Self-organization of 2-acylaminopyridines in the solid state and in solution

Article abstract of DOI:10.1021/jp1063116

Aggregation of 2-acylaminopyridines and their 6-methyl derivatives in chloroform solution was studied by ¹H, ¹³C, and ¹⁵N NMR spectroscopies. The results were compared with ¹³C and ¹⁵N CPMAS NMR and IR spectral as well as with X-ray structural data. Intermolecular interactions in solution and in solid state were found to have a similar nature. Relatively strong N_amide-H...N _pyridine intermolecular hydrogen bonds enable dimerization to take place. Steric interactions in N-pivaloyl- and N-1-adamantylcarbonyl as well as that caused by the 6-methyl group hinder formation of the dimeric aggregates stabilized by the N_amide-H...N_pyridine intermolecular hydrogen bonds. In general, the DFT optimized geometries of the aggregates in chloroform solution are in agreement with the X-ray crystal structures. Wavenumbers of the stretching vibration band of the CdO group were also found indicative of the type of hydrogen bond present in the solid state.

Full text of DOI:10.1021/jp1063116

J. Phys. Chem. A 2010, 114, 10421–10426
10421
Self-Organization of 2-Acylaminopyridines in the Solid State and in Solution
Borys Os´miałowski,*,† Erkki Kolehmainen,‡ Robert Dobosz,† Ryszard Gawinecki,†
Reijo Kauppinen,‡ Arto Valkonen,‡ Juha Koivukorpi,‡ and Kari Rissanen‡
Faculty of Chemical Technology and Engineering, UniVersity of Technology and Life Sciences, Seminaryjna 3,
PL-85-326 Bydgoszcz, Poland, and Department of Chemistry, P.O. Box 35, FIN-40014 UniVersity of JyVa¨skyla¨, Finland
ReceiVed: July 9, 2010; ReVised Manuscript ReceiVed: August 18, 2010
Aggregation of 2-acylaminopyridines and their 6-methyl derivatives in chloroform solution was studied by
1H, 13C, and 15N NMR spectroscopies. The results were compared with 13C and 15N CPMAS NMR and IR
spectral as well as with X-ray structural data. Intermolecular interactions in solution and in solid state were
found to have a similar nature. Relatively strong Namide-H · · · Npyridine intermolecular hydrogen bonds enable
dimerization to take place. Steric interactions in N-pivaloyl- and N-1-adamantylcarbonyl as well as that caused
by the 6-methyl group hinder formation of the dimeric aggregates stabilized by the Namide-H· · ·Npyridine
intermolecular hydrogen bonds. In general, the DFT optimized geometries of the aggregates in chloroform
solution are in agreement with the X-ray crystal structures. Wavenumbers of the stretching vibration band of
the CdO group were also found indicative of the type of hydrogen bond present in the solid state.
Introduction
CHART 1: Hydrogen Bonding Patterns in Amides
Hydrogen bonding is a reversible and directional noncovalent
interaction.1 Although it is much weaker than the covalent bond,
large number of acidic and/or basic centers present in the
molecules enables formation of the quite stable aggregates.2-5
Several biologically important systems are stabilized by the
multiple hydrogen bonds.2-5 Multiple hydrogen bonds are an
important factor that governs organization of the extended
structures.6 Such interactions are very important in crystal
engineering, a branch of the supramolecular chemistry concerned
with design and synthesis of these systems in the crystalline
state.6
CHART 2: Chains of the Peptide Hydrogen Bonds
Secondary structure of peptides7-9 is stabilized by the net of
NsH· · ·OdC hydrogen bonds.10-13 Amides can have the cyclic
or catenary (ribbon) hydrogen bonded structures (Chart 1).14
Strong hydrogen bonds in these compounds, N+sH· · ·OdC,
N+sH· · ·OdC-, and NsH· · ·OdC- are called the “salt
bridges”.13
Molecules of the ordinary amides may also interact with each
other in a similar way. Experimental studies show N-methy-
lacetamide to be the most simple secondary amide involved in
a net of the intermolecular hydrogen bonds; chains of the peptide
hydrogen bonds were detected in its crystals (Chart 2).15,16
Similar intermolecular interactions take place in solid benza-
nilide, PhCONHPh.17
Among different secondary amides, N-(pyridin-2-yl) deriva-
tives seem especially interesting from a point of view of self-
association. This structural fragment is present in many com-
pounds designed to aggregate in a predictable way.18-29
Although 2-(N-nitramino)pyridine is the tautomer of minor
importance,30,31 2-acetylaminopyridine seems to be the preferred
tautomeric form.32 N-(Pyridin-2-yl) secondary amides contain
one acidic (NH) and two basic (ring nitrogen and carbonyl
oxygen) centers. This enables formation of the intermolecular
hydrogen bonds of both NsH· · ·N and NsH· · ·OdC type.
