A computational, X-ray crystallographic and thermal stability analysis of TETROL and its pyridine and methylpyridine inclusion complexes

Article abstract of DOI:10.1016/j.tet.2013.07.094

The identification and application of (+)-(2R,3R)-1,1,4,4- tetraphenylbutane-1,2,3,4-tetrol (TETROL) as an efficient and selective host compound is described. Computational and single crystal X-ray diffraction analyses revealed that the butane backbone of TETROL adopts a relatively rigid anti-conformation, with the hydroxy groups oriented syn and connected through a cyclic, homodromic arrangement of their O-H bonds. This structure is stabilised through a pair of 1,3-hydrogen bonding interactions. TETROL forms inclusion complexes with pyridine and 3- and 4-methylpyridine, and does so selectively from mixtures of the pyridines. X-ray diffraction (single crystal and powder) and thermal analyses of the inclusion compounds are described.

Full text of DOI:10.1016/j.tet.2013.07.094

Tetrahedron 69 (2013) 8713e8723
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A computational, X-ray crystallographic and thermal stability
analysis of TETROL and its pyridine and methylpyridine inclusion
complexes
a,*
b
a
a
Benita Barton , Mino R. Caira , Eric C. Hosten , Cedric W. McCleland
a
Department of Chemistry, PO Box 77000, Nelson Mandela Metropolitan University, Port Elizabeth 6031, South Africa
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2013
Received in revised form 15 July 2013
Accepted 30 July 2013
Available online 3 August 2013
The identification and application of (þ)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,4-tetrol (TETROL) as an ef-
ficient and selective host compound is described. Computational and single crystal X-ray diffraction analyses
revealed that the butane backbone of TETROL adopts a relatively rigid anti-conformation, with the hydroxy
groups oriented syn and connected through a cyclic, homodromic arrangement of their OeH bonds. This
structure is stabilised through a pair of 1,3-hydrogen bonding interactions. TETROL forms inclusion com-
plexes with pyridine and 3- and 4-methylpyridine, and does so selectively from mixtures of the pyridines. X-
ray diffraction (single crystal and powder) and thermal analyses of the inclusion compounds are described.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Hosteguest chemistry
Inclusion
TETROL
Methylpyridine
1. Introduction
Hydroxy groups are common structural features for both
TETROL and the TADDOLs. An important feature of the TADDOL
The chiral auxiliaries TADDOLs (
,5-dimethanols) 1, which are readily synthesised from inexpensive
naturally-occurring tartaric acid, have been widely exploited as
a
,
a
,
a
,
a
-tetraaryl-1,3-dioxolane-
structure is rigidity, owing to the presence of the 1,3-dioxolane
ring; structural rigidity is a property frequently associated with
effective host compounds. However, in TETROL the conformational
4
4
1
,2
host compounds in inclusion complexes. We were intrigued by
mobility usually associated with a butane chain could be signifi-
cantly constrained as a result of intramolecular hydrogen bonding
between the hydroxy groups. The expected favourable 1,3-
interactions are shown in 2a and 2b; 1,2- and 1,4-interactions are
also possible, as exemplified by 2c. The resultant stiffening of the
1,2,3,4-tetrol moiety, coupled with its inter-molecular hydrogen
bonding capability, would be expected to impart favourable in-
clusion host properties to TETROL.
This hypothesis was tested by performing a computational
conformational analysis and an X-ray crystal structure de-
termination on TETROL, and then by investigating hosteguest in-
teractions between TETROL and pyridine 3 as well as its methyl-
substituted derivatives, 2-, 3- and 4-methylpyridine (4a, 4b and
the possibility that the closely related compound, (þ)-(2R,3R)-
1
,1,4,4-tetraphenylbutane-1,2,3,4-tetrol 2 (TETROL) might show
3
similar potential. Although TETROL is not a novel compound, its
use as an inclusion host compound has, to the best of our knowl-
edge, not been reported previously.
Ar
Ar
Ph
Ph
R
1
O
O
HO
HO
OH
OH
OH
OH
R
2
Ar
Ar
Ph
Ph
1
2
4c, respectively).
H
O
H
O
H
O
H
H
H
O
Ph
Ph
O
H
O
H
O
O
H
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
H
O
H
O
O
Me
H
2a
2b
2c
N
N
Me
N
N
*
Corresponding author. Tel.: þ27 41 504 4859; fax: þ27 41 504 4236; e-mail
addresses: benita.barton@nmmu.ac.za, benita.barton@gmail.com (B. Barton).
3
4a
4b
4c
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.094

8714
B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
We now report on our findings.
. Results and discussion
This effect could increase the possibility of TETROL acting enan-
tioselectively when forming complexes with other compounds.
2
In the next significantly less stable group of conformers (e.g.,
2c), the butane chain adopts a gauche conformation in which a 1,4-
TETROL 2 was prepared from optically active (þ)-diethyl
L
-tar-
hydrogen bonding interaction is evident.
trate using standard Grignard reaction methodology with phenyl
magnesium bromide.
