except for alcohol 5.
anti/syn Ratios for 3-(X-pyridyl)-2,2,4,4-
tetramethylpentan-3-ols, 7 and 8
Small samples (ca. 10 mg) of alcohols 7 and 8 were
dissolved in various solvents (0.5 ml) at 298 K and the
anti/syn ratio (ꢂ0.01) determined by integration of the 1H
NMR spectra. Results were as follows. 7: benzene, 0.06;
chloroform, 0.04; methanol, 0.13; acetone, 0.13; pyridine,
0.24; DMSO, 0.57. 8: benzene, 1.41; chloroform, 1.30;
pyridine, 1.00; DMSO, 0.93.
Rotation kinetics on 3-(X-pyridyl)-2,2,4,4-
tetramethylpentan-3-ols, 7-9
Molecular mechanics calculations
Dynamic 1H NMR spectroscopy on solutions of alcohols
7-9 in DMSO and of 9 in nitrobenzene was used. Rate
constants were determined by means of the gNMR
program. Activation enthalpies (kcal molꢀ1) and entro-
pies (cal molꢀ1 Kꢀ1) determined from Eyring plots are as
follows (compound, rotation direction, DH , DS ): 7,
anti ! syn, 20.2 ꢂ 0.1, 1.6 ꢂ 0.3 (mean value
Molecular mechanics calculations were performed using
the MMFF94 force field46 with the MMFF94 charge
model in the Sybyl 7.0 package. Steric energies
(kcal molꢀ1) for the most stable conformations of free
alcohols and, where possible, the corresponding polymers
are given in Table S7.
¼
¼
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 295–307

306
J. S. LOMAS, A. ADENIER AND C. CORDIER
1967; 64: 1019-1029, 1030–1040; (e) Biais J, Dos Santos J,
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