2-acylamino- and 2,4-bis(acylamino)pyrimidines as supramolecular synthons analyzed by multiple noncovalent interactions. DFT, X-ray diffraction, and NMR spectral studies

Article abstract of DOI:10.1021/jo301643z

Intermolecular interactions of ten 2-acylamino and 2,4-bis(acylamino) pyrimidines (7 of which are previously unknown) have been investigated by X-ray structural, quantum chemical (DFT), and NMR spectral methods. Especially the concentration dependencies of the ¹H NMR chemical shifts and titrations with other molecules capable of multiple hydrogen bonding provided useful information regarding their association via triple or quadruple hydrogen bonding, which is controlled by the conformational preferences of 2-acylamino- and 2,4-bis(acylamino)pyrimidines. On comparison of the properties of 2-acylamino- and 2,4-bis(acylamino)pyrimidines with the corresponding pyridines, an additional nitrogen in the heterocyclic ring is the crucial factor in explaining the stability of various conformers and dimers of pyrimidines. Computational modeling of their dimerization (self-association) and heteroassociation supports the experimental findings. The substituent effects in 2-acylamino- and 2,4-bis(acylamino)pyrimidines are discussed via inter- and intramolecular terms. The subtle balance between several structural factors and their influence on the aggregation of studied pyrimidines was confirmed also by variable-temperature NMR and NOE experiments. X-ray structures of 2-methyl- and 2-adamantyl-CONH-pyrimidines revealed very different intermolecular interactions, showing the importance of the substituent size on the self-assembly process. As a whole NMR spectral, X-ray structural, and computational data of 2-acylamino- and 2,4-bis(acylamino)pyrimidines can be interpreted in terms of multiple intra-/intermolecular interactions.

Full text of DOI:10.1021/jo301643z

Article
pubs.acs.org/joc
2‑Acylamino- and 2,4-Bis(acylamino)pyrimidines as Supramolecular
Synthons Analyzed by Multiple Noncovalent Interactions. DFT, X‑ray
Diffraction, and NMR Spectral Studies
Borys Osmiałowski,*,† Erkki Kolehmainen,‡ Satu Ikonen,‡ Arto Valkonen,‡ Adam Kwiatkowski,†
́
Izabela Grela,† and Esa Haapaniemi‡
†Faculty of Chemical Technology and Engineering, University of Technology and Life Sciences, Seminaryjna 3, PL-85-326 Bydgoszcz,
Poland
‡Department of Chemistry, University of Jyvaskyla, P.O. Box 35, FI-40014 Finland
̈
̈
S
* Supporting Information
ABSTRACT: Intermolecular interactions of ten 2-acylamino
and 2,4-bis(acylamino)pyrimidines (7 of which are previously
unknown) have been investigated by X-ray structural, quantum
chemical (DFT), and NMR spectral methods. Especially the
1
concentration dependencies of the H NMR chemical shifts
and titrations with other molecules capable of multiple
hydrogen bonding provided useful information regarding their association via triple or quadruple hydrogen bonding, which is
controlled by the conformational preferences of 2-acylamino- and 2,4-bis(acylamino)pyrimidines. On comparison of the
properties of 2-acylamino- and 2,4-bis(acylamino)pyrimidines with the corresponding pyridines, an additional nitrogen in the
heterocyclic ring is the crucial factor in explaining the stability of various conformers and dimers of pyrimidines. Computational
modeling of their dimerization (self-association) and heteroassociation supports the experimental findings. The substituent
effects in 2-acylamino- and 2,4-bis(acylamino)pyrimidines are discussed via inter- and intramolecular terms. The subtle balance
between several structural factors and their influence on the aggregation of studied pyrimidines was confirmed also by variable-
temperature NMR and NOE experiments. X-ray structures of 2-methyl- and 2-adamantyl-CONH-pyrimidines revealed very
different intermolecular interactions, showing the importance of the substituent size on the self-assembly process. As a whole
NMR spectral, X-ray structural, and computational data of 2-acylamino- and 2,4-bis(acylamino)pyrimidines can be interpreted in
terms of multiple intra-/intermolecular interactions.
molecular hydrogen bonding47,48 controls the form of a
INTRODUCTION
■
molecule and thus its interactions with other molecules,49−56
only a couple of papers have focused on the significance of
conformational equilibrium.57,58
Molecular self-assembly via noncovalent interactions between
supramolecular synthons1−4 with predictable associations5,6 is
of continuing interest in organic and bioorganic chemistry.
Studies on 2-aminopyridine and its acyl derivatives,7−10 2,6-
diaminopyridines and their derivatives,11−17 various naphthyr-
idines,18−24 and other compounds capable of multiple hydro-
gen bonds have been reported. The strengths of the
intermolecular interactions are determined by the number of
hydrogen bonds, the array of hydrogen bond donors (D) and
acceptors (A), secondary interactions25,26 in multiply hydrogen
bonded systems,27−29 the character of influence of the
substituents (electronic30,31 or steric32−34), weak CH···N/O
hydrogen bonds,15,35,36 cooperative effects,37 and proton
transfer reactions,38−43 as well as the types of atoms involved
in hydrogen bonding (Etter’s rules).6
Our recent interest has focused especially on the steric effects
in the formation of doubly,32,44 triply,34,45,46 and quadruply47
hydrogen bonded assemblies. The electronic repulsion (Chart
1a)45 and steric effects (Chart 1b)34 influence the association in
solution. Steric effects are also responsible for the very different
arrangement of molecules in the unit cell in the crystalline state
(Chart 1c).32 Although some papers describe how intra-
An inspiration for our present study on pyrimidines and their
comparison with pyridines originates from the different
behavior of pyridines vs diazines59,60 and triazines,11,49 where
the association in solution11,59 or specific interactions in the
solid state49,60 depends mainly on the presence of a nitrogen
atom (instead of CH) in positions 3 and 5 in the heterocyclic
ring (Chart 2). The effects of related structural changes were
also studied by Limbach et al. in doubly hydrogen bonded
N,N′-bisarylformamidines42,43 vs N,N′-bisaryltriazenes.41,43 In
2,6-bis(acylamino)pyridines the weak CH···O interaction favors
the close mutual proximity of CH and CO groups, which
does not depend on the mesomerism of the amide moiety (in
red and blue, Chart 2). Rotation about the NH−CO bond
causes repulsion between aromatic and aliphatic protons. Thus,
the 2,6-bis(acylamino)pyridines exist in a conformation that
gives a DAD hydrogen bonding array but not the ADADA
Received: August 6, 2012
Published: September 30, 2012
© 2012 American Chemical Society
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conformational preferences, and (d) characterize the type of
their dimers. The tautomerism/rotamerism of similar com-
pounds (2-acylaminopyridines) was studied before by Katritzky
et al.,75 while publications by Wilson et al. have described the
conformation-independent binding of hydrogen-bonded mole-
cules.48,76
Chart 1. Association Influenced by the Electronic (a) and
Steric (b) Effects in Solution and the Structure of 2-
Acylaminopyridines in the Solid State (c)
Chart 3 collects the structures of compounds used in this
study and their atom numbering.