Although the ideal linear arrangement of the atoms involved in
hydrogen bonding (OeH/O) is not achieved owing to the geo-
metrical constraints of the intramolecular interaction, hydrogen
bonding is nevertheless discernable from the directionality of the
OeH bonds in the donor hydroxy groups, as well as the proximities of
the interacting atoms. Inspection of the computed OeH/OH bond
2
.1. Conformational analyses
2
.1.1. TETROL. A conformational search performed on TETROL at
y
ꢀ
ꢀ
the molecular mechanics level using the MMFF force field revealed
the lowest energy conformers to comprise a family of structures
with butane in the anti geometry, the four hydroxy groups in a syn
arrangement on the butane backbone and stabilised through a pair
of 1,3-hydrogen bonding interactions (Table 1 and Fig. 1). The hy-
lengths (ranging from 1.62 A to about 2.32 A) indicates that the
intramolecular hydrogen bonds range in strength from intermediate
to weak (Table 1). The overall stabilisation achieved is significant,
ꢀ1
ꢀ1
giving rise to barriers of about 98 kJ mol and 129 kJ mol , re-
spectively, to rotations about the C(1)eC(2) and C(2)eC(3) bonds of
Table 1
#
Computed energies and structural parameters in conformers 2aec and 5a
x
droxy groups were found to adopt cyclic, homodromic arrange-
ments of the OeH bonds in which a pair of weaker 1,2-hydrogen
bonds possibly also contribute. The two lowest energy con-
formers 2a and 2b differ only in the clockwise and anti-clockwise
orientations of the OeH bonds. In the case of 2a the terminal hy-
the butane unit in conformer 2a. The barriers arise from a combi-
nation of steric hindrance between bulky groups and disruption of
the intramolecular hydrogen bonds.
The geometries of the three lowest energy structures were
progressively refined further at the DFT level , which confirmed the
{
z
droxy groups act as hydrogen bond donors and in 2b, as hydrogen
bond acceptors. Clearly, the chirality of the underlying C(2) and C(3)
atoms influences the directionality of the hydrogen bonding array.
x
The barriers were computed at the MMFF level by applying incremental rotations
ꢁ
through 360 about the butane C(1)eC(2) and C(2)eC(3) bonds. Complex potential
energy curves were obtained, characterised by several precipitous energy changes,
which reflect the sudden release of pent-up strain energy as interfering groups rotate
past each other, enabling the structure to snap into more stable conformations.
Geometry optimisations were performed with the B3LYP functional model
successively employing the 6-31G*, 6-311G* and 6-311þþG** basis sets.
y
The MMFF force field has been explicitly parameterised to reproduce known
5
{
hydrogen-bond distances.
z
Understoodintermsofthehydroxygroupwhosehydrogenatombecomesinvolved.

B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
8715
relative stability of the anti conformer. In vacuo calculations for all
basis sets used reversed the stability order for conformers 2a and
2b, but the energy differences were small. Solvation effects were
determined by repeating the B3LYP/6-31G* calculations using the
SM8 aqueous solvation model; the stability order for 2a and 2b
reverted to that found for the MMFF calculations, but again the
energy difference was small (Table 1).
Inspection of the electrostatic potential surfaces computed for
the optimised DFT structures (Fig. 1) is informative as they reveal
the extents of the various hydrogen bonding interactions. For ex-
ample, for structure 2b the positive polarity associated with the
hydrogen atoms of the C(2) and C(3) hydroxy groups is clearly
dispersed as a result of their involvement in 1,3-hydrogen bonding.
In contrast, the C(1) and C(2) hydroxy groups are more polar and
consequently have potential for inter-molecular hydrogen bonding.
The computed conformers show some differences compared to
the crystal structure of TETROL (vide infra) insofar as the four OeH
bonds in the crystal adopt a linear rather than cyclic arrangement.
The pair of intramolecular 1,3-hydrogen bonds is also evident in the
crystal structure, while the C(2) and C(3) hydroxy groups are fur-
thermore involved in inter-molecular hydrogen bonds (one as a do-
nor and the other as an acceptor) with the corresponding hydroxy
groups of a second TETROL molecule, which is located close by, with
its array of hydroxy groups facing that of the first molecule (Fig. 2).
Single point energy calculations, followed by geometry optimi-
sations, were carried out on this hydrogen bonded supramolecular
motif (a TETROL dimer) at both the molecular mechanics and DFT
levels. The geometry optimised structures were shown to be sta-
bilised relative to TETROL at both computational levels, presumably
as a result of the inter-molecular hydrogen bonding interactions
(Table 2). The MMFF and DFT geometry optimisations both resulted
in tighter intra- and inter-molecular hydrogen bonding in-
teractions, compared to the crystal structure.
Changes in the relative orientations of the phenyl groups were
also evident after the geometry optimisations. The MMFF optimi-
sation minimised any steric interactions between adjacent rings,
leaving both intramolecular pairs of ‘axial’ phenyl rings, as well as
the two pairs of inter-molecular ‘equatorial’ phenyl rings, in face-on
orientations (Fig. 2). In contrast, the twisted relative orientations of
the phenyl rings in each of these pairs were largely retained in the
DFT optimised structure, possibly reflecting the effect of CHe
p
interactions.
