Investigating the influence of the sulfur oxidation state on solid state conformation

Article abstract of DOI:10.1039/c2ce26298c

Design, synthesis and structural characterization of a series of diphenylacetylene derivatives bearing organosulfur, amide and amine moieties has been achieved in which the molecular conformation is controlled through variation of the hydrogen bond properties on alteration of the oxidation level of sulfur.

Full text of DOI:10.1039/c2ce26298c

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
CrystEngComm
Cite this: CrystEngComm, 2012, 14, 7848–7850
www.rsc.org/crystengcomm
COMMUNICATION
Investigating the influence of the sulfur oxidation state on solid state
conformation{
Carla A. Daly,a Kevin S. Eccles,a Lorraine M. Bateman,a Noel M. O’ Boyle,a Simon E. Lawrencea and
Anita R. Maguire*b
Received 14th August 2012, Accepted 12th September 2012
DOI: 10.1039/c2ce26298c
Design, synthesis and structural characterization of a series of
diphenylacetylene derivatives bearing organosulfur, amide and
amine moieties has been achieved in which the molecular
conformation is controlled through variation of the hydrogen
bond properties on alteration of the oxidation level of sulfur.
The ability to understand and rationally predict the conformation
Scheme 1 Controlling the conformation of benzamidodiphenylacety-
adopted by solid state structures has been actively pursued for
lenes by changing the acidity of the hydrogen bond donors.11
many years.1 Crystal engineering specifically focuses on inter-
molecular interactions with the aim to identify supramolecular
amide encouraged us to expand this system by incorporating sulfur
synthons for the design of materials with specific properties e.g.
functionalities (Scheme 2).
optical, magnetic, electronic.2,3 Control of the solid state physical
The basic concept involves creating competition between
properties of organic and inorganic materials e.g. solubility,
hydrogen bond acceptors for the strongest hydrogen bond donor
bioavailability, dissolution rate, hygroscopicity also demands an
by altering the oxidation level of the sulfide and exploiting the
understanding of the nature of the interactions in the solid state at
difference in acidity between amides and amines.12 At the sulfide
a fundamental level.4–6
level, interaction between the sulfur and amide or amine is not
Previous research in our group focused on organosulfur
expected based on results from earlier fundamental studies12 and
functional groups, specifically sulfides, sulfoxides and sulfones,
with the aim to develop an understanding of how the molecular
structure of the compounds impacts upon the solid state crystalline
structure and, in particular, to probe the relative importance of
different inter/intramolecular non-covalent interactions. In parti-
cular, our research highlighted the effective use of sulfoxides in
supramolecular synthons, due to their nature as strong hydrogen
bond acceptors,7,8 including with amides as N–H donors.9
…
the dominant solid state interaction predicted is the N–H OLC
intermolecular interaction. As a result we would expect the sulfide
to lie on the opposite side to the amide as illustrated (A), thereby
…
enabling the intermolecular N–H OLC interaction. On oxidation
…
to the sulfoxide, the strong intramolecular N–H OLS interaction
…
should compete effectively with the intermolecular N–H OLC
interaction as sulfoxides are potent hydrogen bond acceptors13 and
amides are stronger hydrogen bond donors than amines.12 In this
case we expect the sulfoxide to lie on the same side as the amide
(B), following Hamilton’s model. On further oxidation to the
sulfone, which is a weaker hydrogen bond acceptor than the
To further expand on this work we aimed to incorporate sulfur
and amide functionalities within a single molecule and study the
effects of varying the oxidation level of sulfur on the hydrogen
bond interactions in the solid state. The diphenylacetylene unit
involving ester and amide functionalities recently explored by
Hamilton provided us with a suitable scaffold on which to
construct this system (Scheme 1).10,11 Their success in controlling
the conformation of the molecule by varying the acidity of the
…
sulfoxide, we anticipated at the outset that the strong N–H OLC
intermolecular interaction would once again dominate, resulting in
the sulfone lying on the opposite side to the amide (C).
aDepartment of Chemistry, Analytical and Biological Chemistry
Research Facility, University College Cork, Cork, Ireland
bDepartment of Chemistry and School of Pharmacy, Analytical and
Biological Chemistry Research Facility, University College Cork, Cork,
Ireland. E-mail: a.maguire@ucc.ie
{ Electronic supplementary information (ESI) available: CCDC 891708–
891710. Synthetic procedures for 1–4; computational studies on 3. For ESI
and crystallographic data in CIF or other electronic format see 10.1039/
c2ce26298c
Scheme 2 Predicting the conformation of A, B and C by applying the
rationale of differential hydrogen bonding ability of sulfur functionalities.
7848 | CrystEngComm, 2012, 14, 7848–7850
This journal is ß The Royal Society of Chemistry 2012

