The unexpected but predictable tetrazole packing in flexible 1-benzyl-1H-tetrazole

Article abstract of DOI:10.1039/c2ce25940k

The crystal structure of 1-benzyl-1H-tetrazole, C₈H ₈N₄, was undertaken to study the geometry and intermolecular interactions of the (1-substituted) 1H-tetrazole moiety. It crystallizes in the monoclinic space group P2₁ with unit cell dimensions a = 7.6843(5), b = 5.5794(4), c = 9.4459(7) A, β = 100.949(4)°, V = 397.61(5) A³, Z = 2, density (calculated) = 1.338 gcm^-3. The packing of the molecules in the crystal structure is dominated by a number of weak intermolecular hydrogen bonds of the type CH...N and CH...C. This results in segregated infinite S-shaped layers of phenyl and tetrazole rings where each tetrazole ring is coordinated by six others. There are no π...π interactions. A group developing crystal structure prediction methods for highly flexible molecules was challenged to predict this Z′ = 1 crystal structure from the chemical diagram. The experimental structure was found, having essentially the same lattice energy (ΔE_latt ～0.1 kJmol^-1) as the most stable computationally generated structure, which had the expected π...π interaction and no segregation of tetrazole rings. The successful crystal structure prediction confirms that the intra and intermolecular interactions of the tetrazole group can be adequately represented by single molecule ab initio-based methods, which represent the electrostatic effects of the lone pairs and π electron density. The predicted structure provided a starting model, which was easily refined in SHELXL-97, providing indisputable proof that it is an accurate reproduction of the crystal structure. This journal is

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PAPER
The unexpected but predictable tetrazole packing in flexible 1-benzyl-
1H-tetrazole{
ab
a
c
d
John Spencer, Hiren Patel, John J. Deadman, Rex A. Palmer,* Louise Male, Simon J. Coles,
ef
e
g
Ogaga G. Uzoh and Sarah L. Price
g
Received 12th June 2012, Accepted 3rd August 2012
DOI: 10.1039/c2ce25940k
The crystal structure of 1-benzyl-1H-tetrazole, C
8 8 4
H N , was undertaken to study the geometry and
intermolecular interactions of the (1-substituted) 1H-tetrazole moiety. It crystallizes in the monoclinic
˚
1
with unit cell dimensions a = 7.6843(5), b = 5.5794(4), c = 9.4459(7) A, b =
space group P2
00.949(4)u, V = 397.61(5) A , Z = 2, density (calculated) = 1.338 gcm . The packing of the
molecules in the crystal structure is dominated by a number of weak intermolecular hydrogen bonds
3
23
˚
1
…
…
of the type CH N and CH C. This results in segregated infinite S-shaped layers of phenyl and
…
tetrazole rings where each tetrazole ring is coordinated by six others. There are no p p interactions.
A group developing crystal structure prediction methods for highly flexible molecules was challenged
to predict this Z9 = 1 crystal structure from the chemical diagram. The experimental structure was
2
1
found, having essentially the same lattice energy (DElatt y0.1 kJmol ) as the most stable
…
computationally generated structure, which had the expected p p interaction and no segregation of
tetrazole rings. The successful crystal structure prediction confirms that the intra and intermolecular
interactions of the tetrazole group can be adequately represented by single molecule ab initio-based
methods, which represent the electrostatic effects of the lone pairs and p electron density. The
predicted structure provided a starting model, which was easily refined in SHELXL-97, providing
indisputable proof that it is an accurate reproduction of the crystal structure.
3
Introduction
environments and energies. In contrast, a short review, which
discusses data on drugs containing tetrazole, a synthetic moiety
that is not known to occur in nature, shows that the
The 5-substituted 1H-tetrazole motif (Fig. 1a) has been
frequently mentioned in the drug discovery literature as a
1
-substituted 1H-tetrazole (Fig. 1b) has not yet been widely
bioisostere for the carboxylic acid group, due to their similar pK
a
used in the design of pharmaceutical products. The best known
1
values, shape and steric interactions. A recent study using
are derivatives of b-lactam antibiotics and optically active
2
crystal structures in the Cambridge Structural Database (CSD),
tetrazole-based antifungal preparations of the azole type, such
4,5
shows that both the 1H-tetrazole/COOH and tetrazolate/
as TAK-456 (Fig. 1c).