Such interactions are expected to be present in solid 2-acylami-
nopyridines and even in their solutions in solvents of moderate
polarity. The influence of structural factors on the aggregation
of 2-acylaminopyridines has been studied occasionally. Only
the NamidesH· · ·Npyridine intermolecular interactions were detected
by X-ray analysis to be present in solid 2-benzoylaminopy-
ridines33 and 2-(pentafluorobenzoylamino)pyridine.34
It is known from its NMR spectra that 2-cyclohexylcar-
bonylaminopyridine in chloroform solution at 298 K is
predominantly monomeric (Kdimer ) 2 M-1).35 On the other
hand, IR spectra (Nujol mulls) show that 2-acetylaminopy-
ridine in a condensed phase forms stable dimers by strong
N
amidesH· · ·Npyridine intermolecular hydrogen bonds.36 Its 6-m-
ethyl derivative can also be dimeric: two monomeric subunits
in its crystal37 are surprisingly bound to each other not by the
NH· · ·N but by NH · · ·OdC hydrogen bonds.38,39 Although we
found these results very interesting, no other compounds of this
type were studied. Lacking data for the steric influence of the
alkyl groups in 2-acylaminopyridines on their self-association
in the solid state and in solution prompted us to prepare and
* To whom correspondence should be addressed, borys.osmialowski@
utp.edu.pl.
† University of Technology and Life Sciences.
‡ University of Jyva¨skyla¨.
10.1021/jp1063116  2010 American Chemical Society
Published on Web 09/01/2010

10422 J. Phys. Chem. A, Vol. 114, No. 38, 2010
Os´miałowski et al.
CHART 3: The Compounds Studied
carbonyl signal at 176.03 ppm, after which the chemical shifts
were recalculated to tetramethylsilane δ(13C) ) 0.00 ppm. The
15N CP/MAS NMR experiments were carried out for all samples
at a 10 kHz spinning rate (except of 2b where it was 5 kHz)
under Hartmann-Hahn condition. A contact time of 4 ms was
used for efficient polarization transfer with a 5 s recycle delay
to acquire the CP/MAS spectra. A number of 1000-15000
(overnight) scans were acquired to obtain the 15N CP/MAS
NMR spectra for each sample. All FIDs were processed by
exponential apodization function with line broadening of 10 Hz
prior to FT. Originally, the 15N CP/MAS NMR spectra were
referenced to the signal of glycine nitrogen at -345.25 ppm,
after which the chemical shifts were recalculated to nitromethane
δ(15N) ) 0.0 ppm.
study the respective derivatives carrying sterically varying acyl
groups (Chart 3). The steric influence of the 6-methyl group in
the molecules seemed also worthy to be considered. Moreover,
2-acylaminopyridines have not been earlier studied by the single
crystal X-ray diffractometry.
Liquid state NMR acquisition and processing parameters are
the same as those in our other publication.45 1H NMR spectra
in the dilution experiments were recorded at various concentra-
tions of the compounds studied. δ(H7) was used as a probe.
Dimerization constants were calculated according to the previ-
ously reported procedures.46 IR spectra of KBr pellets of the
compounds studied were recorded on a Bruker Vector 22 IR
spectrophotometer.
Calculations. Calculations at the M05/6-31+G(d,p) level for
geometry optimizations of all structures studied have been
performed in Gaussian.47 The PCM48 model of solvation was
used. The energy minimum was confirmed by the frequency
calculations (all positive frequencies were obtained).