Chart 3. Compounds Studied and Their Atom Numbering
array. In 2,4-bis(acylamino)-s-triazine CH···O attractions are
replaced by electronic repulsions between N and O atoms. This
leads to increased rotational freedom about the NH−CO bond
and formation of DADA and ADADA self-complementary
hydrogen bonded arrays. The subtle balance between the two
dimers of s-triazine shown in Chart 2 arise from the fact that in
one intramolecular electronic repulsion takes place (dimer on
the left-hand side), while in the other (right-hand side) two
additional repulsions are present. The rotamerism of s-triazines
is probably more or less similar in 2,4-bis(acylamino)-
pyrimidines.
The intramolecular hydrogen bond can act as a conforma-
tional lock.61 This interaction is frequently used in supra-
molecular chemistry,30,62−72 although in the current study such
an interaction is not important. Knowledge of the intermo-
lecular interactions of pyrimidine derivatives is also important
from a medicinal chemistry point of view.73,74
RESULTS AND DISCUSSION
■
Self-Association of 2-Acylaminopyrimidines. 2-Acyla-
minopyrimidine contains three basic centers (two nitrogen
atoms and an oxygen) and an acidic proton (NH) capable of
hydrogen bonding. 1a was previously used by us in studies of
the influence of cycloalkyl ring size on the heteroassociation of
2,6-bis(cycloalkylcarbonylamino)pyridines.33 The 1H NMR
dilution experiments revealed that 2-acylaminopyrimidines
form dimers in CDCl3 solution (current study). The
dimerization constant (Kdim) is low and comparable to those
for 2-acylaminopyridines:32 i.e., Kdim (M−1) = 8.033 (1a), 4.0
(2a), and 1.4 (3a).
In the X-ray crystal structures of the two derivatives 1a (R =
methyl) and 5a (R = adamantyl) (Figure 1) the major
difference is in the conformation of the −NHCO− group. In 1a
the conformation is cis (H7N7C8O9 = 4°), whereas in 5a it is
trans (H7N7C8O9 = 165°). 1a forms quadruply hydrogen
bonded dimers, which further interact via nonconventional
The aim of this study is to (a) determine the self-association
constants of 2-acylamino- and 2,4-bis(acylamino)pyrimidines,
(b) study their heterocomplexation with selected triply and
quadruply hydrogen bonding counterparts, (c) find their
Chart 2. Intramolecular Interactions That Control the Structures of 2,6-Bis(acylamino)pyridines and 2,4-Bis(acylamino)-s-
triazines
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interactions (Chart 4a), the NH···N doubly hydrogen bonded
dimer (Chart 4b), and the associated N···H(N)···O arrange-
ment (Chart 4c). 5a does not form dimers but a ribbonlike
structure like that of 2-(1-adamantoylamino)pyridine;32 there-
fore, this compound was not taken into consideration for
calculations.
The self-association of 2-acylaminopyrimidines is controlled
by the size of R. The correlation of Kdim with Taft’s constants
(Es)80 is poor (R2 = 0.76, n = 3) and can be explained by
competitive association via hydrogen bond bifurcation or
formation of various dimers instead of exclusive stabilization
of the dimer by two NH···N hydrogen bonds (form b in Chart
4). The interaction shown by c in Chart 4 was observed in the
crystal structures of other derivatives and will be published in
due course (the NH···N and NH···O distances are 2.296 and
2.432 Å in one molecule and 2.355 and 2.172 Å in the other,
respectively).81
Figure 1. ORTEP77 plots for 1a and 5a (most CH protons omitted for
clarity).
The QTAIM data for the structures (Table 1) are in
agreement with those obtained from computations based on X-
ray structures. Also, the different dimers (Chart 4) and the
calculated Eint values suggest the existence of NH···N dimers
stabilized further by weak CH···O interactions (Table 1), as
claimed by Zimmerman et al. for DNA bases.82
Pyrimidines with large alkyl substituents do not form dimers
in chloroform solution. The intermolecular steric crowding of
pyrimidines with bulky substituents prevents their efficient
dimerization (DA pattern, Z conformer, Chart 4b), as
previously found for other derivatives.32,34,83 This is called a
direct steric effect. On the other hand, a large substituent in
pyrimidine hinders the rotation about the NH−CO bond,
decreasing the stability of the ADA hydrogen bonding array (E
conformer, Chart 4a). This effect is called an indirect steric
effect.
Heteroassociation of 2-Acylaminopyrimidines. The
heteroassociation of 1a−4a with B and C (Chart 3) was
studied by 1H NMR titration, as done before for 2-acylamino-6-
[1H]pyridones.46 The association constants (Kassoc) for the 1a
+ B pair are 450 M−1 (probe NH proton) and 500 M−1 (probe
aromatic CH 1a) (titration curves are given in the Supporting
Information). Kassoc values and complexation-induced shifts
(CIS) of 1a−3a with C are collected in Table 2, and Chart 5
depicts the structures of the complexes.