2.1.2. MESOTETROL. For comparison, the conformations of the
corresponding meso isomer of TETROL, (2R,3S)-1,1,4,4-tetraphenyl
butane-1,2,3,4-tetrol 5 (MESOTETROL) were also analysed. At the
MMFF level, the lowest energy conformer was found to be the
gauche conformation 5a, which exhibits 1,4-hydrogen bonding and
possibly also a weak 1,2-interaction. The nearest anti conformer,
which displays a pair of 1,2-hydrogen bonds, was found to be about
ꢀ1
ꢀ1
4
.6 kJ mol higher in energy. The next anti conformer, 7.7 kJ mol
higher in energy than 5a, is stabilised through a single 1,3-
hydrogen bond as well as a weak 1,2 interaction. The first anti
conformer, exhibiting a pair of 1,3-hydrogen bonds 5b, was found to
ꢀ1
be 8.5 kJ mol higher in energy than 5a.
H
H
Ph
Ph
H
H
O
O
O
O
O
O
Ph
Ph
Ph
Ph
HO
HO
Ph
Ph
OH
OH
Ph
Ph
O
H
O
Ph
Ph
H
H
H
5
5a
5b
Further refinement of the set of lower energy MMFF structures
at the DFT level (B3LYP/6-31G*) gave 5b as the most stable con-
former, 18.5 kJ mol lower in energy than 5a. In 5b the two 1,3-
Fig. 1. Perspectives of the DFT optimised structures 2aec and 5a and their electrostatic
potential surfaces.
ꢀ
1

8716
B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
dihydroxy units adopt an anti disposition on the butane chain, in
contrast to syn in TETROL 2b. The calculated dipole moment for 5b
is zero, in contrast to a value of 1.58 D for the lowest energy con-
former of TETROL, 2b. The lowest energy conformer found for
ꢀ
1
MESOTETROL 5a was 11.2 kJ mol
sponding stereoisomer 2b (Table 1).
The computed barrier to rotation about the C(2)eC(3) bond in 5
less stable than its corre-
ꢀ1
was about 89 kJ mol , which is significantly lower than the cor-
responding value for 2, implying that the meso isomer is likely to be
a less rigid structure.
2.2. Single crystal X-ray crystallographic analysis of TETROL
Crystal data and refinement details are listed in Table 3 (Suitable
crystals of TETROL were obtained by slow recrystallisation from eth-
anol). With six independent TETROL molecules in the crystal asym-
metric unit, the volume of geometrical parameters for the TETROL
molecular and crystalstructure isextensive. Full lists of derived crystal
and molecular parameters are provided as Supplementary data. A
summary of the essential structural features follows.
Table 3
Crystallographic data for TETROL (2)
Chemical formula
Formula weight
Crystal system
28 26 4
C H O
426.49
Trigonal
Space group
P3
0.083
23.7521(12)
23.7521(12)
20.5299(10)
90
90
120
10030.5(9)
18
1
)/mm 1
ꢀ
m
(Mo K
a
ꢀ
a/A
b/A
c/A
ꢀ
ꢀ
ꢁ
ꢁ
a/
b
/
ꢁ
ꢀ
g
/
3
V/A
Z
F(000)
4068
Temp
173(2)
1
16,611
1754
0.0313
0.0771
1.004
1.71, 28.29
152,936
16,611
15,808
0.0511
0.999
Restraints
Nref
Npar
R1
wR2
S
ꢁ
q
min, max/
Tot. data
Unique data
Observed data [I>2.0s(I)]
R
int
Diffrn measured fraction
Min. resd. dens. (e/A )
Max. resd. dens. (e/A )
Fig. 2. Perspectives of the dimeric motif of TETROL and its electrostatic potential
surface*. *The electrostatic potential energy surfaces of the crystal and MMFF struc-
tures were generated via single point DFT calculations on the respective molecular
geometries.
q full
ꢀ
3
ꢀ0.213
ꢀ
3
0.264
Table 2
Computed energies and structural parameters for dimeric TETROL motif

B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
8717
The six crystallographically unique molecules (AeF) adopt
2.3. Formation of inclusion complexes
similar conformations, the primary features being the common
anti-conformation of the butane chain [the corresponding
TETROL 2 was dissolved separately in pyridine 3 and the methyl-
pyridines 4aec, and the solvents were then allowed to slowly evap-
orate under ambient conditions. The resulting crystals were collected,
washed thoroughly with hexane and dried, all under suction filtra-
ꢁ
CeCeCeC dihedral angle spanning a narrow range from ꢀ169.4(2)
ꢁ
to ꢀ172.2(2) ] while the four eOH groups are in a syn arrangement,
displaying 1,3-H-bonding. A space-filling view of molecule A of
TETROL as representative is shown in Fig. 3. It is noteworthy that in
the crystal, the twofold symmetry of the homodromic hydrogen
bonding motifs shown in 2a and 2b above is not manifested. In-
stead, only 1,3- and 2,4-hydrogen bonds stabilise the conformation
while the eOH group at the 3-position is suitably disposed as
a donor for inter-molecular hydrogen bonding to an oxygen atom
1
tion. H NMR spectroscopy was used to determine the extent of in-
clusion and, where applicable, the host/guest (H/G) ratio (Table 4).