Experimental Methods
X-ray Experiments. Suitable single crystals for X-ray
experiments were these synthesized (no further crystallization
was necessary). Unfortunately, crystals of 5b were of too poor
quality for the data collection. The obtained single crystals
were mounted on a Nylon loop sample holder with perfluoro
polyether oil and data were collected at 123(2) K using Bruker-
Nonius KappaCCD diffractometer with APEX-II detector and
graphite monochromatized Mo KR (λ ) 0.71073 Å) radiation.
COLLECT40 software was used for the data collection (θ and
ω scans) and DENZO-SMN41 for the processing. The structures
were solved by direct methods with SIR200442 and refined by
full-matrix least-squares methods with WinGX-software,43 which
utilizes the SHELXL-97 module.44 Lorentzian polarization
correction was applied on all data, and absorption correction
was not used. All C-H hydrogen positions were calculated and
refined as the riding atom model with 1.2 and 1.5 times the
thermal parameter of the C atoms, respectively. The N-H
hydrogen positions were found from the electron density map
and fixed (by DFIX) to a distance of 0.91 Å from N atom with
the thermal parameter set to 1.2 times that of the N atom
parameter. The disorder of acylamino side chain in 3b was found
from the electron density map as secondary positions for non-
hydrogen atoms and refined with standard disorder refinement
with two partitions (occupation factor ratio ) major/minor 65:
35). The disordered 6-methyl H atoms in 2b were refined with
AFIX 123 instruction, constraining each hydrogen to two
positions with occupation factors of 0.5 and rotated from each
other by angle of 60°. Crystal data and parameters as well as
the ORTEP plots for the compounds studied can be found in
the Supporting Information.
Syntheses. Solution of acid chloride (10.6 mmol) in dry
methylene chloride (10 mL) was added dropwise to the
magnetically stirred solution of 2-aminopyridine or its 6-methyl
derivative (10.6 mmol) and triethylamine (10.6 mmol) in dry
methylene chloride (20 mL) at 5 °C. The reaction mixture was
allowed to reach room temperature and stirred for an additional
2 h. Water (20 mL) was then added, the organic layer separated
and dried (Na2SO4), the solvent evaporated, and the residue
recrystallized from hexane/ethyl acetate (10:1).
1a. Yield 1.24 g (86%). Mp 73-74 °C (lit. mp 68-68.5 °C,49
1
71 °C50). H NMR (CDCl3) δ: 9.43 (br s, 1H, H7), 8.23-8.24
(m, 2H, H3 and H6), 7.69 (t, 3JH,H ) 8.5 Hz, 1H, H4), 7.02 (m,
1H, H5), 2.19 (s, 3H, CH3); 13C NMR: 168.98 (C8), 151.84
(C2), 147.21 (C6), 138.64 (C5), 119.53 (C4), 114.46 (C3), 24.48
(CH3).
2a. Yield 1.43 (90%). Mp 66-67 °C (lit. mp 62 °C,51 66-67
°C52). 1H NMR (CDCl3) δ: 8.75 (br s, 1H, H7), 8.24-8.25 (m,
2H, H3 and H6), 7.69 (t, 3JH,H ) 8.5 Hz,1H, H4), 7.02 (m, 1H,
H5), 2.41 (q, 2H, CH2), 1.23 (t, 3H, CH3), 13C NMR: 172.49
(C8), 151.71 (C2), 147.45 (C6), 138.44 (C5), 119.53 (C4),
114.23 (C3), 30.67 (CH2), 9.32 (CH3).