CH···O contacts to form two-dimensional sheets (Figures S1−
S3, Supporting Information). The dimer is stabilized by two
NH···N and two CH···O hydrogen bonds (compare 2-
acylaminopyridines32). In the NH···N bridge the H···N and
N···N distances are 2.08(2) and 2.973(2) Å, respectively, while
the CH···O distances (H···O and C−O) are 2.67 and 3.405(3)
Å. Three other weak C−H···N/O type interactions were found
to connect the dimers to neighboring ones.
The structure of 1a was also modeled by DFT methods
(three dimers, with two different amide group conformations).
Table 1 collects the calculated energy of interaction (Eint),
Table 1. QTAIM and Eint Data for Dimers of 1a
form
Eint, ρ, ∇2ρ, EHB for NH···N
ρ, ∇2ρ, EHB for CH···O
form a
form a
−86.9, 0.024, 0.066, −20.5
−, 0.022, 0.067, −19.0
0.008, 0.026, −6.5
0.006, 0.022, −5.1
a
form b
form c
−40.3, 0.023, 0.061, −18.7
−35.5, 0.022, 0.022, −20.7
b
c
a
Calculations based on geometry from XRD. Two more CH···O
contacts are present in the solid state (Figure S2 (Supporting
Information), H5···O9″ and H6···O9″) with the H-BCP properties
b
0.006, 0.023, −5.2 and 0.005, 0.021, −4.3, respectively. NH···O
c
interaction. Two weak CH···N and CH···O interactions (from CH3
group) are present with ρ, ∇2ρ, and EHB values of 0.005, −0.004, −3.5
and 0.007, −0.006, −5.4, respectively.
The chemical shift data did not allow the calculation of Kassoc
values of 4a and 5a with C, suggesting that the association is
completely restricted or is very weak.
Table 3 contains the calculated data for complexes 1a + B
and 1a + C.
The greater association constant of 1a + B (Chart 5b)
compared to the 1a−3a + C complexes (order of magnitude)
can be explained by the higher rigidity of B with respect to C
QTAIM-derived data (electron density (ρ) and the Laplacian of
electron density (∇2ρ)) at H-BCP (hydrogen-bond critical
point), and the energy of the hydrogen bonds (EHB) according
to the Espinosa approach78,79 for 1a in different arrangements:
i.e., the dimer stabilized by two NH···N and two CH···O
Chart 4. Two Isomeric (isom.) Dimers (b, c) of the 2-Acylaminopyrimidines and One Rotameric (rotam.) Dimer Obtained by
NH−CO Rotation (a)
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Table 2. Association Constant Values for Complexes of 2,4-
Bis(acylamino)pyrimidines with C
Table 4. Dimerization Constants (Kdim) for Compounds 1b−
5b
a
compd
Kassoc (M−1) with C
CIS (ppm)
compd
Kdim (M−1
)
a
b
1a
2a
3a
36
35
1.54
1.40
0.94
1b
2b
3b
4b
5b
550 (600)
c
140
b
d
e
20, 15
30 (25)
a
f
f
CIS (Δδ(H7)) observed for the same [titrant]:[titrated compound]
ratio equal to 8.5. Value based on changes of the chemical shift of
methine CH in the iPr group.
b
a
b
Based on two NH's and one aromatic proton. Based on CH3
protons (two methyl groups). The different nuclei gave the same Kdim
c
value. Based on two NH's, one methylene group, and one aromatic
Chart 5. Association of 2-Acylaminopyrimidines with B and
C
d
e
proton. Based on two NH's and one methine proton. Based on one
methine and one aromatic proton. Compound does not dimerize in
f
CDCl3.
Information, Tables S3 and S4). Because triply34 and
quadruply83 hydrogen bonded systems are generally more
stable than doubly hydrogen bonded systems,32 these were not
taken into account.
Self-Association of 2,4-Bis(acylamino)pyrimidines. In
Table 4 are collected the dimerization constants (Kdim
)
obtained by observing the chemical shift changes of several
protons (charts are given in the Supporting Information).
The data in Table 4 show that Kdim is related to the size of
the substituent, which is in agreement with our previous
results.34 As mentioned before in 2,4-bis(acylamino)-
pyrimidines two types of steric effects are present, i.e. indirect
and direct, related to the steric interactions34 of R groups
(Chart 7).
Table 3. Calculated Energy of Interaction (Eint) and Energy
of NH···N and NH···O Hydrogen Bonds (EHB) in
Heterocomplexes of 2-Acetylaminopyrimidine with B and C
Table 5 gives the energy of interaction (Eint) for all dimers of
1b, which varies from −28.5 to −69.7 kJ/mol. For
simplification only compound 1b was studied.
EHB (kJ/mol)
complex Eint (kJ/mol) NH···N NH···N NH···O ∑EHB (kJ/mol)
a
1a + B
1a + C
−65.0
−43.5
−30.4
−16.0
−10.4
−12.7
−24.1
−25.1
−72.6
−53.8
The Eint energy cutoff at ca. 20 kJ/mol was used as a barrier
above which other dimeric forms are less probable. From 11
dimers lying below that cutoff (Eint values in bold font), 8
structures contain weak CH···O interactions. Only these dimers
are shown in Figure 2. The same figure collects the data of
relative energy of the monomer that builds the respective dimer
(Erel, kJ/mol) and the sum of the energies of hydrogen bonds
(∑EHB, kJ/mol) derived from QTAIM (Espinosa ap-
proach78,79).
In Table 6 are collected the energies of hydrogen bonds
(from left to right as in Figure 2) in dimers of 1b lying under
the 20 kJ/mol Eint cutoff (the remaining energies are collected
in the Supporting Information).