View Article Online
Fig. 2 Hydrogen bond interactions in compound 2.
hydrogen bonding to both a neighbouring N–H of an amide and
C–H of a methyl group (Fig. 2).
Scheme 3 The synthesis of 2, 3 and 4. Reagents and conditions: a)
1-ethynyl-2-methylthiobenzene, PdCl2(PPh3)2, CuI, DMF, NEt3. b)
NaIO4, MeOH/H2O. c) 2-methylsulfonylethynylbenzene, PdCl2(PPh3)2,
CuI, DMF, NEt3.
Interestingly, although the conformation switches in the
sulfoxide, 3, the key non-covalent interactions observed were not
…
as anticipated (Fig. 3). Instead of an intramolecular N–H OLS
bond occurring between the amide and sulfoxide, an intermole-
…
To explore this concept, N-(2-iodo-3-aminophenyl)benzamide 1,
was synthesised following Hamilton’s procedure.10 Then the
alkynes, bearing sulfide and sulfone functional groups, were
attached via Sonogashira coupling to form 2 and 4 (Scheme 3).
The sulfoxide, 3, was readily obtained by oxidation of 2. These
systems with the substituents in the ortho position were designed to
allow the exploration of intramolecular hydrogen bonding between
the key functional groups. The successful Sonogashira coupling to
provide the sulfide 2 is particularly interesting in the context of
Larock’s report involving a related system where the coupling
product could not be obtained.14
cular N–H OLS is formed between the sulfoxide and a
neighbouring amine. The oxygen from the sulfoxide points away
from the amide, with the result that intramolecular hydrogen
…
bonding does not occur. The strong N–H OLC interaction
prevails in the crystal structure and oxidation to the sulfoxide has
not disrupted this interaction. Comparison of the structural
features of Hamilton’s amide–ester system with our amide-
sulfoxide system is very interesting. Although the sulfoxide is
expected to be a stronger hydrogen bond acceptor than the ester,
the planar intramolecular hydrogen bond which we anticipated to
form did not occur in practice. Examination of the amide to
…
Single crystal X-ray diffraction of compounds 2, 3 and 4, each
recrystallized from the same solvent, CH2Cl2, demonstrated the
predicted conformational change as a result of altering the
oxidation level of sulfur (Fig. 1).{ As expected the sulfide lies on
the opposite side to the amide, then switches after oxidation to the
sulfoxide and switches back again when the sulfone is formed. For
sulfoxide N–H OLS intramolecular distance available in 3
˚
(y2.05 A), together with analysis of the Cambridge Structural
…
Database15 and comparison with the amide-ester N–H OLC
10
hydrogen bond distance (2.23 A), suggests that intramolecular
˚
hydrogen bonding, while not observed, is feasible in our system.
Overall the solid state structure of the sulfoxide adopts a
conformation that enables two structure-defining intermolecular
…
compound 2, the strong intermolecular N–H OLC dominates the
…
…
crystal packing, and the CLO of the amide is involved in bifurcated
interactions: the amine N–H OLS and the amide N–H OLC.
The key feature that arose was the unanticipated orientation of the
sulfoxide out of the plane. While computational studies (see ESI{)
demonstrate that an intramolecular hydrogen bond is possible, it
would require the axial phenyl rings to twist out of planarity,
therefore leading to a decrease of extended conjugation and
stabilisation. As a result, the observed conformation, which has the
Fig. 1 Single crystal X-ray structures obtained for compounds 2, 3 and
4.
Fig. 3 Hydrogen bond interactions in compound 3.
CrystEngComm, 2012, 14, 7848–7850 | 7849
This journal is ß The Royal Society of Chemistry 2012