Of the four pyridines tested, only 2-methylpyridine 4a was
not included by TETROL. The H/G ratio for the inclusion complex
with pyridine was 1:2, while those of both 3- and 4-methylpyridine
were 1:1.
Fig. 3. Space-filling model of representative molecule A in the crystal of TETROL (left) and stereoview of a representative hydrogen bonded dimer (AeB) of TETROL (right).
acceptor at the 2-position of an adjacent molecule. The represen-
tative dimeric motif AeB shown in Fig. 3 is thus maintained by two
inter-molecular OeH/O hydrogen bonds. Analogous interactions
occur in dimers CeD and EeF.
Each of the three dimers is the repeating motif in an infinite
column propagating parallel to the crystal c-axis via the threefold
Table 4
TETROL 2/guest (H/G) ratios of complexes formed
Guest (G)
Pyridine
H/G
1:2
d
-Methylpyridinea
2
3-Methylpyridine
4-Methylpyridine
1:1
1:1
1
screw axis of the space group P3 . A portion of this column is shown
in Fig. 4 for the AeB pair as representative. This arrangement fea-
tures two interwoven spiral chains of hydrogen bonds that maintain
the columnar structure. All of the hydrogen bonding features re-
ported for the six independent molecules of TETROL are based on the
a
Crystallisation occurred with difficulty, requiring the addition of dichloro-
methane, methanol and hexane to the host and potential guest mixture.
2
.4. Competition experiments
2
4 hydroxyl group hydrogen atom positions that were observed in
TETROL 2 was dissolved in equimolar mixtures of two or more
difference Fourier syntheses and subsequently idealised in a riding
ꢀ
pyridines and the solutions were then cooled to induce crystal-
lisation. The resulting crystals were recovered, purified and ana-
lysed as described previously. H/G ratios of the resultant complexes
are given in Table 5.
model with OeH¼0.84 A. Also shown in Fig. 4 is the complete crystal
packing arrangement viewed along [001]. Geometrical data for the
hydrogen bonds are included in the Supplementary data.
Fig. 4. Stereoview of a portion of a representative hydrogen bonded column comprising AeB dimers in TETROL (left) and crystal packing in TETROL viewed down the c-axis (right).
Given the somewhat unusual structural features of TETROL and
its extensive hydrogen bonding capacity, its potential as a host
compound was subsequently investigated.
It is clear that TETROL is much more selective towards including
4-methylpyridine compared to the other pyridines (Table 5). This
was the case for all solvent combinations involving 4-

8718
B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
ꢁ
Table 5
associated with the ultimate release of 3-methylpyridine (115.4 C,
peak maximum), compared to 4-methylpyridine (130.8 C).
Competition experiments and H/G ratios of complexes formed
ꢁ
Pyridine
2-Methyl-
pyridine
3-Methyl-
pyridine
4-Methyl-
pyridine
Guest
ratios
Overall
H/G ratio
In all three cases there is a small endotherm between 142 and
143 C, just prior to the host melting, and is possibly due to a phase
ꢁ
X
X
X
X
1:14
0:1
1:4.5
1:3.7
1:1.7
0:0
1:1
1:1
1:1
1:1
1:1
1:0
1:1
1:1
change in the host.
X
X
The term (TonꢀT
b
), where Ton is the onset temperature of guest
X
release and T the boiling point of pure guest, has long been used as
b
X
X
7
an indicator of the relative stabilities of complexes. The more
positive this value is found to be for a particular host, the more
stable the complex is considered. In the present case the values for
X
X
X
X
X
X
X
X
X
0:0:1
1:0:0:9
X
(
T
onꢀT
b
) are negative for all three complexes (Table 6), and their
suggested stability is in the order pyridine>4-methylpyridinez3-
methylpyridine. This contradicts the host selectivity order that
emerged from competition experiments where the inclusion of 4-
methylpyridine was favoured over the other pyridines. The lack of
crystal isostructurality among the three complexes is possibly
a factor, which renders the predictive value of the parameter
methylpyridine, including its binary mixtures with pyridine, 2-
methylpyridine and 3-methylpyridine, respectively, as well as an
equimolar ternary mixture containing 2-, 3- and 4-methylpyridine,
and a quaternary mixture of pyridine and the three methylpyridines.
The competition experiments also showed that TETROL selects
(
T
onꢀT
b
) less reliable. In the present case, the peak temperatures at
which the last of the guest compounds are released (Tpf) correlate
best with the inclusion selectivities arising from the competition
experiments (Table 6).
3
-methylpyridine over pyridine and 2-methylpyridine. It is in-
teresting that in this case the 2-isomer was included from this
mixture, albeit to a minor extent, even though no complex was
obtained when TETROL was recrystallised from pure 2-
methylpyridine. An experiment involving a mixture of pyridine
and 2-methylpyridine showed no significant inclusion of either
solvent. The presence of 2-methylpyridine appears to suppress the
affinity of the host for pyridine.
