H/F isosteric substitution to attest different equi-energetic molecular conformations in crystals

Article abstract of DOI:10.1039/c3ce40697k

The sequential replacement of aromatic H-atoms by F-atoms in 1,6-bis(phenylcarbonate) hexa-2,4-diyne allows access to its possible iso-energetic "syn", "gauche" and "anti" conformations. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ce40697k

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H/F isosteric substitution to attest different equi-
energetic molecular conformations in crystals3{
Cite this: DOI: 10.1039/c3ce40697k
Amol G. Dikundwar,a Ch. Venkateswarlu,b R. N. Chandrakala,b
Srinivasan Chandrasekaran*b and Tayur N. Guru Row*a
Received 26th February 2013,
Accepted 9th May 2013
DOI: 10.1039/c3ce40697k
www.rsc.org/crystengcomm
The sequential replacement of aromatic H-atoms by F-atoms in
1,6-bis(phenylcarbonate) hexa-2,4-diyne allows access to its
possible iso-energetic ‘‘syn’’, ‘‘gauche’’ and ‘‘anti’’ conformations.
The repertoire of a molecule in adopting a specific molecular
conformation decides the efficiency of the intermolecular packing
in the solid state.5 The basic rules governing molecular packing
indicate that molecules with a centre of symmetry prefer to
acquire an inversion centre in the crystal lattice leading to crystal
structures with centrosymmetric space groups.6 In a centrosym-
metric conformation with the molecular dipole moment being
zero, the resulting crystal structure is nearly always centrosym-
metric.7 However, Brock and Dunitz8 demonstrated that centro-
symmetric molecules can even adopt noncentrosymmetric
conformations and pack with a higher crystallographic symmetry
at the expense of noncovalent intermolecular interactions.9 When
present in a non-centric conformation, molecules can arrange so
as to cancel the intermolecular dipoles resulting in a centrosym-
metric organization or they can even afford a polar crystal
packing.7 Interestingly, in the literature, there have been
arguments that a particular conformation is inherent in a
molecule, which is mainly determined by its covalent connectivity
with the intermolecular interactions being just a consequence of
the crystal packing.10 On the contrary, there are several reports
explaining the stabilization of unusual molecular conformations
through molecular aggregation in the solid, liquid and gas
states.11 This issue takes prime importance in cases where the
molecular conformation observed in the crystal structure deviates
significantly from the ideal conformation calculated for the gas
phase or in solution.12
The crystallization of organic molecules depends on several factors
with the molecular conformation being the key component. With
the X-ray crystallographic technique providing an unambiguous
determination of 3D structure in the solid state, conformational
analysis has become facile in molecular crystals. The specific
conformation of a molecule in a crystal results from a delicate
balance of intra and intermolecular forces such as dipole–dipole
interactions, steric (van der Waals) interactions and hydrogen
bonding.1,2 While the interactions within a molecule ensure
conformational locking, the intermolecular interactions provide
tools for crystal engineering, exploiting conformational flexibility
in the molecule. In the literature, there are several examples where
different molecular conformations of a compound have been
obtained by allowing the molecules to assemble in a different
crystallization milieu. Such an ‘experimental conformational scan’
has been conventionally achieved by conformational polymorph-
ism3 and cocrystallization experiments.4 The variability in the
conformation of a molecule may also be brought about by
decorating the surface of a molecule with substituents providing
both electronic and steric influences. In this article, we explore the
utilization of the isosteric (equi-volume) properties of a hydrogen
atom and a fluorine atom in constituting different equi-energetic
molecular conformations of the conformationally flexible mole-
cule, 1,6-bis(phenylcarbonate) hexa-2,4-diyne, 1 (Scheme 1).
The non-availability of any strong H-bonding pairs makes 1 a
suitable candidate to examine the effect of fluorination on the
resulting molecular conformations in the solid state.13 In its
aSolid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore
560012, Karnataka, India. E-mail: ssctng@sscu.iisc.ernet.in;
Fax: +91-080-23601310; Tel: +91-080-22932796
bDepartment of Organic Chemistry, Indian Institute of Science, Bangalore 560012,
Karnataka, India. E-mail: scn@orgchem.iisc.ernet.in; Fax: +91-80-23600529;
Tel: +91-80-22932404
In memory of Professor A. Srikrishna (1955–2013)
3
{ Electronic supplementary information (ESI) available: detailed synthetic proce-
dures and characterization data for compounds 1–6; CIFs, ORTEPs and packing
diagrams of compounds 1–6 and CSD search details. CCDC numbers 759062 and
922272–922275. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3ce40697k
Scheme 1 Chemical structures of compounds 1–6 with a general scheme for
their synthesis.