View Article Online
and a Health Research Board Career Development Fellowship,
PD/2009/13 (N.O’B.). We thank the SFI/HEA Irish Centre for
High-End Computing (ICHEC) for the provision of computa-
tional facilities.
References
{ Single crystal X-ray diffraction data were collected on either a Bruker
SMART X2S diffractometer (2) or a Bruker APEX II DUO diffractometer
(3 and 4). All calculations and refinement were made using the APEX
software,16,17 and diagrams prepared using Mercury.18 Crystal data for 2:
˚
˚
C22H18N2OS, M = 358.44, a = 18.140(3) A, b = 5.0400(9) A, c = 19.369(3)
3
˚
˚
A, V = 1770.8(5) A , T = 300(2) K, orthorhombic, space group Pna21, Z =
4, 13 743 reflections measured, 3012 independent reflections (Rint = 0.0631).
The final R1 value was 0.0548 [I > 2s(I)] and the final wR(F2) value was
0.1638 (all data). Crystal data for 3: C22H18N2O2S, M = 374.44, a =
Fig. 4 Hydrogen bond interactions in compound 4.
˚
˚
˚
8.8488(15) A, b = 21.149(4) A, c = 10.0801(17) A, b = 98.541(4)u, V =
3
1865.5(5) A , T = 296(2) K, monoclinic, space group P21/c, Z = 4, 19 006
˚
sulfoxide oxygen pointing away from the amide, is predicted to be
slightly lower in energy.
reflections measured, 3277 independent reflections (Rint = 0.0763). The final
R1 value was 0.057 [I > 2s(I)] and the final wR(F2) value was 0.175 (all
The sulfone, 4, crystallises with Z9 = 2, with both molecules
adopting the same conformation as seen in the sulfide, i.e. the
sulfone lies on the opposite side to the amide (Fig. 4). The key
interactions involving the two crystallographically independent
˚
data). Crystal data for 4: C22H18N2O3S, M = 390.44, a = 10.511(2) A, b =
3
˚
˚
˚
34.171(8) A, c = 11.778(3) A, b = 113.517(5)u, V = 3879.0(15) A , T =
296(2) K, monoclinic, space group P21/n, Z = 8, 21 664 reflections
measured, 7387 independent reflections (Rint = 0.0505). The final R1 value
was 0.0504 [I > 2s(I)] and the final wR(F2) value was 0.1279 (all data).
…
bonds. The combination gives rise to a visually appealing R44 (12)
molecules are intra- and intermolecular N–H OLS hydrogen-
1 G. R. Desiraju, J. Chem. Sci., 2010, 122, 667–675.
2 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311–2327.
3 G. R. Desiraju, Nature, 2001, 412, 397–400.
4 L. F. Huang and W. Q. Tong, Adv. Drug Delivery Rev., 2004, 56,
321–334.
motif at the binary level. Also present within this motif is a C–
…
H OLS intermolecular interaction between one of the sulfone
oxygen atoms and a methyl group. Significantly, the strong
…
intermolecular N–H OLC between the amides, which was the
5 D. A. Snider, W. Addicks and W. Owens, Adv. Drug Delivery Rev.,
2004, 56, 391–395.
key structure-defining feature in the sulfide and sulfoxide
structures, was disrupted on oxidation to the sulfone, therefore
altering very substantially the crystal packing of the molecule.
To investigate the solution properties of compounds 2 and 3
NMR studies were undertaken. Results from NOESY 2D NMR
experiments did not result in any substantial correlation between
spectroscopic features and the solid state interactions.
6 B. Rodriguez-Spong, C. P. Price, A. Jayasankar, A. J. Matzger and N.
Rodriguez–Hornedo, Adv. Drug Delivery Rev., 2004, 56, 241–274.
7 K. N. Lehane, E. J. A. Moynihan, N. Brondel, S. E. Lawrence and
A. R. Maguire, CrystEngComm, 2007, 9, 1041–1050.
8 N. Brondel, E. J. A. Moynihan, K. N. Lehane, K. S. Eccles, C. J.
Elcoate, S. J. Coles, S. E. Lawrence and A. R. Maguire,
CrystEngComm, 2010, 12, 2910–2927.
9 K. S. Eccles, C. J. Elcoate, A. R. Maguire and S. E. Lawrence, Cryst.
Growth Des., 2011, 11, 4433–4439.
10 I. M. Jones and A. D. Hamilton, Org. Lett., 2010, 12, 3651–3653.
11 I. M. Jones and A. D. Hamilton, Angew. Chem., Int. Ed., 2011, 50,
4597–4600.
12 C. A. Hunter, Angew. Chem., Int. Ed., 2004, 43, 5310–5324.
13 A. Nangia and G. R. Desiraju, Chem. Commun., 1999, 605–606.
14 S. Mehta, J. P. Waldo and R. C. Larock, J. Org. Chem., 2009, 74,
1141–1147.
In conclusion, the predicted change in molecular conformation
of the sulfide 2 to the sulfoxide 3 and sulfone 4 was observed as a
direct result of altering the oxidation state of sulfur and therefore
impacting on the key hydrogen bonding features in the solid state.
This significant result, particularly the observed rotation of the
diphenylacetylene unit after oxidation, may lead to future
applications in a molecular switching mechanism.
15 F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci., 2002, 58, 380–388.
16 APEX2 v2009.3-0, Bruker AXS, Madison, WI, 2009.
17 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
64, 112–122.
18 C. F. Macrae, I. J. Bruno, J. A. Chrisholm, P. R. Edgington, P.
McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de Streek
and P. A. Wood, J. Appl. Crystallogr., 2008, 41, 466–470.
Acknowledgements
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland, under
Grant Numbers 08/RFP/MTR1664 and 05/PICA/B802/EC07,
7850 | CrystEngComm, 2012, 14, 7848–7850
This journal is ß The Royal Society of Chemistry 2012