On the basis of dilution experiments alone, it is not possible
to conclude which of the many possible rotameric forms
interacts, but simultaneous probing of several protons can help
to draw conclusions on the complex equilibrium. In 2,4-
bis(acylamino)pyrimidines exist two NH and two non-
equivalent CH protons. There is no significant correlation
between Kdim and Taft’s constant (R2 = 0.578, n = 3). Kdim
values suggest that the dimerization takes place by triple and/or
quadruple hydrogen bonding. Kdim(1b) = 550−600 M−1 is
slightly higher than Kdim for 2-acylamino-6-[1H]pyridones46
and does not fit either a triply or quadruply hydrogen bonded
dimercompare Kdim= 1800−1900 M−1 for B83 and Kassoc = 15
M−1 for 2-acetylaminopyrimidine (1a) with 2,6-bis-
(cyclopropylcarbonylamino)pyridine.33 Moreover, both NHs
and one aromatic CH proton behave similarly during the
dilution experiments, while the other aromatic CH proton
behaves more or less randomly (see the Supporting
a
Weak CH···O interaction (Chart 5) with EHB = −7.7 kJ/mol
included.
and to some extent by the presence of the weak CH···O
interaction (Chart 5b, atoms in red). The chemical shift
changes of aromatic protons in 1a (doublet signal, see the
titration curve in the Supporting Information) are in line with
the changes in NH and can be caused by weak hydrogen
bonding and/or by magnetic anisotropy of the CO group of
B. In general, the indirect steric effect plays a dominant role in
heteroassociation of 1a−5a with C, which is seen not only in
Kassoc but also in CIS values. The computational results reveal
that the measured association constants are in agreement with
the calculated intermolecular interaction energies and the sum
of hydrogen bond energies calculated by the Espinosa
approach.78,79
2,4-Bis(acylamino)pyrimidines. The 2,4-bis(acylamino)-
pyrimidine can exist in several conformations (Chart 6). Their
hydrogen bond arrays can be AD, DAD/ADA, DADA, and
ADADA (EEEE rotamer). In some conformations electronic
repulsions (solid black dot, Chart 6) or CH/CH interactions
(solid blue dot) are also possible. The latter repulsion is
especially important in pyrimidines with large substituents and
was also found in N,N′-bisarylformamidines.43 Among the
arrays, ZEEZ is complementary with ZEZE, which is also
complementary with ZEEE, but in this case a weak CH···O
hydrogen bond can be formed. All rotamers shown in Chart 6
and their dimers were energetically optimized (Supporting
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Chart 6. Rotamers of 2,4-Bis(acetylamino)pyrimidine with the Intramolecular Repulsions Crucial to Destabilization of the
Respective Forms
Chart 7. Dimerization and Heteroassociation in 2,4-Bis(acylamino)pyrimidines Highlighting Direct and Indirect Steric Effects
Information). This suggests that both NH protons are involved
in hydrogen bonding and one aromatic CH is located in the
vicinity of moieties responsible for magnetic anisotropy or it
forms a weak CH···OC hydrogen bond. Finally, the NOESY
spectrum of 3b recorded at −50 °C revealed weak NOE
contacts (see the Supporting Information). Also, the variable-
temperature (VT) spectra suggested that 2,4-bis(acylamino)-
pyrimidines exist as a mixture of dimers. At −50 °C we have
observed three NH signals, which split at −40 °C into four
signals. These signals became more shielded as the temperature
was raised, and the intensity of two of them decreased. For H5
at −50 °C two doublets were observed, which coalesce as the
temperature increased. The methine of the i-Pr group is a good
indicator for the coexistence of various dimeric forms of 3b.
Four CH multiplets with very different chemical shifts (range
2.5−4.1 ppm) have been observed. The methine proton was
previously used by us as an additional probe in the
determination of association constants.33 The VT H NMR
1
spectra are collected in the Supporting Information. The Kdim
values and their poor dependence on steric Es constant suggest
a coexistence of two different dimers as in 2-acylaminopyr-
imidines. At this stage the results can be summarized shortly
that the 2,4-bis(acylamino)pyrimidines dimerize by three or
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a
Table 5. Interaction Energy (Eint) for All Dimers of 1b Considered
dimer (form)
Eint (kJ/mol)
dimer
Eint (kJ/mol)
dimer
Eint (kJ/mol)
ZEEE/ZEEE
−69.7
−65.9
−63.6
−61.5
−60.7
−60.6
−57.4
−55.8
−54.2
−51.8
−49.9
ZEEZ/EEZE (2)
ZEEZ/ZEZE (2)
EEEE/ZZZE (2)
EEEE/EZZE (2)
ZEEZ/ZZZE (1)
ZEEZ/EZZE (1)
EEEE/EEZE (2)
ZEEZ/ZEZE (1)
EEEE/ZEZE (2)
ZEEZ/EEZE (1)
EEEE/EZZE (1)
−49.6
−49.4
−48.8
−48.7
−48.5
−47.1
−46.5
−45.4
−44.9
−44.3
−43.7
EEEE/ZZZE (1)
EEEE/EEZE (1)
EEEE/ZEZE (1)
EEEZ/ZZZE (2)
EEEZ/EZZE (2)
EEEZ/ZEZE (2)
EEEZ/EEZE (2)
ZEEE/ZZZE (1)
ZEEE/ZEZE (1)
ZEEE/EEZE (1)
ZEEE/EZZE (1)
−42.8
−42.6
−41.5
−40.1
−39.1
−38.7
−37.6
−36.2
−35.1
−33.2
−28.5
ZEEE/ZZZE (2)
ZEEE/EZZE (2)
ZEEE/EEZE (2)
EEEZ/ZZZE (1)
ZEEE/ZEZE (2)
EEEZ/EEZE (1)
EEEZ/ZEZE (1)
EEEZ/EZZE (1)
ZEEZ/ZZZE (2)
ZEEZ/EZZE (2)
a
For graphic representations of dimers and related Cartesian coordinates see the Supporting Information.
four hydrogen bonds (or both of that within two dimers), while
the analogous pyridine derivatives do not.33,34,59
The possibility of formation of associates in various rotameric
states of 2,4-bis(acylamino)pyrimidines can be studied by
titrations (see later in text), while computational methods
provide the relative energies of various dimers.
Three rotameric forms of 1b (EEEZ, ZEEE and EEEE) may
form complexes with B (Table 9). One rotamer is able to form
two forms with different spatial arrangements of the molecules.