With the exception of the last result, the overall H/G ratios were
found to be 1:1 in the competition experiments, irrespective of the
nature of the included guest.
The competition experiments show that the inclusion selectivity
order displayed by TETROL is 4-methylpyridine>3-methyl-
pyridine>pyridine>2-methylpyridine. Since the separation of
mixtures of isomeric substituted pyridines, such as the methyl-
pyridines through distillation is difficult owing to similar boiling
points, their selective inclusion by TETROL could in principle be
used to separate them. Heating the inclusion complex releases the
guest (vide infra) and the host can then be recycled for further use.
Pyridines are valuable building blocks in the synthesis of numerous
2.6. Powder diffraction patterns
The polymorphic characteristics of the host residue after release
of the guest were determined by obtaining the X-ray powder dif-
fraction patterns for the residues in all three cases (Supplementary
data). Identical powder diffraction patterns were found, indicating
that the same polymorph had been obtained in each of the three
cases. The patterns were furthermore similar to that obtained for
the host compound prior to complexation, but matched the pattern
computed from the single crystal X-ray analysis very well. From the
latter, we deduce that the initial sample of TETROL was affected to
some extent by preferred orientation.
2
2
.7. Single crystal X-ray diffraction analyses of the 2$pyridine,
$3-methylpyridine and 2$4-methylpyridine inclusion
complexes
6
agrochemicals, pharmaceuticals and polymers, amongst others,
and hence the development of new methodologies for their puri-
fication is always interesting.
The X-ray crystallographic data (Table 7) show that the three
complexes belong to different crystal systems, namely, triclinic for
the 2$pyridine complex (space group P1), orthorhombic for the
1 1 1
2$3-methylpyridine complex (P2 2 2 ) and monoclinic for the 2$4-
2
.5. Thermal stability analyses
methylpyridine complex (C2). Figs. 6e8 show the unit cells for the
three complexes, with the guest in space-filling representation.
Hydrogen bonds are highlighted with light blue dashed lines. Dis-
order across a centre of inversion was noted for the guest in the
case of 2$4-methylpyridine, the two components being present
with site-occupancies 0.5 each (Fig. 8). In both the pyridine and 4-
methylpyridine complexes (where the guest molecules are sym-
metrical structures), the angles subtended by the intersecting
Differential scanning calorimetric (DSC) and thermogravimetric
(
TG) experiments were performed on the inclusion complexes of
TETROL. Fig. 5aef shows the thermal events that occurred when
each complex was heated at a constant rate of 5 K min through
the range 30e200 C.
The mass losses observed for each of the complexes upon
heating were close to their theoretically predicted values (Table 6).
ꢀ1
ꢁ
2
planes of the geminal phenyl rings in each CPh OH group are either
ꢁ
ꢁ
The guest compound release onset temperature for pyridine
very similar [105.1(11) and 105.9(13) ] for the pyridine complex or
ꢁ
ꢁ
(
43.8 C) was the lowest of the three inclusion complexes, while the
identical [108.7(13) for the 4-methylpyridine complex]. The in-
temperatures for the 3- and 4-methylpyridine complexes were
tersection angles differ significantly when 3-methylpyridine is the
ꢁ
ꢁ
ꢁ
ꢁ
similar (51.4 C and 52.6 C, respectively). The low initial release
temperature for pyridine may be the reason for the slight dis-
crepancy in overall weight loss for this complex (24.2% vs the
predicted value of 27.1%) since some guest compound is probably
lost during preparation of the sample for the thermal analyses.
The TG and DSC traces for the pyridine inclusion complex show
included guest, with values of 95.2(8) and 109.8(8) being ob-
served. The unsymmetrical alignment of the geminal pairs of
phenyl rings is most likely due to the unsymmetrical guest mole-
cule in this case. The pyridine guest molecules are found in con-
tinuous, though somewhat constricted, channels (Fig. 9), while
both the 3- and 4-methylpyridine guest molecules occupy discrete
cavities in the host frameworks (Figs. 7 and 8).
It has been noted that for a specific host compound, the in-
clusion complexes in which the guest molecules reside in channels,
generally have lower relative thermal stabilities than those in
which the guests are contained in isolated cavities in the host
that loss of pyridine occurs in three stages, with the last release at
ꢁ
1
05.3 C (Fig. 5b). The thermal events evident for the inclusion
complexes of TETROL with 3- and 4-methylpyridine are simpler
than for pyridine (Fig. 5cef). They are themselves similar, the main
difference being the shift to a higher temperature of the endotherm

B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
8719
Fig. 5. (a) DSC and TG traces (overlayed) for 2$pyridine; (b) TG and its derivative for the 2$pyridine complex (c) DSC and TG traces (overlayed) for 2$3-methylpyridine; (d) TG and its
derivative for the 2$3-methylpyridine complex (e) DSC and TG traces (overlayed) for 2$4-methylpyridine; (f) TG and its derivative for the 2$4-methylpyridine complex.
