Pyridine variant 3
Crystal forms of the benzene variant 2
Synthesis was done according to the general procedure using 2,6-
pyridinedicarbonyl dichloride as a reagent. After reflux, tetra-
hydrofuran was evaporated leaving a yellow-green precipitate.
The precipitate was recrystallized from ethyl acetate as a white
solid with a yield of 68%. mp. 251–253 uC; 1H NMR (ESI{)
(500 MHz, DMSO-d6, 30 uC): d = 7.21 (t, 3JHH = 7.9 Hz, 4H; b),
7.31–7.37 (m, 4H; f), 7.43 (tt, 3JHH = 1.2 Hz, 3JHH = 7.4 Hz, 2H;
Three single crystal structures were obtained for the oligoamide
2, namely, an unsolvated 2-form I (crystallized from DMF), and
two DMSO solvates (2-DMSO I and 2-DMSO II), which were
crystallized from DMSO–EtOAc and neat DMSO, respectively
(Fig. 1, Table 1). Hydrogen bonding parameters for the
structures can be found in the ESI.{
Structure 2-form I has two intramolecular hydrogen bonds
with an S(7) motif. One of the hydrogen bonds is formed
between an inward bent inner CLO (Scheme 1, amides 2 and 3)
and an outer N–H (amides 1 and 4), and the other bond between
an outer CLO (1 or 4) and an inner N–H (2 or 3). These
hydrogen bonds cause the molecule to adopt a loosely folded
structure (Fig. 1a). Adjacent molecules connect to each other
with hydrogen bonds between a carbonyl oxygen and an amide
hydrogen (an R22(14) motif), which are available for the
intermolecular hydrogen bonds, forming a chain structure
(Fig. 1a). The molecular chains are connected by weak hydrogen
bonds, van der Waals forces and parallel displaced p-stacking
interactions between two of the 1,2-substituted phenyl rings.
The 2-DMSO I solvate has two intramolecular hydrogen
bonds with an S(7) motif similarly to 2-form I, but both of these
bonds are formed between the inner CLO groups (2 and 3) and
the outer N–H groups (1 and 4). Therefore, the molecule has a
more open conformation than 2-form I (Fig. 1b and Fig. 2).
Also, the crystal packing into chains of molecules is similar in
comparison to 2-form I, with two hydrogen bonds in an R22(14)
motif (Fig. 1b). Interestingly, although DMSO is a powerful
hydrogen bond acceptor it does not form any significant
hydrogen bonds in this structure. It is only connected to other
molecules with van der Waals interactions and weak hydrogen
bonds and located in the structural cavities between the chains of
molecules.
3
3
a), 7.63–7.71 (m, 4H; d, e), 7.75 (dd, JHH = 1.2 Hz, JHH = 7.1
Hz, 4H; c), 8.27–8.31 (m, 1H; h), 8.36–8.38 (m, 2H; g), 10.19 (s,
2H; i), 10.99 (s, 2H; j) ppm; 13C NMR (ESI{) (126 MHz,
DMSO-d6, 30 uC): d = 125.0 (g), 125.5 (e), 125.6 (f), 125.7 (d),
127.5 (c), 128.0 (b), 130.7 (d9), 131.1 (e9), 131.5 (a), 134.0 (c9),
140.3 (h), 148.2 (g9), 161.2 (j9), 165.9 (i9) ppm; MS (ESI-TOF) m/
z: 578.16 [M
+
Na+]; Elemental analysis calcd (%) for
C33H25N5O4: C 71.3, H 4.5,N 12.6; found C 71.2, H 4.4, N 12.7.
Crystallizations
The benzene and pyridine variants, 2 and 3, were crystallized in
acetone, acetonitrile (MeCN), chloroform, 1,2-dichloroethane
(DCE), dichloromethane (DCM), dimethylacetamide (DMA),
dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-
dioxane, ethyl acetate (EtOAc), methanol (MeOH), tetrahydro-
furan (THF) and toluene. In addition, compound 3 was
crystallized from ethanol. Amounts of 3–50 mg of compounds
2 and 3 and 0.4–6 ml of solvent were used in the crystallization
experiments. Due to the low solubility of compound 2 in most
organic solvents, a small drop of DMA, DMF or DMSO (20–
40 ml) were added to many solutions of 2; in these cases the
results of the crystallizations are referred to as solution mixtures
in the text. Heating and stirring were used to help the dissolving
process. After the compounds had dissolved, the solutions were
allowed to evaporate at room temperature until crystals formed.
The 2-DMSO II solvate has similar intramolecular hydrogen
bonds S(7) between the inner CLO groups (2 and 3) and the outer
N–H groups (1 and 4), as does the 2-DMSO I solvate (Fig. 1c).
However, unlike in the 2-DMSO I solvate and 2-form I, both of
the inner CLO groups (2 and 3) are facing inwards to the
molecule and form a curved conformation instead of an open or
a folded one. Again, molecules connect to each other with two
hydrogen bonds forming an R22(14) motif. The unexpected
curved molecular conformation, where both of the inner CLO
groups (2 and 3) are facing inwards, may in fact be caused by the
DMSO that stabilizes the curved structure by forming a
hydrogen bond into an amide hydrogen with a D motif. In both
of the 2-DMSO I and 2-DMSO II solvates, the closest DMSO
molecule to the benzene variant 2 is located near the central
benzene ring. This may prevent tighter folding and cause more
open molecular conformations.
Slurries
Slurries of the oligoamides 2 and 3 were made by stirring 10–50 mg
of the compound in 2–4 ml of solvent (MeCN, DCM, EtOAc or
THF; in addition, EtOH was used for compound 2 and toluene for
compound 3) for two weeks at room temperature. After two weeks
the mixtures were allowed to dry in open vessels.
Results and discussion
Synthesis and NMR
Compounds 2 and 3 were synthesized in two steps from acyl
halides and substituted anilines using a nucleophilic substitution
reaction with good to excellent yields (Scheme 1). In addition to
1H and 13C NMR spectroscopy, compounds 2 and 3 were
characterized using 2D NMR spectroscopic techniques (COSY,
HMQC and HMBC; see ESI for details{). The conformational
properties of 3 in solution were studied with NOESY.{ The
NOESY spectra measured both in acetone-d6 and in THF-d8,
showed correlations between the inner amide group peak (amide
groups 2 and 3, Scheme 1) and an aromatic hydrogen peak of the
outer phenyl rings. This indicates that oligoamide 3 is at least
partially folded when dissolved in these solvents. NOESY
spectra were not measured for 2 because of its poor solubility.
The reason for the two different DMSO solvates is likely due
to the presence of EtOAc in the crystallization of 2-DMSO I.
Since the DMSO does not form strong hydrogen bonds to the
oligoamide in 2-DMSO I, as it does in 2-DMSO II, it is probable
that the crystallization starts as an EtOAc solvate and later on
the EtOAc molecules are forced out of the crystal and replaced
by DMSO.
The packing efficiency of the three forms was compared using
fingerprint plots of the structures (Fig. 1). The fingerprint plots
This journal is ß The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 7398–7407 | 7401
Suhonen, Aku