The respective data for 1b + C are summarized in Table 10.
5b was excluded from titrations due to a higher rigidity of its
R moiety in comparison with the other moieties. However, 5b
+ A (a complex that should be stabilized by three hydrogen
bonds) was studied. The NH chemical shifts in 5b did not
change more than 0.1 ppm, suggesting very weak association
owing to the large size and rigidity of the 1-adamantyl group.
The situation is comparable with that for 2-acylaminopyridines,
where the methyl derivative forms a doubly NH···N hydrogen
bonded complex, adamantyl forms ribbonlike polymers
stabilized by NH···O interactions, and tert-butyl forms both
species, as reported by us.32 Thus, the change from t-Bu to 1-
adamantyl is crucial for intermolecular interactions of the
NHCOR group, its rotation about the N−C bond, and steric
crowding. This is also confirmed by the magnitude of the Es
constant found by us for 1-adamantyl.83 The reported Es for 1-
adamantyl is 33% higher with respect to the value for the t-Bu
group.
Direct comparisons between series of heterocomplexes can
only be done for A and B, due to the missing data in the C
series (Table 7). It is interesting that the association constants
of 2,4-bis(acylamino)pyrimidines with A and B behave
similarly. The association constant decreases on going from R
= Me to R = Et and then strongly increases to R = t-Bu (Figure
3). The mutual correlation between Kassoc for 1b−4b + A and
Kassoc for 1b−4b + B is high (R = 0.974). This means that both
A and B titrants act in a similar fashion, decomposing the
dimers of 2,4-bis(acylamino)pyrimidines. On the other hand,
the magnitudes of Kassoc values suggest that heterocomplexation
is easier when the substituent is larger because its size hinders
efficient dimerization. There are three or four large substituents
in the dimer (Figure 2) that hinder dimerization in a direct or
indirect fashion, while in the heteroassociate one or two of them
influences aggregation (Chart 8). In other words, the larger
substituent preventing dimerization causes the high concen-
tration of the monomer capable for heterocomplexation.
Some titration curves possess complex shapes, making them
impractical for the calculation of the association constant.
Those sigmoidal shapes can be caused by multiple monomer/
oligomer equilibria, as argued before.46,80 Interestingly, titration
curves behave differently: decreasing (1b with A) or increasing
(3b and 4b with A) and first decreasing and after that
increasing (2b + A, sigmoidal shape). In Figure 4 example
curves are shown. Curve c shows evidently that more than two
From Table 6 it is easy to notice that the CH···O interaction
contributes to the overall stabilization of dimers at a level of ca.
13%. The difference between the sums of EHB and Eint is the
sum of the repulsive energy according to Jorgensen’s secondary
interactions25 model. This difference is ca. 10 kJ/mol lower for
dimers lying below the said cutoff than for those that have
higher relative energy. This, most probably, is because the NH/
CH bond dipoles do not repulse as strongly as, for example,
NH/NH or NH/OH dipoles. The calculated interaction
energies also suggest that in 1b more than one dimer is present.
Heteroassociation of 2,4-Bis(acylamino)pyrimidines.
The X-ray structure of 1a reveals that the presence of N1 and
N3 allows free rotation within the NHCOR moiety and
therefore 1b−5b can form various heteroassociates due to the
same “N1+N3 effect”. To screen the conformational prefer-
ences of 2,4-bis(acylamino)pyrimidines and their potential
association with various counterparts, compounds A−C were
1
used as H NMR titrants. The i-Pr derivative B was chosen
instead of one bearing a smaller substituent (Me or Et) due to
the good solubility of B in comparison with other
naphthyridine congeners.83 It is also worth mentioning that
the dimerization constants (Kdim (M−1)) for titrants are 2.3 for
A
33 and 1800−1900 for B,83 while 2,6-bis(acetylamino)pyridine
(C) does not dimerize in CDCl3.34,59
The possible heterocomplexes of 2,4-bis(acylamino)-
pyrimidines with A−C are shown in Chart 8.
In Table 7 are collected Kassoc values for the complexes
shown in Chart 8 (data for 5b are missing due to the reasons
given below).
The geometry optimization for heterocomplexes of 1b with
A−C were performed for these rotamers that fit the hydrogen-
bonding pattern of A−C counterparts. Tables 8−10 collect the
crucial data. Due to the very time-consuming calculations, these
were only performed for the 1b derivative.
There are four rotamers of 2,4-bis(acylamino)pyrimidines
that are able to form three hydrogen bonds with A. These are
ZEEZ, ZEEE, EEEZ and EEEE forms (Chart 6). Table 8
collects the energy of interaction in 1b+A complex with various
rotameric forms of 1b.
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Table 6. Energy (EHB) of Individual Hydrogen Bonds
EHB (kJ/mol)
a
dimer
NH···O NH···N NH···N
CH···O
∑EHB
ZEEE/ZEEE
−32.8
−27.8
−27.3
−26.8
−24.6
−27.2
−24.2
−24.6
−24.9
−27.1
−26.5
−9.3
−23.3
−22.2
−22.9
−25.8
−22.3
−25.1
−25.0
−22.8
−17.4
−17.7
−84.2
−72.0
−70.5
−70.5
−70.5
−70.1
−69.3
−69.4
−67.4
−58.1
−58.8
ZEEE/ZZZE (2)
ZEEE/EZZE (2)
ZEEE/EEZE (2)
EEEZ/ZZZE (1)
ZEEE/ZEZE (2)
EEEZ/EEZE (1)
EEEZ/ZEZE (1)
EEEZ/EZZE (1)
ZEEZ/ZZZE (2)
ZEEZ/EZZE (2)
−10.2
−9.5
−9.7
−10.7
−9.8
−10.5
−10.7
−8.9
−10.7
−11.5
−11.1
−9.4
−10.8
−9.5
−9.1
−10.8
−13.6
−14.6
a
The dimers are sorted as in Table 5 (by Eint energy).