The latter exhibits potent activity
carboxylate isosteric pairs exhibit very similar hydrogen bonding
against Candida, Cryptococcus and Aspergillus when adminis-
tered perorally. An improved water-soluble form of TAK-457
4
was developed from TAK-456 (Fig. 1c).
a
School of Science, University of Greenwich, Medway Campus, Central
Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom
,5
b
3
Department of Chemistry, School of Life Sciences, University of Sussex,
Falmer, Brighton, East Sussex, BN1 9QJ, United Kingdom
Since the review there has been a marked increase in the
number of crystal structures in the CSD containing the
1-substituted C–H version, with 32 such tetrazole molecules in
version 5.33 March 2012, but this list includes only one drug-like
c
JDJ Biosciences, 576 Swan Street, Melbourne, 3121, Australia
School of Crystallography, Birkbeck College, University of London,
d
Malet Street, London, WC1E 7HX, United Kingdom.
E-mail: rex.palmer@btinternet.com
National X-ray Crystallography Unit Department of Chemistry,
4
compound (refcode BEGRIP) a derivative of TAK456 (Fig. 1c).
e
The steric differences between the 1 and 5-substituted 1H-
tetrazoles may be small (Fig. 1a and b), but the intermolecular
interactions are very different, as the N–H group is a classic
hydrogen bond donor, but the C–H group is much less polar.
University of Southampton, Southampton, SO17 1BJ, United Kingdom
School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
f
B15 2TT, United Kingdom
Department of Chemistry, University College London, 20 Gordon Street,
g
London, WC1H 0AJ, United Kingdom
Electronic supplementary information (ESI) available:
3
The review depicts the distribution of bonds in the tetrazole ring
{
Crystallographic data tables, the conformational energy grid used in
the search, table of low energy computed crystal structures, further
comparisons with other tetrazole structures. CCDC reference number
without reference to any crystal structural data. Hence, the
8 8 4
X-ray structure of 1-benzyl-1H-tetrazole, C H N , (Fig. 2), was
undertaken in order to consolidate data on the geometry and
804779. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ce25940k
chemical nature of the bonds in the 1H-tetrazole moiety. It was
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were collected, using monochromated Mo-Ka radiation, l =
0
˚
.71073 A, on a Bruker-Nonius APEX II CCD camera, employ-
ing Q and v scans to cover an asymmetric unit. Programs
7
used were: unit cell determination with the program DirAx;
8
data collection controlled by Collect; data reduction and cell
9
refinement using the program Denzo; an absorption correction
1
0,11
was made with SORTAV.
An Oxford Cryosystems
1
Cryostreams 700, enabled the data to be collected at 120 K.
2
The crystals are monoclinic space group P21 with unit cell
˚
dimensions a = 7.6843(5), b = 5.5794(4), c = 9.4459(7) A,
3
˚
b = 100.949(4)u, V = 397.61(5) A , Z = 2, density (calculated) =
2
3
.338 gcm , linear absorption coefficient = 0.088 mm . The
21
1
crystal structure determination was carried out with Mo-Ka
X-ray data measured at 120(2) K. In total 5629 integrated
reflections were collected, reducing to a data set of 977 [Rint
=
0
.0625], and completeness of data to h = 27.45u of 98.4%. The
˚
resolution range was 6.49 to 0.771 A. There was no significant
variation in intensity during the course of data collection.
Fig. 1 The 1H-tetrazole moiety (a) 5-substituted 1H-tetrazole (b)
1
-substituted 1H-tetrazole and (c) the antifungal TAK-456,1-[(1R,2R)-
-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) pro-
X-ray structure analysis
2
pyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone an example of an
active compound having a 1H-tetrazole group (A).
The crystal structure was solved by Direct Methods and refined
1
3,14
using SHELXL-97
implemented in the WinGX system of
1
programs. In the final refinement cycles Friedel pairs were
5
also seen as a test of the competing intermolecular interactions
between this tetrazole and a phenyl ring, in the expectation that
…
1
6
merged because in previous cycles the Flack parameter had
failed to resolve the absolute space group configuration. The
molecule does not contain any anomalous scatterers or asym-
metric centres so this result has little or no consequence. Non-
hydrogen atoms were refined anisotropically by full-matrix least
some form of p p stacking of the two aromatic groups might be
the dominant packing motif.