Spectroscopy. The 13C CP/MAS NMR spectra were recorded
on a Bruker Avance 400 NMR spectrometer equipped with a 4
mm standard bore CP/MAS probehead, whose X channel was
tuned to 100.62 MHz for 13C and 40.55 MHz for 15N,
respectively. The other channel was tuned to 400.13 MHz for
the broad band 1H decoupling. Approximately 100 mg of finely
powdered sample was packed into the ZrO2 rotor, which was
closed with a Kel-F cap. The spinning rate was 10 kHz except
in the case of 2b where it was 9 kHz (at 10 kHz spin rate no
quaternary carbons were visible). The 13C CP/MAS NMR
experiment for all samples was carried out under Hartmann-Hahn
conditions with Spinal-64 decoupling. A 2 ms contact time was
used to obtain efficient polarization transfer. A short 50 µs
contact time was used to suppress the signals of quaternary
carbons and to help in spectral assignment. A number of
100-200 scans were recorded with a 4 s recycle delay for each
sample. All FIDs were processed by an exponential apodization
function with line broadening of 10 Hz prior to FT. Originally,
the 13C CP/MAS NMR spectra were referenced to the glycine
3a. Yield 1.45 g (83%). Mp 60-61 °C (lit. mp 51-53 °C53).
1H NMR (CDCl3) δ: 8.53 (br s, 1H, H7), 8.24-8.25 (m, 2H,
3
H3, and H6), 7.68 (t, JH,H ) 8.5 Hz, 1H, H4), 7.01 (m, 1H,
H5), 2.54 (m, 1H, CH), 1.23 (s, 6H, CH3). 13C NMR: 175.73
(C8), 151.75 (C2), 147.54 (C6), 138.36 (C5), 119.58 (C4),
114.21 (C3), 36.57 (CH), 19.38 (CH3).
4a. Yield 1.68 g (89%). Mp 76-77 °C (lit. mp 71-73 °C54).
1H NMR (CDCl3) δ: 8.22-8.24 (m, 2H, H3, and H6), 8.00 (br
s, 1H, H7), 7.67 (t, 3JH,H ) 7.5 Hz, 1H, H4), 7.00 (m, 1H, H5),
1.34 (s, 9H, CH3). 13C NMR: 176.95 (C8), 151.55 (C2), 147.63
(C6), 138.28 (C5), 119.60 (C4), 113.87 (C3), 39.72 (quaternary
C), 27.42 (CH3).
5a. Yield 2.07 g (76%). Mp 124-125 °C (white crystals).
1H NMR (CDCl3) δ: 8.23-8.24 (m, 2H, H3, and H6), 7.95 (br
3
s, 1H, H7), 7.66 (t, JH,H ) 8 Hz, 1H, H4), 6.99 (m, 1H, H5),
2.08-1.70 (15H, 1-adamantyl). 13C NMR: 176.42 (C8), 151.61

Self-Organization of 2-Acylaminopyridines
J. Phys. Chem. A, Vol. 114, No. 38, 2010 10423
1
TABLE 1: Selected H,13C, and 15N Chemical Shifts (ppm)
s, 1H, H7), 7.56 (t, 3JH,H ) 8 Hz, 1H, H4), 6.86 (d, 3JH,H) 7.5
Hz, 1H, H5), 2.50 (m, 1H, CH), 2.42 (s, 3H, 6-CH3), 1.23 and
1.24 (s, 3H + 3H, two nonequivalent CH3 groups). 13C NMR:
175.43 (C8), 156.61 (C6), 150.75 (C2), 138.58 (C5), 119.02
(C4), 110.72 (C3), 36.72 (CH), 23.90 (6-CH3), 19.37 (CH3).
Anal. Calcd: C, 67.39; H, 7.92; N, 15.72. Found: C, 67.34; H,
7.87; N, 15.70.
for 0.1-0.2 M Solutions of (6-Methyl-)2-acylaminopyridines
in CDCl3 at 303 K
compound H7
C2
C6
C8
N1
N7
1a
2a
3a
4a
5a
1b
2b
3b
4b
5b
9.43 151.84 147.21 168.98 -105.4 -238.2a
8.75 151.71 147.45 172.49 -103.7 -240.4
8.53 151.75 147.54 175.73 -102.5 -242.1
8.00 151.55 147.63 176.95 -101.4 -246.7b
7.95 151.62 147.69 176.42 -100.8 -247.0
8.16 150.63 156.62 168.51 -101.7 -242.0
7.91 150.63 156.66 172.16 -103.4 -240.2
7.94 150.75 156.61 175.43 -102.6 -242.1
7.91 150.90 156.63 176.92 -102.2 -246.5
7.88 150.93 156.63 176.39 -102.3 -246.9
4b. Yield 1.78 g (87%). Mp 68-69 °C (lit. mp 66-68 °C54).