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crystalline form,
1 adopts an unusually folded molecular
conformation with the two diacetylene spaced aryl carbonate
groups oriented in a ‘‘cisoid’’ fashion with the torsion angle, w
being 8.4(1)u (Fig. 1). Molecules with this chiral dissymmetric
conformation pack in the centrosymmetric space group Pccn with
half a molecule in the asymmetric unit (Z = 4).14
Intrigued by the elusive conformation of 1, we carried out a
Cambridge Structural Database (CSD)15 search to obtain an overall
estimate of the different molecular conformations adopted by
such symmetrically disubstituted diacetylenes. The search results
(see ESI ) clearly indicated a preference towards the centrosym-
3
metric molecular conformation with the torsion angle, w = 180u as
depicted in Fig. 2. This prompted us to probe the gas phase
molecular conformation of 1. Geometry optimization calculations
(Table 1) suggested the most stable conformation to be the
untwisted one with the torsion angle of 77.6u, whereas the
generally preferred ‘‘anti’’ conformation (w = 180u, indicated by
CSD) lies just above this on the energy axis (DESP = 0.08 kcal
mol21, Table 1). Within computational uncertainties, these
conformations can be called iso-energetic. More importantly, the
energy gaps between the crystal conformation (8.4(1)u) and the
conformations mentioned above (77.6u and 180u) are significantly
small (Table 1) indicating the possibility of conformational
flipping upon a slight manipulation at the molecular or
supramolecular levels.
Taking into account the equi-volume (isosteric) nature of the H-
and F-atoms and inspired by the peculiarly ‘‘inert’’ behavior of the
‘‘organic’’ fluorine in crystals,13 it was thought that the H/F
isosteric interchange could be exploited to show the predicted
conformations of 1 in crystals. Accordingly, compounds 2, 3, 4, 5
and 6 were designed (Scheme 1); 2, 3 and 4 are ortho, meta and
para monofluorinated analogs of 1, whereas 5 and 6§ are 2,4,6-
trifluro and pentafluoro analogs, respectively. The crystal struc-
tures14 of compounds 2, 3, 4, 5 and 6 indeed exhibited interesting
trends in terms of their molecular conformations (Fig. 3) with the
corresponding energy values (Table 1).
Fig. 2 A plot of number of hits versus the torsion angle (Q) for the symmetrically
1,6-disubstituted hexa-2,4-diyne structures with a diacetylene spacer; the
substituent group R ranges from simple methyl groups to bulkier polysub-
stituted groups (total no. of hits = 79).
conformations, they differ significantly with the former being
completely open (extended) and the latter being partially open
(unextended) (Fig. 3(d) and 3(e), respectively).
As the molecular conformations in crystals are primarily
guided through noncovalent interactions,11,12 it is important to
rationalize the genesis of a particular conformation based on the
supramolecular packing features involved. A close inspection of
the isostructural crystal packing of 1, 2 and 4 reveals that the
molecules in the twisted conformation are held together mainly
…
…
with (Ph)Cmeta–H O hydrogen bonds and Csp3–H p interactions
…
as shown in Fig. 4. Interestingly, the C–H O hydrogen bond
formed through the involvement of the meta H-atom (H9) with the
carbonyl oxygen (O2) seems to be an important prerequisite
satisfying the geometry (spatial) requirements for the efficient
packing of the molecules in the twisted conformation. The
replacement of one of the meta H-atoms (participating in the
…
(Ph)Cmeta–H O interaction) on the phenyl rings by an F-atom flips
the molecular conformation from ‘‘cisoid’’ to ‘‘gauche’’ whereas,
the further replacement of the 2,4,6 positioned H-atoms and all
five ring H-atoms by F-atoms results in an ideal ‘‘anti’’
conformation of compounds 5 and 6 where the main inter-
Although both 2 and 4 adopt a similar conformation to that of
1 (w = 8.6(1)u and w = 4.1(1)u, respectively), compound 3, which has
its meta H-atom replaced by an F-atom, adopts an entirely
different ‘‘gauche’’ conformation with w = 85.7(1)u which is closer
to the gas phase optimized structure (77.6u) of 1. Compounds 5
and 6, on the other hand, adopt a well anticipated open ‘‘transoid’’
conformation with w = 180u. Although both 5 and 6 adopt ‘‘anti’’
…
…
molecular interactions are Csp3–H O and Csp3/sp2–H F hydrogen
bonds (Fig. S1–S6, ESI ). It is important to note that the trifluoro-
3
and pentafluoro-substitution on the phenyl ring results in the
Table 1 Conformational energy differences in 1, 2, 3, 4, 5 and 6a
Torsion angle w (u)
Compound Crystal Opt
DE (kcal mol21
DEOpt DESP
)
SP
DEOpt–SP
1
2
3
4
5
6
8.4(1)
8.6(1)
85.7(1)
4.1(1)
180
77.6
180
180
180
180
9
20.445 0.080 0.525
20.539 0.021 0.560
20.036 0.470 0.506
20.004 0.204 0.208
99.3
104.2
9.6
180
180
0
0
0.416 0.416
1.340 1.340
180
9
a
Opt: optimized geometry; SP: single point energies at the given w.