Table 6
Thermal data from DSC/TG traces for 2$pyridine, 2$3-methylpyridine and 2$4-methylpyridine
ꢁ
a
ꢁ
ꢁ
a,b
Guest
T
on/ C
T
b
/ C
(TonꢀT
b
)/ C
T
pf
Observed mass loss (%)
Expected mass loss (%)
Pyridine
43.8
51.4
52.6
115
144
145
ꢀ71.2
ꢀ92.6
ꢀ92.4
105.3
115.4
130.8
24.2
17.3
17.8
27.1
17.9
17.9
3
4
-Methylpyridine
-Methylpyridine
a
Estimated from the TG derivatives (Figs. 4, 6 and 8).
The peak temperature at which the last of the guest is released.
b
8
crystal. In the latter case, complete disruption of the host frame-
work, necessitating a higher temperature, is required to release the
guests, while channel-occupying guests are able to diffuse out at
lower temperatures. Our findings from the thermal stability studies
showed that the pyridine complex is less stable than the two
methylpyridine complexes. This can be attributed to the fact that
the pyridine molecules occupy channels rather than discrete
cavities.
Figs. 10e12 are stereoviews of the guest packing arrangements
in the crystals. Only 1,3-intramolecular and no inter-molecular

8720
B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
Table 7
Crystallographic data for 2$pyridine, 2$3-methylpyridine, 2$4-methylpyridine
2
$Pyridine 2$3-Methylpyridine 2$4-Methylpyridine
Chemical formula C28 $2C N C28 $C $C
H
26
O
4
5
H
5
H
26
O
4
6
H
7
N
C
28
H
26
O
4
6 7
H N
Formula weight 584.69 519.61
Orthorhombic
P2
0.081
519.61
Monoclinic
C2
Crystal system
Space group
Triclinic
P1
1 1 1
2 2
)/mm 1 0.083
ꢀ
0.080
m
(Mo K
ꢀ
a
a/A
8.2430(2)
9.7660(2)
10.8739(9)
90.663
108.101(1)
113.368
754.62(3)
1
10.5753(4)
14.6758(5)
17.8006(6)
90
17.8433(8)
8.1284(4)
12.7853(6)
90
131.175(1)
90
ꢀ
b/A
ꢀ
c/A
ꢁ
ꢁ
a
/
b
/
90
90
ꢁ
g
/
ꢀ
3
V/A
2762.67(17)
4
1395.77(12)
2
Z
F(000)
310
1104
552
Temp
150
150
200
Restraints
3
0
1
Nref
Npar
R
wR2
S
3732
405
3835
361
1830
213
0.0330
0.0898
1.05
2.3, 28.3
15,317
1830
1780
0.0336
0.0908
1.04
2.3, 28.4
38,700
3732
0.0310
0.0881
1.03
2.2, 28.3
29,517
3835
ꢁ
q
minemax/
Tot. data
Unique data
Observed data
3666
3627
[
I>2.0s(I)]
Fig. 7. Unit cell for the 1:1 complex of 2 with 3-methylpyridine.
R
int
0.016
0.017
0.998
0.016
0.994
Dffrn measured 0.992
fraction full
Min. resd. dens. ꢀ0.26
q
ꢀ0.16
ꢀ0.17
ꢀ
3
(
e/A )
Max. resd. dens. 0.29
0.28
0.27
ꢀ
3
(
e/A )
Fig. 8. Unit cell for the 1:1 complex of 2 with 4-methylpyridine.
less clear. Both guests engage in (guest)N/HeO(host) hydrogen
bonds that of 3-methylpyridine being marginally stronger
ꢀ
ꢀ
[
2.7094(18) A] compared with the 4-methyl isomer [2.790(5) A]. No
intramolecular stacking interactions are observed in either
pep
complex. Furthermore, no inter-molecular host/host hydrogen
bonds occur in the 4-methylpyridine complex, though they are
Fig. 6. Unit cell for the 1:2 complex of 2 with pyridine; the guest is shown in space-
filling representation and hydrogen bonding by means of dashed light blue lines.
2 2
apparent in the 3-methylpyridine complex [CPh OH/O(H)CPh
ꢀ
ꢀ
OeH/OH hydrogen-bonding is observed in the pyridine complex.
The host framework is thus expected to be less rigid, possibly
allowing for more facile guest escape. The pyridine molecules
themselves are held in the crystal by means of (guest)
N/HeO(host) hydrogen bonds (N/O 2.742(2) and 2.754(2) A).