The expected mode of packing was not realized and instead an
unusual mode of packing was observed. Consequently, it was
decided to carry out a completely independent blind crystal
structure prediction of 1-benzyl-1H-tetrazole. This would
provide a stringent test of the ability to predict the crystal
structure of a molecule with sufficient conformational flexibility
to adopt a wide range of molecular shapes, and that contains an
unusual functional group with a different electronic structure
from those used in developing the CSP methodology.
2
squares methods. Benzyl and CH protons were set geometrically
and refined in riding mode. H(5) on C(5) in the tetrazole ring was
located on an electron density difference map and freely refined
isotropically. Geometrical calculations including characteriza-
…
…
tion of intermolecular CH N and CH H contacts were made
1
7
with the program PARST as implemented in WinGX. In the
final refinement cycle there were 977 data to 113 parameters,
2
resulting in a final goodness-of-fit on F of 1.259. Final R indices
for [I . 2s(I)] were R = 0.0426, wR = 0.0753 and R indices (all
1
2
Experimental
data) R1 = 0.0636, wR2 = 0.0827. The largest and smallest
2
3
˚
difference electron density regions were +0.186 and 20.207 eA
1
-Benzyl-1H-tetrazole, C
H
8 8
N
4
was synthesised according to the
literature method on a ca. 50 mmol scale from benzylamine,
respectively. Crystal data are summarized in ESI, Table S1{.
sodium azide and triethylformate. Its spectroscopic and analy-
6
tical data were consistent with those of the literature. It was
Crystal structure prediction
crystallized from dichloromethane/hexane by the vapour diffu-
sion method.
Those working on this independent prediction study were
provided only with the chemical diagram of the molecule and
were informed that the crystal structure had one molecule per
asymmetric unit. Initially the modelling study investigated
possible steric hindrance to rotation about the two torsion
Data collection
3
A colourless crystal fragment of dimensions 0.09 6 0.03 6 0.02 mm
was mounted on a glass fibre and flash frozen to 120 K. Intensities
1 2
angles j and j (Fig. 2 and ESI, Fig. S1{), which indicated a
high degree of flexibility in the molecule. This degree of
flexibility, where a wide range of very different molecular shapes
are possible, has to be taken into account from the beginning of
the search, a significant change to the approach that can be used
1
8–20
for nearly rigid molecules.
The methodology used here for
the prediction of crystal structures of flexible molecules was that
2
1
developed and successfully used for a pharmaceutical-like
molecule, with 7 torsion angles linking four aromatic rings and a
peptide group, in the fifth blind test of crystal structure
Fig. 2 1-Benzyl-1H-tetrazole showing the tetrazole ring bond distribu-
tion determined from the current analysis and the torsion angles j
C(7)–C(6)–N(1)–C(5) and C(12)–C(7)–C(6)–N(1) which were
allowed to vary in the CSP search.
1
=
j =
2
2
2
prediction.
6
442 | CrystEngComm, 2012, 14, 6441–6446
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2
3
The search using the program CrystalPredictor covering the
9 most commonly occurring space groups, generated about
5
1
70 000 structures. The lattice energy, Elatt = Uinter + DEintra
,
where Uinter is the intermolecular packing energy and DEintra is
the energy penalty for changing the conformation of the
molecule, was minimised by varying the cell parameters and
1 2
torsion angles j and j . At this stage the lattice energy was
crudely calculated by using a grid of ab initio calculations for
DEintra, and an atomic point charge model and empirical
repulsion-dispersion model for Uinter. Minimising this lattice
energy reduced the search to approximately 44 000 unique
structures, which were labelled by their energy ordering with this
atomic-charge-model based intermolecular potential.