Chart 8. Association of 2,4-Bis(acylamino)pyrimidines with
Chosen Counterparts
a
Table 7. Kassoc Values for the Complexes Studied
Kassoc (M−1
)
compd
A
B
C
b
c
d
b
d
e
be
,
g
1b
40, 25, 25, 30
700, 600, 800,
18, 11
700
e
d
f
b
e
b
g
j
2b
3b
7, 16, 28, 17
200, 190, 195
23, 90, 80
b
e
d
g
h
i
b
e
20, 20, 24, 14, 95, 14,
550, 300, 425
k
31
b
b
4b
180, 180
1800, 1800
k
Values based on:
Figure 2. The chosen 11 dimers of 1b with the highest energies of
interaction.
a
b
Average values are given in boldface. Value based on NH (low-field
c
d
signal). Value based on CH3 signal. Value based on aromatic CH
e
proton (low-field signal). Value based on NH (high-field signal).
individual species are present in solution. These are, most
probably, two dimers and the heterocomplex 2b + A.80 For
similar examples see our previous work.46
f
g
Value based on CH2 (low-field signal). Value based on aromatic CH
h
signal (high-field signal). Value based on methine CH proton (low-
i
field signal). Value based on methine CH proton (high-field signal).
The sigmoidal shape is observed only with A. The probable
explanation is that in the case of B and C at least one rotamer
of the initial mixture of two dimers does not change. This
means that A associates with the ZEEZ form of 2,4-
bis(acylamino)pyrimidines, while B and C associate with
rotamers that are also present in more stable dimers of 2,4-
bis(acylamino)pyrimidine. Thus, the most dramatic changes in
the ratio and the type of rotamers present in solution (dimers
j
k
Value based on CH2 (high-field signal). It was not possible to
calculate the association constants due to the linear (3b) or random
(4b) character of δ = f([titrant]) function.
vs heteroassociates) are the easiest to observe during the
titration with A. In other words, compounds B and C replace
one of the rotamers in the dimer of 2,4-bis(acylamino)-
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associate 1b + C, four rotamers are capable of efficient
hydrogen bonding. Since the rotation of one acylamino group is
free, due to not having any contribution to intermolecular
hydrogen bonding, the Eint energies (Table 10) are very close to
one another.
Table 8. Calculated Energies of Interaction between 1b and
A
form of 1b
Eint (kJ/mol)
∑EHB (kJ/mol)
ZEEZ + A
ZEEE + A
EEEZ + A
EEEE + A
−54.4
−43.8
−58.7
−31.1
−63.0
−62.4
−64.9
−64.3
CONCLUSIONS
■
A change of carbon-3 to nitrogen in the pyridine ring leads to
the formation of pyrimidine and an additional basic center in
the heteroaromatic ring. This structural change results in an
easy rotation in the RCONH moiety of 2-acylamino- and 2,4-
bis(acylamino)pyrimidines and consequently several conform-
ers are possible, which are further capable of multiple
intermolecular interactions. The subtle balance among intra-/
intermolecular steric effects, intramolecular electronic repul-
sions, intermolecular secondary interactions, and weak CH···O
hydrogen bonding is characteristic of self-assembly and
heteroassociation of 2-acylamino- and 2,4-bis(acylamino)-
pyrimidines. This study reveals that in supramolecular
assemblies of these pyrimidines the structure of the frontier
(interacting) part of the molecule is crucial but also that the
whole molecular backbone is important and should be taken
into account. The conclusions are drawn via a multidisciplinary
approach, combining NMR spectral, X-ray structural, and
computational data, which are all needed for this very complex
research topic.
Table 9. Calculated Energies of Interaction between 1b and
B
form of 1b
EEEZ + B
Eint (kJ/mol)
∑EHB (kJ/mol)
−74.8
−84.1
−56.5
−63.7
−86.6
−88.3
−86.0
−90.2
ZEEE + B
EEEE + B (form 1)
EEEE + B (form 2)
Table 10. Calculated Energies of Interaction between 1b and
C
form of 1b
Eint (kJ/mol)
∑EHB (kJ/mol)
ZEZE + C
EEZE + C
EZZE + C
ZZZE + C
−43.4
−42.1
−45.2
−45.9
−54.7
−54.3
−56.2
−54.8
EXPERIMENTAL SECTION
General Considerations. All substrates for synthesis were
purchased from Aldrich and were used as received. The melting
■
points were determined with the use of a Buchi apparatus with 5 °C/
̈
min gradient. Compounds 1a−5a were synthesized as described earlier
for 2-acylaminopyridines.32 The yields of syntheses varied from 74 to
85%. Compounds were purified by recrystallization from a hexane/
ethyl acetate mixture (10/1 v/v). Crystals suitable for X-ray
determination were obtained during slow evaporation of solutions
used in NMR experiments. Compounds 1b−5b were obtained by
heating 2,4-diaminopyrimidine with the respective acid chloride (2
equiv) in boiling, dry pyridine for 10 h. After this time the mixture was
evaporated to dryness and a saturated aqueous Na2CO3 solution was
added (20 mL). The mixture was extracted several times with
chloroform, and the combined organic fractions were evaporated. The
solid was heated to 70 °C under ca. 3 mmHg vacuum to remove the
residual pyridine. The remaining solids were recrystallized twice from
hexane/ethyl acetate.
The recording of NMR spectra46 and solution of the solid-state
structures by X-ray diffractometry91 were performed as described in
our previous papers.
Spectral and Characterization Data. It is quite hard to assign
the signals to the respective protons in molecules 1b−5b in CDCl3.
The problem arises when one realizes that (a) the low-field
(deshielded) NH proton should belong to the acylamino group
located at position 2 (two electronegative nitrogen atoms close to the
NH group), (b) the same NH proton forms the hydrogen bond with
the nitrogen atom of another molecule, and (c) the high-field NH
(shielded) proton should belong to the acylamino in position 4 but
(d) this proton forms a hydrogen bond with the oxygen in another
molecule. Since the NH···O hydrogen bond is stronger than the
NH···N bond, the aforementioned interactions cause opposite effects.
Thus, the assignment of chemical shifts in 1b−5b is based on the
1H,15N HMBC spectra in DMSO-d6. The assumption was made that in
this solvent compounds do not form dimers.