3
1H NMR (CDCl3) δ: 8.03 (d, JH,H ) 8 Hz, 1H, H3), 7.91 (br
3
3
s, 1H, H7), 7.56 (t, JH,H ) 7.5 Hz, 1H, H4), 6.86 (d, JH,H
)
7.5 Hz, 1H, H5), 2.43 (s, 3H, 6-CH3), 1.31 (s, 9H, CH3). 13C
NMR: 176.92 (C8), 156.63 (C6), 150.90 (C2), 138.56 (C5),
119.05 (C4), 110.63 (C3), 39.74 (quaternary C), 27.48 (CH3),
23.93 (6-CH3).
a 1
b 1
J
) 89 Hz.
J
) 88 Hz.
N,H
N,H
5b. Yield 2.36 g (82%). Mp 127-128 °C (pale yellow
crystals). 1H NMR (CDCl3) δ: 8.04 (d, 3JH,H ) 8 Hz, 1H, H3),
TABLE 2: Dimerization Constants for
(6-Methyl-)2-acylaminopyridines (solutions in CDCl3)
3
7.88 (br s, 1H, H7), 7.55 (t, JH,H ) 8 Hz, 1H, H4), 6.85 (d,
3JH,H ) 7.5 Hz, 1H, H5), 2.09-1.71 (15H, 1-adamantyl). 13C
NMR: 176.39 (C8), 156.63 (C6), 150.93 (C2), 138.50 (C5),
118.97 (C4), 110.72 (C3), 1-adamantyl 41.63, 39.12, 36.40,
28.10, 23.96 (6-CH3). Anal. Calcd: C, 75.52; H, 8.20; N, 10.36.
Found: C, 75.47; H, 8.16, N, 10.32.
compound
Kdimer
1a
2a
3a
1b
2b
13.0
17.0
4.5
2.5
1.5
Results and Discussion
(C2), 147.69 (C6), 138.20 (C5), 119.53 (C4), 113.95 (C3),
adamantyl 41.62, 39.10, 36.37, 28.06. Anal. Calcd: C, 74.97;
H, 7.86; N, 10.93. Found: C, 74.90; H, 7.83; N, 10.90.
1b. Yield 1.42 g (89%). Mp 91-92 °C (lit. mp 85-88 °C55).
1H NMR (CDCl3) δ: 8.16 (br s, 1H, H7), 7.97 (d, 3JH,H ) 8 Hz,
NMR spectral data seemed very promising when used in
evaluation of the association susceptibility of the compounds
studied both in solution and in solid state. The 1H, 13C, and 15
N
chemical shifts in chloroform solutions are collected in Table
1 as well as in Experimental Methods and in Supporting
Information.
3
3
1H, H3), 7.57 (t, JH,H ) 8 Hz, 1H, H4), 6.87 (d, JH,H ) 7.5
Hz, 1H, H5), 2.43 (s, 3H, 6-CH3), 2.16 (s, 3H, CH3). 13C NMR:
168.51 (C8), 156.62 (C6), 150.63 (C2), 138.66 (C5), 119.13
(C4), 110.78 (C3), 23.89 (6-CH3), 24.58 (CH3).
Analysis of the chemical shifts shows that H7 is most and
least shielded in 5 and in 1, respectively, both in series a and
b. This proves that H7 is the most deshielded in 1a. There is a
significant difference in the chemical shifts of H7 in 1a and
other compounds within the series. Although the changes of
δH7 show the same tendency in series b, the respective
differences are less distinct. The presence of the 6-methyl group
was found to have a vanishing effect on sequence of changes
in δC8 (δC8: 4 > 5 > 3 > 2 > 1). It is similar for δN1 in series
a (δN1: 5 > 4 > 3 > 2 > 1). Thus, N1 is the most and least
basic in 1a and 5a, respectively. On the other hand, N1 is more
deshielded in compounds of series b, which shows that basicity
2b. Yield 1.33 g (76%). Mp 34-35 °C (yellow crystals). 1H
3
NMR (CDCl3) δ: 7.91 (br s, 1H, H7), 8.00 (d, JH,H ) 8 Hz,
3
3
1H, H3), 7.57 (t, JH,H ) 8 Hz, 1H, H4), 6.87 (d, JH,H ) 7.5
Hz, 1H, H5), 2.43 (s, 3H, 6-CH3), 2.39 (q, 2H, CH2), 1.23 (t,
3H, CH3). 13C NMR: 172.16 (C8), 156.66 (C6), 150.63 (C2),
138.61 (C5), 119.03 (C4), 110.66 (C3), 23.93 (6-CH3), 30.76
(CH2), 9.35 (CH3). Anal. Calcd: C, 65.81; H, 7.37; N, 17.06.