Fig. 3 1-Benzyl-1H-tetrazole showing thermal ellipsoids at 50% prob-
ability. j
1
2
= C(7)–C(6)–N(1)–C(5) = 289.8(3)u and j = C(12)–C(7)–
34
35
C(6)–N(1) = 98.5(3)u. Drawn with ORTEP and RASTER3D.
which is always close to planar. The external torsions angles, j
1
and j
consistent with the large range of low energy conformations
ESI, Fig. S1{) despite the range of functional groups bonded to
2
exhibit a wide range of values (ESI, Fig. S4{), which is
The model for the electrostatic interactions and conforma-
tional energy was then improved. For each of the lowest 10 000
crystal structures, the energy of the molecule and its charge
distribution were calculated at the PBE0/6-31G(d,p) level of
(
C(6).
2
4
theory, using GAUSSIAN, to provide a better estimate of
DEintra, and a more accurate representation of the charge density
Crystal packing: weak hydrogen bonding
2
5
26
in terms of a distributed multipole model using GDMA. This
was combined with an atom-atom exp-6 repulsion-dispersion
potential using parameters that had been fitted to azahydro-
The mode of packing of the molecules in this crystal structure is
unusual. A molecule such as 1-benzyl-1H-tetrazole, based on
linked delocalized rings, might be expected to form crystal
2
7
28
carbons and polar crystal structures, which were assumed
transferable to this tetrazole. The crystal structure was lattice
energy minimised, with the molecule held rigid using
2
9
DMACRYS. The 100 most stable structures were then further
refined by allowing the molecular conformation to adjust more
accurately to the intermolecular forces using the program
3
0,31
24
CrystalOptimizer
to combine GAUSSIAN calculations
2
9
on the molecular conformations and DMACRYS optimisa-
tions of the crystal structure. Finally, the effect of the crystal
environment on the conformational energies DEintra and charge
density was estimated by calculating the conformational energy
and charge distribution in a polarizable continuum, with e = 3,
3
2
a value typical of organic molecules, using the Polarizable
24
3
3
Continuum Model (PCM) as implemented in GAUSSIAN at
PBE0/6-31+G(d) level of theory.
Results and discussion
Molecular geometry
Overall the benzyl and tetrazole rings are essentially planar,
including the H atom on the CH group belonging to the
5
-membered tetrazole ring. The individual rings are also each co-
planar with the inter-ring link C atom. The dihedral angle
between the two rings is 68.52(5)u (Fig. 3). The N–N bonds are of
three different types, consistent with Fig. 2: N(1)–N(2) = 1.343(2)
˚
A is typically of a diazene; N(2)–N(3) = 1.301(2) A is longer than
˚
3
6
a typical NLN bond but shorter than a typical aromatic bond;
3
6
˚
N(3)–N(4) = 1.368(2) A is also largely aromatic in character.
The two C–N bonds have different characteristics: C(5)–N(4) =
˚ ˚
.314(2) A is a double bond; C(5)–N(1) = 1.336(2) A is typically
1
3
6
aromatic. The experimental bond lengths are also typical of
those in the other crystal structures containing the 1-substituted
1
H-tetrazole group (Fig. 4). There are some significant
Fig. 4 Histograms showing the bond length distributions of 32
˚
differences (¡ 0.02 A) between the ab initio computed values
and experimental bond lengths, but both are within the observed
ranges. The variations in tetrazole bond angles (ESI, Fig. S4{)
are consistent with the bond length variations for this moiety,
1
-susbtituted 1H-tetrazole rings in the CSD. The experimental bon-
dlength in1-benzyl-1H-tetrazole is denoted by the red square, while the
ab initio bondlength in the corresponding calculated structure #2BT_23
is denoted by the black square.
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Fig. 5 1-Benzyl-1H-tetrazole crystal structure: (a) partial view of the
…
crystal packing showing close CH N contacts between a central
tetrazole and six surrounding tetrazoles (see also ESI, Table S3{); (b)
…
…
…
partial view showing CH N, CH C and CH p contacts.
…
structures involving p p bonding (ring stacking). However, no
such interactions occur in the present structure (Fig. 5). Instead,
the structure is held together through a large number of weak
Fig. 7 Crystal energy landscape of 1-benzyl-1H-tetrazole. Each point
represents a crystal structure that is a lattice energy minimum with the
final PCM model. The structure that matches the experimental crystal
structure, #2BT_23 is labelled with its energy rank #2. The global
minimum structure #1BT_120 is labelled GM.
3
7,38
intermolecular hydrogen bonds:
…
12 of these are of the type
…
CH N; and 3 are of the weaker type CH C (ESI, Table S3{)
involving atoms in the phenyl ring.