Calculations performed at the b3lyp/6-31++g(d,p) level using
Gaussian 09.16
Fig. 1 The crystal conformation of 1,6-bis(phenylcarbonate) hexa-2,4-diyne.
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…
Fig. 4 The packing diagram of 1 showing the intermolecular C–H O and C–
…
H
p interactions (these packing features are conserved in the isostructural
crystals of 2 (o-fluoro analog) and 4 (p-fluoro analog)).
increased acidity of the protons and also in the reversal of the
polarity of the ring (p to pF).17 Along with the steric factors, these
effects may also have leading contributions towards the genesis of
the ‘‘anti’’ conformations of compounds 5 and 6.
In conclusion, it is shown that the selective substitution of
H-atoms by F-atoms can be exploited to explore the conforma-
tional landscape of a flexible molecule containing little energy
difference among various conformations. Furthermore, the results
clearly show the unequivocal dominance of the weak intermole-
…
cular interactions (herein a guiding C–H O interaction supported
18
…
by a surrogate C–H p interactions) in stabilizing unusual
molecular conformations, as opposed to an ideal conformation,
in crystals. A mutual compromise between the molecular
symmetry, the crystallographic site symmetry and the intermole-
cular H-bonds (supramolecular synthons) can conceive, bear and
nurture the so-called ‘‘unusual’’ molecular conformations in the
solid state.
AGD thanks CSIR, New Delhi for SRF. CV thanks CSIR for the
Shyama Prasad Mukherjee (SRF) Fellowship and TNGR thanks
DST, India for the J. C. Bose Fellowship.
Fig. 3 Molecular conformations of (a) 1,6-bis(2-fluorophenylcarbonate) hexa-
2,4-diyne, 2; (b) 1,6-bis(3-fluorophenylcarbonate) hexa-2,4-diyne, 3; (c) 1,6-
bis(4-fluorophenylcarbonate) hexa-2,4-diyne, 4; (d) 1,6-bis(2,4,6-trifluorophe-
nylcarbonate) hexa-2,4-diyne, 5; (e) 1,6-bis(2,3,4,5,6-pentafluorophenylcarbo-
nate) hexa-2,4-diyne, 6 in their respective crystal structures.
Notes and references
§ The crystal structure of compound 6 has already been reported by us
(CCDC 784071; ref. 9) and has been used here for comparison with other
related structures.
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922274, MF: C20H12F2O6; orthorhombic; a = 9.9560(50) Å; b =
22.6650(50) Å; c = 7.4420(50) Å; V = 1679.31(15) Å3; T = 150 K;
space group, Pccn, Z = 4; Robs = 0.037; wR2obs = 0.092; Drmin,max
= 20.19, 0.19 e Å23; gof = 1.06; 3, CCDC 922273, MF:
C20H12F2O6; monoclinic; a = 20.8305(12) Å; b = 3.9051(3) Å; c =
22.4954(12) Å; b = 110.433(7)u; V = 1714.78(44) Å3; T = 150 K;
space group, P21/n, Z = 4; Robs = 0.036; wR2obs = 0.097; Drmin,max
= 20.22, 0.16 e Å23; gof = 1.05; 4, CCDC 922275, MF:
C20H12F2O6; orthorhombic; a = 9.6359(9) Å; b = 23.7478(21) Å; c
= 7.2680(6) Å; V = 1663.15(3) Å3; T = 150 K; space group, Pccn, Z
= 4; Robs = 0.037; wR2obs = 0.101; Drmin,max = 20.21, 0.23 e Å23
;
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5.2422(3) Å; b = 7.1560(4) Å; c = 13.2155(7) Å; a = 93.426(4)u; b =
98.645(4)u; c = 109.868(5)u; V = 457.66(10) Å3; T = 150 K; space
¯
group, P1, Z = 1; Robs = 0.029; wR2obs = 0.073; Drmin,max = 20.20,
0.19 e Å23; gof = 1.02; 6, CCDC 784071; MF: C20H4F10O6;
monoclinic; a = 5.8951(9) Å; b = 10.1943(16) Å; c = 17.245(2) Å; b
= 108.115(5)u; V = 985.0(2) Å3; T = 150 K; space group, P21/n, Z =
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