Found: C, 65.73; H, 7.33; N, 17.01.
3b. Yield 1.61 g (85%). Mp 79-80 °C (pale yellow crystals).
1H NMR (CDCl3) δ: 8.00 (d, 3JH,H ) 8.5 Hz, 1H, H3), 7.94 (br
TABLE 3: Solid State 13C and 15N CPMAS Chemical Shifts (ppm) for (6-Methyl-)2-acylaminopyridines at 298 K
compound
C2
C3
C4
C5
C6
C8
N1
N7
1aa
152.78
114.07
118.85
139.05
147.15
149.89
147.78
147.43
168.75
-107.0
-235.5
2a
3a
152.74
152.40
114.82
114.64
117.56
120.79
138.89
141.04
172.91
177.23
-108.0
-103.1
-104.6
-100.4
-94.0
-237.4
-238.2
4a
152.24
153.64
113.34
116.17
118.91
119.68
120.79
121.57
121.80
117.10
137.76
139.88
147.84
149.06
176.97
177.80
179.00
-244.0
-242.1
-90.7
5a
1b
152.21
150.93
114.6
136.80
137.78
137.18
137.40
136.27
147.06
156.47
178.00
171.47
-90.6
-91.2
-242.1
-232.2
109.39
108.37
108.78
111.27
2b
3b
151.51
151.20
150.83
151.80
117.61
118.84
156.04
156.61
175.67
178.14
177.73
178.47
-93.8
-86.3
-235.4
-234.4
4b
5b
110.17
118.24
136.70
157.42
-87.9
-95.0
-88.9
-243.3
151.18
110.39
117.71
136.98
156.18
176.67
-242.8
a Two signals at 23.92 and 23.01 ppm suggest that two conformationally different molecules are present in the unsymmetric unit. Other
substituent chemical shifts are available in the Supporting Information.

10424 J. Phys. Chem. A, Vol. 114, No. 38, 2010
Os´miałowski et al.
CHART 4: ORTEP Diagrams56 of Different Self-Associations in Some (6-Methyl-)2-acylaminopyridines (thermal
ellipsoids drawn at 50% probability level)a
a Most hydrogen atoms were omitted for clarity.
TABLE 4: Selected X-ray Determined (first row) and Optimizeda (second row) Interatomic Distances (Å) as Well as Valence
and Dihedral Angles (deg) in 1a-4ab,c
1a
2.11
2a
3a
4a
H7· · ·N1′
N7· · ·N1′
N1· · ·N1′
N7· · ·N7′
N1C2N7
2.10
2.14
2.21, 2.24
2.07
2.08
3.10
3.62
3.79
113.7
128.7
123.6
167.9
0.9
2.09
3.11
3.59
3.72
113.8
128.3
123.4
160.0
4.1
2.17
2.99
3.00
3.02
3.60
3.48
112.9
128.3
123.3
166.6
1.9
3.06, 3.08
3.37
3.09
3.16
3.61
3.60
3.60
3.41
3.85
3.62
3.75
3.78
3.72
113.4
127.1
123.9
163.7
0.0
113.3
127.5
123.7
162.6
4.29
113.0, 114.1
126.8, 124.4
122.3, 121.8
156.1, 139.2
0.1, 4.3
113.6
128.6
123.8
166.8
-0.1
55.2
114.04
127.2
122.2
153.3
1.4
C2N7C8
N7C8O9
N1C2N7C8
C2N7C8O9
C2N7N1′C2′
C8N7N1′C6′
25.2, 24.3
28.7, 37.4
55.7
67.2
43.8
62.7, 69.6
63.5, 74.1
54.1
61.7
76.5
42.5
39.6
38.7
50.1
68.0
a M05/6-31+G(d,p), solution in chloroform, PCM. b Unprimed and primed atoms are these in two different interacting molecules. c Double
experimental parameters show that some dimers are not symmetric.