The complex is further stabilised by guesteguest as well as
(2.7233(15) A) and ortho AreCH/O(H)CH (3.2603(18) A)]. How-
ever, weak interactions, which are evident between the host
pep
and the 4-methylpyridine guest molecules [4.139(2) E] are not
significant in the 3-methylpyridine case, which may account for the
observed thermal stability difference. A contributing factor may be
that each guest molecule in the 4-methylpyridine complex expe-
ꢀ
hosteguest aromatic ring
CHe interactions were observed between the host and guest
(guest)meta-CeH/Ar(host) and (host)meta-CeH/Ar(guest)],
p
e
p
stacking interactions. Only weak
riences two weak CHe
C3 and C5 hydrogens of 4-methylpyridine interact favourably with
p interactions with a host aromatic ring: the
p
ꢀ
ꢀ
ꢁ
[
host aromatic rings [3.658(7) A and 3.670(6) A, with angles of 148
ꢀ
ꢁ
ꢁ
ranging from 3.55 to 3.8 A (133e151 ).
and 147 , respectively], while only one guest CH
2
H/host aromatic
Reasons for the lower thermal stability of the 3-methylpyridine
complex relative to that of the 4-methylpyridine analogue are
CHe
p interaction is observed per guest molecule in the 3-
ꢀ
ꢁ
methylpyridine case [3.635(2) A, 166 ].

B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
8721
Fig. 9. (a) The 1:2 complex of 2 with pyridine showing the channel-occupation of the guest; the view is along the a-axis, and the structure shown is several molecules thick; (b) the
guest has now been deleted to show the channels more clearly.
Fig. 10. Stereoview of the 1:2 complex of 2 with pyridine.
Fig. 12. Stereoview of the 1:1 complex of 2 with 4-methylpyridine.
interactions. The stabilisation achieved through intramolecular
hydrogen bonding is significant, giving rise to a calculated (MMFF)
ꢀ1
barrier of about 129 kJ mol to rotation about the C(2)eC(3) bond
of the butane unit. The resultant rigidity of the butane backbone
was predicted to impart favourable host characteristics to TETROL
when involved in inclusion complexation. This was confirmed
by the formation of inclusion complexes when the host was
recrystallised from pyridine and 3- and 4-methylpyridine. The
pyridines were included selectively when TETROL was recrystal-
lised from binary, ternary and quaternary mixtures of the pyridines,
with the preference order being 4-methylpyridine>3-methyl-
pyridine>pyridine>2-methylpyridine. Thermal stability studies
were carried out on the three inclusion complexes. The X-ray
crystal structures of TETROL and its inclusion complexes were de-
termined, with the insights obtained into the inter-molecular in-
teractions allowing the thermal stabilities of the complexes to
be rationalised. It is proposed that the inclusion selectivity dis-
played by TETROL could be used for separating the isomeric
methylpyridines.
Fig. 11. Stereoview of the 1:1 complex of 2 with 3-methylpyridine (hydrogens omitted
for clarity).
3
. Conclusions
A computational conformational analysis of TETROL at both the
molecular mechanics and DFT levels revealed that in the lowest
energy structure the conformation of the butane chain is anti, with
the four hydroxy groups in a syn arrangement with respect to the
butane backbone, and involved in a pair of 1,3-hydrogen bonding
The obvious potential of TETROL as a host compound is currently
being explored in our laboratories. It forms complexes with nu-
merous guest species, and enantiomeric separations have been

8722
B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
achieved when TETROL was recrystallised from racemates, due to
the chiral environment it provides to chiral guest species. Further
communications in this regard are imminent.
discontinuing heating just before the melting point of the host
was reached.
4
4
. Experimental
4.5. Single crystal X-ray diffraction
.1. General
X-ray diffraction studies of the three inclusion complexes were
performed at 150 K or 200 K using a Bruker Kappa Apex II dif-
Melting points were recorded on an Electrothermal IA9000
fractometer with graphite-monochromated Mo Ka radiation
ꢀ
9
9
Series digital melting point apparatus and are uncorrected. In-
frared spectra were recorded on a Bruker Tensor 27 Platinum ATR
(
l
¼0.71073 A). APEXII was used for data collection and SAINT for
cell refinement and data reduction. The structure was solved by
direct methods using SHELXS-97 and refined by least-squares
procedures using SHELXL-97 with SHELXLE as a graphical in-
1
13
10
system and analysed using Opus version software. H and
NMR spectra were obtained using a Bruker Ultrashield Plus
00 MHz spectrometer and analysed using TopSpin 3.0 software.
C
10
11
4
terface. All non-hydrogen atoms were refined anisotropically. C-
DSC and TG traces were collected using a TA SDT Q600 Module
system and analysed using TA Universal Analysis 2000 data
analysis software. Samples were placed in open ceramic pans with
an empty ceramic pan functioning as a reference. High purity
nitrogen gas was used as purge gas. Optical rotations were mea-
sured using an A. Kr u€ ss Optronic polarimeter (Germany) equipped
bound H atoms were placed in calculated positions and refined as
ꢀ
riding atoms, with CeH 1.00 (CH), 0.95 (aromatic CH), 0.98(CH
3
) A
and with U(H)¼1.2(1.5 for methyl) Ueq(C). The H atoms of the
methyl groups were allowed to rotate with a fixed angle around the
CeC bond to best fit the experimental electron density (HFIX 137 in
10
the SHELX program suite ). The H atoms of the hydroxy groups
were allowed to rotate with a fixed angle around the CeO bond to
best fit the experimental electron density (HFIX 148 in the SHELX
with a sodium lamp.