Figure 3. Relationship between Kassoc values of 2,4-bis(acylamino)-
pyrimidines with A and B.
pyrimidine, leaving the remaining rotamer unchanged, while A
changes the rotameric form of both constituents of the dimer.
The computational data support conclusions based on
experiments. The energy of interaction of 1b + A (see also
Supporting Information) is comparable to the energy of triply
hydrogen-bonded dimers of 1b (Table 8). The energy of
interaction for two forms of the 1b + B associate (Table 9) is
higher than any interaction for the dimer of 1b (Table 5). This
is in agreement with the Kdim (Table 4) and Kassoc (Table 7)
data obtained by experimental methods. With regard to the
2-Acetylaminopyrimidine (1a, R = Me). 1H NMR (CDCl3): δ 9.52
3
(bs, 1H, H7), 8.62 (d, 2H, H4 and H6, JH,H = 4.9 Hz), 6.99 (t, 1H,
H5, 3JH,H = 4.9 Hz), 2.51 (s, 3H, CH3). 13C NMR: δ 171.4 (C8), 158.3
(C4 and C6), 157.8 (C2), 116.0 (C5), 25.2 (CH3). 15N NMR: δ
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Figure 4. Comparison of the shapes of titration curves for the 1b−4b series: (a) titrant A, low-field NH; (b) titrant A, high-field aromatic CH; (c)
sigmoidal shape of the methylene (2b) based titration curve.
−120.0 (N1 and N3), −232.8 (N7). Mp: 146.3−148.0 °C (lit.84 mp
146−147 °C).
(C12), 175.18 (C8), 159.21 (C6), 158.68 (C2), 157.35 (C4), 105.12
(C5), 34.48 (CH, substituent), 34.31 (CH, substituent), 19.18 (CH3,
substituent) (CH2), 29.45 (CH2), 9.18 (CH3), 8.99 (CH3), 15N NMR:
δ −122.9 (N1), −140.9 (N3), −238.6 (N11). Mp: 195.6−199.4 °C
(off-white crystals). Anal. Calcd: C, 57.58; H, 7.25; N, 22.38. Found:
C, 57.41; H, 7.41; N, 22.22.
1
2-Propionylaminopyrimidine (2a, R = Et). H NMR (CDCl3): δ
3
8.95 (bs, 1H, H7), 8.61 (d, 2H, H4 and H6, JH,H = 4.9 Hz), 6.98 (t,
3
1H, H5, JH,H = 4.9 Hz), 2.80 (q, 2H, CH2), 1.24 (t, 3H, CH3). 13C
NMR: δ 174.3 (C8), 158.3 (C4 and C6), 157.7 (C2), 116.0 (C5), 30.8
(CH2), 9.0 (CH3). 15N NMR: δ −118.5 (N1 and N3). Mp: 127.2−
128.3 °C (lit.85 mp 125−126 °C).
2,4-Bis(tert-butylamino)pyrimidine (4b, R = t-Bu). 1H NMR
(DMSO-d6): δ 10.08 (bs, 1H, H11), 9.806 (bs, 1H, H7), 8.53 (d, 3JH,H
1
3
2-Isobutyryloaminopyrimidine (3a, R = i-Pr). H NMR (CDCl3):
= 5.5 Hz, 1H, H6), 7.80 (d, JH,H = 5.5 Hz, 1H, H5), 1.23 (s, 9H,
δ 9.09 (bs, 1H, H7), 8.61 (d, 2H, H4 and H6, 3JH,H = 4.9 Hz), 6.97 (t,
CH3), 1.21 (s, 9H, CH3). 13C NMR: δ 178.29 (C12), 175.94 (C8),
159.09 (C6/C2 overlapped), 157.53 (C4), 106.28 (C5), 26.87 (CH3,
substituent), 26.54 (CH3, substituent), quaternary carbon belonging to
t-Bu overlapped with DMSO-d6. 15N NMR: δ −117.6 (N1), −244.2
(N11), −245.3 (N7). Mp: 130.2−134.9 °C (off-white crystals). Anal.
Calcd: C, 60.41; H, 7.97; N, 20.13. Found: C, 60.32; H, 8.04; N, 20.02.
2,4-Bis(1-adamantoylamino)pyrimidine (5b, R = 1-Adaman-
3
3
1H, H5, JH,H = 4.9 Hz), 3.12 (m, 1H, methine CH, JH,H = 6.9 Hz),
1.23 (d, 6H, CH3, 3JH,H = 6.9 Hz), 13C NMR: δ 176.8 (C8), 158.3 (C4
and C6), 157.7 (C2), 116.1 (C5), 35.5 (methine CH), 19.1 (CH3).
15N NMR: δ −118.4 (N1 and N3), −238.4 (N7). Mp: 125.4−126.9
°C. Anal. Calcd: C, 58.17; H, 6.71; N, 25.44. Found: C, 58.15; H, 6.73;
N, 25.40.
1
1
tane). H NMR (DMSO-d6): δ 9.95 (bs, 1H, H11), 9.667 (bs, 1H,
2-Pivaloylaminopyrimidine (4a, R = t-Bu). H NMR (CDCl3): δ
3
3
3
H7), 8.50 (d, JH,H = 5.6 Hz, 1H, H6), 7.79 (d, JH,H = 5.6 Hz, 1H,
H5), 1.996−1.657 (30H, 1-adamantyl),. 13C NMR: δ 177.58, (C12),
175.35 (C8), 159.00 (C6), 158.97 (C2), 157.53(C4), 106.09 (C5),
41.52, 41.08, 37.93, 37.44, 35.88, 35.72, 27.62, 27.55 (two
adamantyls). 15N NMR: δ −118.0 (N1), −135.2 (N3), −244.4
(N11), −245.4 (N7). Mp: 228.4−230.7 °C (yellowish crystals). Anal.
Calcd: C, 71.86; H, 7.89; N, 12.89. Found: C, 71.72; H, 7.99; N, 12.67.