of this atom in 6-methyl-2-acylaminopyridines is of quite
different character. The sequence of changes in δN7 is also
almost independent of 6-methyl group (δN7: 1 > 2 > 3 > 4 >
TABLE 5: Selected X-ray Determined Interatomic
Distances (Å) and Valence Angles (deg) in 4a, 5a, and 1b-4b
5).
parameter
4a
5a
1ba
2ba
3b
4b
The 1H NMR dilution experiments (see Experimental Meth-
ods) have been performed to calculate dimerization constants
for the compounds studied. The extremely insignificant effect
of the dilution precludes evaluation of self-association for some
of them. The data presented in Table 2 show that although
susceptibility of 1a to dimerize is relatively high, Kdimer is the
H7· · ·O9′ 2.13 2.10 2.03
2.00
2.90
2.02 2.13
2.87 2.99
O9.. .N7′ 3.01 2.99 2.90, 2.91
C8O9N7′ 130.8 137.2 134.7, 134.4 139.1, 138.8 160.4 85.3
a Double experimental parameters show that there are two
different intermolecular interactions in the asymmetric unit.

Self-Organization of 2-Acylaminopyridines
J. Phys. Chem. A, Vol. 114, No. 38, 2010 10425
TABLE 6: Selected X-ray Dihedral Angles between the O9C8N7 and O9′C8′N7′ Planes (DH1) and between Planes of the
Pyridine Rings (DH2) (deg) as Well as Distances (d) between Centroids of the Pyridine Rings (Å) in Aggregates of 1a-5a and
1b-4ba
parameter
DH1
1a
2a
3a
4a
5a
1b
2bb
3b
4b
49.0
72.1
84.3
86.3
66.9
75.6
79.3
5.52
6.77
63.1
51.6
34.0
32.6
10.1, 1.3
4.7, 1.2
38.4
21.6
74.1
62.9
DH2
D
35.1
43.3
60.0
6.06
6.13
6.13
7.80
8.65
8.84, 8.83
8.33
7.68
a First and second rows refer to the Namide-H· · ·Npyridine and Namide-H· · ·OdC hydrogen bonded aggregates, respectively. b Double
experimental parameters show that there are two different interactions of the hydrogen bond character in the asymmetric unit.
TABLE 7: CdO Stretching Vibrations in the IR Spectra
(KBr pellets) of 1a,b-5a,b
highest for the ethyl derivative 2a (dimerization constants
determined for 1a and 2a are comparable with that observed
earlier for 2-cyclohexylaminopyridine in chloroform solution).35
As this can be also seen, the respective compounds in series b
are less susceptible to dimerization. The steric effect of the
6-methyl group is probably responsible for this behavior.
Separate NMR signals are often observed in the CPMAS
spectrum of the solid sample that contains different crystal forms
(polymorphs), which are averaged in the liquid sample. 13C and
15N NMR CPMAS spectral data (Table 3) 1a,b-5a,b are
comparable with those of their chloroform solution (Table 1).
This gives extra evidence that similar self-aggregation takes
place both in solution and in crystalline state. Since values of
δ(N1) for 1a and 5a are significantly different, one can suppose
that the hydrogen bonding network in their crystals is also
different. X-ray data show this to be the case.
compound
νCdO (cm-1
)
1a
2a
3a
4a
5a
1b
2b
3b
4b
5b
1697, 1690
1690
1693
1684, 1676
1666
1661
a
1666
1667
1658
a A broad band at 1683 cm-1 was observed. The compound is
highly hygroscopic.
To get a reliable insight into crystal structure of the ag-
gregates, single crystal X-ray diffraction studies were performed
(except for 5b). Their crystal parameters are presented in
Supporting Information. Different intermolecular hydrogen
bonding interactions between the molecules of 1a-5a and
1b-4b (Chart 4) are responsible for formation of the aggregates.