10
4
.2. Computational studies
program suite ) with U(H) set to 1.5 Ueq(O). Data were corrected
for absorption effects using the multi-scan method implemented in
9
Calculations were performed using SPARTAN ’10 for Windows
SADABS. In the absence of significant anomalous scattering, Frie-
[
build 1.1.0 (Mar 20 2011)] software, supplied by Wavefunction Inc.
del pairs were merged and the absolute structure was assigned
by reference to an unchanging chiral centre in the synthetic
procedure.
Conformational searches were carried out using the Monte Carlo
algorithm as implemented in the MMFF (Merck Pharmaceuticals)
force field; the first one hundred lowest energy conformations
were retained. Only structures whose relative energies fell within
the first 20 kJ mol range were refined further at the DFT level
using the B3LYP functional and progressively employing the 6-
The crystals of TETROL required special treatment as they were
found to be merohedral twins. Structure solution involved location
of six independent molecules of TETROL and was achieved using
ꢀ
1
10
SHELXD. However, the model failed to refine below R1¼0.22. The
12
3
1G*, 6-311G*, and 6-311þþG** basis sets. The SCF procedure used
twofold nature of the twinning was revealed by PLATON and
subsequent corrections led to rapid convergence of the refinement
of the non-H atoms, first isotropically and then anisotropically
restricted hybrid HF-DFT calculations with Pulay DIIS and geo-
metric direct minimisation. Solvation effects were determined by
repeating the B3LYP/6-31G* calculations using the SM8 aqueous
solvation model.
10
13
(SHELXL-97 operating under the X-Seed graphical interface ).
Successful treatment of the data led to the location of all H atoms
(including those of the 24 independent hydroxyl groups) in suc-
4
.3. Synthesis of (D)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,
cessive difference Fourier syntheses. They were included in ideal-
4
-tetrol 2
ised positions as described for the complexes above with U values
1.2 times those of their parent atoms. Refinement converged with
This compound was synthesised according to a standard Grignard
a BASF parameter of 0.444(1) for the crystal specimen studied.
Since the absolute configuration was known from the synthesis,
and the Flack parameter did not discriminate enantiomers, the
procedure using excess PhMgBr. Addition of the tartrate to the
Grignard reaction was highly exothermic and thus this step was
carried out with cooling in an ice-water bath. In a typical reaction,
the use of bromobenzene (22.99 g, 146.5 mmol) and magnesium
10
Bijvoet pairs were merged (MERG 4 in SHELXL-97 ).
turnings (3.94 g, 162.0 mmol) in anhydrous THF, with (þ)-diethyl
tartrate (5.00 g, 24.3 mmol), also in anhydrous THF, afforded a gum,
which was crystallised and recrystallised from CH Cl /hexane/
MeOH to afford (þ)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,4-tetrol
L-
Acknowledgements
2
2
Financial support is acknowledged from the Nelson Mandela
Metropolitan University, and E. Ferg is thanked for performing
powder diffraction analyses. M.R.C. thanks the University of Cape
Town and the National Research Foundation (Pretoria) for financial
support.
ꢁ
3
2
as a white solid (4.68 g, 10.9 mmol, 45%), mp 147e149 C (lit., mp
ꢁ
23
3
25
1
50e151 C); [
CHCl )}; max(solid)/cm 3440 (br, OH), 3294 (br, OH), 3057 (Ar),
033 (Ar), 1598 (Ar) and 1494 (Ar); (CDCl ) 3.86 (2H, d, 2COH),
.44 (2H, d, 2HCOH), 4.72 (2H, s, 2CPh OH) and 7.2e7.4 (20H, m, Ar);
(CDCl ) 72.11 (HCOH), 81.71 (CPh OH), 124.97 (Ar), 126.05 (Ar),
27.15 (Ar), 127.27 (Ar), 128.10 (Ar), 128.37 (Ar), 128.55 (Ar), 130.08
Ar), 143.85 (quaternary Ar) and 144.16 (quaternary Ar).
a
]
D
þ166 (c 9.32, CH
2
Cl
2
) {lit.,
[
a
]
D
þ154 (c 1.2,
ꢀ
1
3
n
3
4
d
H
3
2
d
C
3
2
1
(
Supplementary data
CCDC-915557, 915561, 915570 and 924355 contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Full geo-
metrical data for the structure of TETROL and PXRD traces
are included in the Supplementary Data. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.07.094.
4
.4. Powder diffraction patterns
These were obtained by subjecting the powders to Cu
ꢀ
K
a
1
radiation (
l
¼1.54056 A) using a Bruker D2 diffractometer.
ꢁ
The scan range was from 5 to 50 at 0.01 steps/s. A Ni filter was
used at the Lynxeye detector. Samples were prepared by heating
the inclusion complexes to expel the guest compounds, and

B. Barton et al. / Tetrahedron 69 (2013) 8713e8723
8723
References and notes
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9
1
1
5
6
. Hehre, W. H. A Guide to Molecular Mechanics and Quantum Mechanical Calcu-
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1
. Sagitullin, R. S.; Shkil, G. P.; Nosonova, I. I.; Ferber, A. A. Chem. Heterocycl.
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