This results in a structure composed of infinite S-shaped
layers, producing a sequence of benzyl and tetrazole layers
(
Fig. 6). An unexpected feature of the packing is the formation of
presents a very different spatial arrangement as shown in Fig. 9.
This structure also has dominant weak hydrogen bonds: 8 of
tetrazole clusters (Fig. 5a), each having a central tetrazole ring
coordinated by six other tetrazoles.
…
…
type CH N; and 1 CH C. There is also one weak p p,
…
…
benzyl benzyl interaction (Fig. 9). Thermodynamically, this
Crystal energy landscape
structure could be a polymorph of 1-benzyl-1H-tetrazole.
Examining this lowest energy calculated structure and the 32
The two most stable crystal structures on the crystal energy
2
1
-substituted 1H-tetrazole structures in the CSD show that none
1
landscape (Fig. 7) are separated by less than 0.1 kJ mol but are
very different from each other. One of these structures, labelled
have the tetrazole cluster seen in the experimental structure.
However, there is some form of tetrazole layer in #1BT_120 and
the experimental structures DOKQIE, EKAJOQ, QALPAV,
QALPOJ, QALPUP and REVMOV, all of which have the
#
1
2BT_23, is in the same space group, P2 , as determined
experimentally and has very similar unit cell dimensions (ESI,
Table S4{). This computed structure gives an excellent overlay
with the experimental structure using the COMPACK facility
3
tetrazole bonded to a sp carbon and are tetrazole hydrocarbons
3
9
(
except QALPAV, which also contains an iodine atom). Hence,
4
as implemented in MERCURY, with a root mean square
0
there is no strong driving force for the tetrazole cluster, but a
layer structure does seem quite favourable, in cases where there
are no competing strong interactions.
difference in the positions of the non-hydrogen atoms in a 15
˚
molecule cluster being only 0.148 A (Fig. 8). #2BT_23 provided
a starting model easily refined in SHELXL-97, which is further
proof that it is a genuine reproduction of the crystal structure.
The structure corresponding to the global minimum in lattice
The successful prediction of a crystal structure is usually a
severe test of the accuracy of the models used to calculate the
1
energy, #1BT_120 (ESI, Table S4{), is in space group P2 /c and
Fig. 6 1-Benzyl-1H-tetrazole crystal structure: (a) View of the infinite
…
…
S-shaped layers held together by weak CH N and CH C hydrogen
bonds; (b) Partial view of the layer structure showing alternative
B(benzyl) and T(tetrazole) layers, and the repeating layer sequence
Fig. 8 Overlay 15 molecules of the experimental (atomic colours) and
the second most stable computed structure, #2BT_23 (green). The
direction of view obscures some of the molecules.
[
BTBT|TBTB].
6
444 | CrystEngComm, 2012, 14, 6441–6446
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distinct most stable structures shows that the unusual layers
do present an optimal compromise between the many different
weak hydrogen bonds and other intermolecular interactions.
Conversely, it also shows that the level of computational
chemistry modelling used is suitable for modelling the molecular
recognition of this functional group, which could become
increasingly useful in pharmaceutical design.
Acknowledgements
We thank Avexa for funding the PhD degree of Hiren Patel.
OGU is financially supported by CCDC and EPSRC EP/
G036675/1 (M3S Centre for Doctoral Training). The CPOSS
project CSP infrastructure is EPSRC funded under EP/F03573X/
1.
Fig. 9 The structure corresponding to the global minimum in lattice
˚
energy, #1BT_23 showing the dominant weak hydrogen bonds (A): 8 of
…
…
…
type CH N; and 1 CH C and the weak p p interaction (benzyl
…-
benzyl).
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2
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The X-ray crystal structure of 1-benzyl-1H-tetrazole shows an
unusual crystal packing with segregated layers of phenyl and
…
tetrazole interactions, tetrazole clusters and no p p interac-
tions. This packing was predicted from the chemical diagram by
a model that accurately modelled the electrostatic forces arising
from molecular charge density, including the anisotropic forces
from the lone pair and p electrons, but otherwise had not been
…
tailored to the tetrazole tetrazole interactions. The successful
2
prediction of the experimental structure as one of the two
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