One can see there that the type of intermolecular interactions
depends on steric effect of the alkyl group attached to C8 and
that of 6-methyl. The NamidesH· · ·Npyridine hydrogen bonds
stabilize dimers in crystals of 1a-3a. Both NamidesH· · ·Npyridine
and NamidesH· · ·OdC interactions are present in the crystal of
4a. Only the later type of hydrogen bond was detected for 5a.
Similar intermolecular hydrogen bonds are also preferred in
crystals of 6-methyl derivatives 1b-4b. It is noteworthy that
among the compounds presented in Chart 4 only 1a-3a form
typical dimers in the solid state.
Some important X-ray geometrical parameters of the ag-
gregates stabilized by the NH · · ·N hydrogen bonds are presented
in Table 4. It is noteworthy that experimental geometries (see,
e.g., C8N7N1′C6′ dihedral angles, H7 · · ·N1′ lengths of hydro-
gen bonds and N1 · · ·N1′ interatomic distances) of the species
present in crystal are very much comparable with these
optimized (Table 4). This coincidence also shows that self-
aggregation of the compounds studied is influenced by steric
interactions. Double experimental parameters in Table 4 show
that some aggregates are not symmetric (two slightly different
molecules are present in the asymmetric unit). One can see that
monomeric units in the dimers are not coplanar and that
intermolecular hydrogen bonds present there are relatively
strong.
Dihedral angles between the O9C8N7 and O9′C8′N7′ planes
and between centroids of the pyridine rings in the aggregate
are shown in Table 6. These data show that bulky R′ groups
are responsible for twisting of the subunits in the aggregate with
respect to each other. This, in turn, results in shortening of the
distance between the pyridine rings in the 1b,3b, and 4b
associates stabilized by the NamidesH· · ·OdC hydrogen bonds.
As this can be seen in Table 6, 2b does not follow the observed
changes in geometrical parameters. This behavior results prob-
ably in its unusual properties such as exceptionally low melting
point (see Experimental Methods) and hydroscopicity.
CdO stretching vibrations can also show the type of
molecular aggregation for the compounds studied. Positions of
the amide I band collected in Table 7 prove that arrangement
of the molecules in the solid state depends on the substituent(s).
Two bands in the IR spectra of 1a and 4a show their aggregates
to be unsymmetric. In solid state compounds 1a-3a form dimers
stabilized by NH· · ·N hydrogen bonds. Observed stretching
vibration shows that CdO groups in their molecules are not
involed in similar interactions. Two CdO stretching bands seen
in the spectrum of 4a show its solid-state aggregate to have
two different carbonyl groups but only one of them is involved
in the intermolecular NamidesH· · ·OdC hydrogen bond (Chart
4). Red shift of the CdO vibration band in the spectra of
comounds 5a, 1b, 3b-5b confirms their molecules to participate
in formation of a network of NH · · ·O hydrogen bonds. X-ray
geometrical parameters prove that NamidesH· · ·OdC interactions
are the only hydrogen bonds used by the molecules of these
compounds to attract each other (Chart 4).
Important X-ray geometrical parameters of the aggregates
stabilized by the NH · · ·O hydrogen bonds are presented in Table
5. One can see that these interactions are also relatively strong.
It seems noteworthy that the 6-methyl group precludes formation
of the dimer of 1b. Its steric effect is comparable with that of
bulky 1-adamantyl group in 5a.
Conclusions
The presence of acidic and basic centers in the molecules of
2-acylaminopyridines forces them to form aggregates. Liquid
1
state H, 13C, and 15N NMR and solid state 13C and 15N NMR
CPMAS as well as IR spectral and X-ray data prove the

10426 J. Phys. Chem. A, Vol. 114, No. 38, 2010
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Acknowledgment. The authors gratefully acknowledge fi-
nancial support from Polish Ministry of Science and Higher
Education (Grant No. N N204 174138). We are very much
indebted to the Academic Computer Centre in Gdansk-TASK
and CYFRONET in Cracow for providing computer time and
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Supporting Information Available: NMR spectra, dilution
experiment curves, IR spectra, X-ray data, and geometries of
the optimized structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
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