Calculations. The calculations were run at the DFT level with the
use of the M05 functional (M05/6-311G(d,p)). This functional was
chosen to sustain the methodology related to our other
papers.32,34,45,46,83 All optimizations and frequency calculations (only
positive frequencies were obtained) were performed in Gaussian 0387
under vacuum. The QTAIM-based properties of hydrogen bond
critical points were computed with the use of AIM2000 software.88
The calculated energies of interaction (difference between the energy
of the complex and the sum of energies of its constituents) were
corrected to BSSE with the use of the counterpoise89,90 method as
implemented in Gaussian with default settings. The zero-point energy
correction was applied.
8.61 (d, 2H, H4 and H6, JH,H = 4.9 Hz), 8.09 (bs, 1H, H7), 7.00 (t,
1H, H5, 3JH,H = 4.9 Hz), 1.33 (s, 9H, CH3). 13C NMR: δ 175.7 (C8),
158.3 (C4 and C6), 157.7 (C2), 116.6 (C5), 40.2 (quaternary C), 27.4
(CH3). 15N NMR: δ −116.4 (N1 and N3), −247.1 (N7). Mp: 112.0−
113.5 °C. Anal. Calcd: C, 60.32; H, 7.31; N, 23.45, Found: C, 60.18;
H, 7.40; N, 23.19.
2-Adamantoylaminopyrimidine (5a, R = 1-Adamantyl). 1H NMR
3
(CDCl3): δ 8.60 (d, 2H, H4 and H6, JH,H = 4.9 Hz), 8.08 (bs, 1H,
H7), 7.00 (t, 1H, H5, 3JH,H = 4.9 Hz), 2.10−1.70 (15H, 1-adamantyl).
13C NMR: 175.2 (C8), 158.3 (C4 and C6), 157.9 (C2), 116.6 (C5),
adamantyl 42.2, 39.1, 36.4, 28.1. 15N NMR: δ −115.9 (N1 and N3),
−247.6 (N7). Mp: 188.8−190.1 °C. Anal. Calcd: C, 70.01; H, 7.44; N,
16.33. Found: C, 69.97; H, 7.47; N, 16.31.
1
2,4-Bis(acetylamino)pyrimidine (1b, R = Me). H NMR (DMSO-
3
d6): δ 10.63 (bs, 1H, H11), 10.22 (bs, 1H, H7), 8.45 (d, JH,H = 5.5
Hz, 1H, H6), 7.70 (d, 3JH,H = 5.5 Hz, 1H, H5), 2.21 (s, 3H, H14 in R′,
CH3), 2.14 (s, 3H, H10 in R′, CH3). 13C NMR: δ 170.68 (C12),
169.31 (C8), 159.24 (C6), 158.44 (C4), 157.36 (C2), 104.62 (C5),
24.64 and 24.15 (CH3). 15N NMR: δ −125.2 (N1), −143.9 (N3),
−235.1 (N11), −234.0 (N7). Mp: 235.0−238.4 °C (lit.86 mp 240−
243 °C).
ASSOCIATED CONTENT
2,4-Bis(propionylamino)pyrimidine (2b, R = Et). 1H NMR
(DMSO-d6): δ 10.58 (bs, 1H, H11), 10.21 (bs, 1H, H7), 8.42 (d,
3JH,H = 5.5 Hz, 1H, H6), 7.73 (d, 3JH,H = 5.5 Hz, 1H, H5), 2.51 (q, 2H,
CH2), 2.45 (q, 2H, CH2), 1.05 (t, 6H, CH3). 13C NMR: δ 174.16
(C12), 172.57 (C8), 159.02 (C6), 158.44 (C2), 157.28 (C4), 104.63
(C5), 29.63 (CH2), 29,45 (CH2), 9.18 (CH3), 8.99 (CH3). 15N NMR:
δ −125.1 (N1), −143.7 (N3), −237.1 (N11), −236.5 (N7). Mp:
215.0−217.9 °C (pale yellow crystals). Anal. Calcd: C, 54.04; H, 6.35;
N, 25.21. Found: C, 53.89; H, 6.42; N, 25.10.
■
S
* Supporting Information
Figures, tables, and CIF files giving NMR spectra, XRD data,
dilution and titration curves, sigmoidal curves, and computa-
tional data (Cartesian coordinates, energies, relative energies,
hydrogen bond energies, energies of interaction). This material
is available free of charge via the Internet at http://pubs.acs.org.
2,4-Bis(isobutyrylamino)pyrimidine (3b, R = i-Pr). 1H NMR
(DMSO-d6): δ 10.65 (bs, 1H, H11), 10.29 (bs, 1H, H7), 8.47 (d,
AUTHOR INFORMATION
■
3
3JH,H = 5.5 Hz, 1H, H6), 7.77 (d, JH,H = 5.5 Hz, 1H, H5), 2.83 (m,
Corresponding Author
2H, CH), 1.07 (s, 6H, CH3), 1.06 (s, 6H, CH3). 13C NMR: δ 177.54
*E-mail: borys.osmialowski@utp.edu.pl.
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Article
(33) Osm
́
iałowski, B.; Kolehmainen, E.; Kauppinen, R.; Kowalska, M.
Notes
Supramol. Chem. 2011, 23, 579.
(34) Osmiałowski, B.; Kolehmainen, E.; Gawinecki, R.; Dobosz, R.;
The authors declare no competing financial interest.
́
Kauppinen, R. J. Phys. Chem. A 2010, 114, 12881.
(35) Green, R. D. Hydrogen Bonding by C-H Groups; Thomson Litho:
East Kilbridge, U.K., 1973.
(36) Sozzani, P.; Comotti, A.; Bracco, S.; Simonutti, R. Chem.
Commun. 2004, 768.
(37) Hunter, C. A.; Anderson, H. L. Angew. Chem., Int. Ed. 2009, 48,
7488.
ACKNOWLEDGMENTS
■
Financial support from the National Science Centre in Krakow
(Grant No. N N204 356840) is gratefully acknowledged. We
are very much indebted to the ICM in Warsaw for providing
computer time and programs.
́
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