Modeling biologically important NH π interactions using peri-disubstituted naphthalenes

Article abstract of DOI:10.1021/acs.joc.0c01697

For the first time, systematic studies of 8-aryl and 8-pyrrolyl derivatives of 1-aminonaphthalene as simple, synthetically available, and nicely preorganized models were conducted for a better understanding the properties of NH π interactions involved in the stabilization of the secondary and tertiary protein structures as well as the recognition of guest molecules by biological receptors. It was shown that the NH π binding is especially effective when the NH-donor is a positively charged group, for example, Me2NH+, and the π-donor is an electron-rich aromatic substituent, in particular, the 1-pyrrolyl or the 4- hydroxyphenyl group. Using protonated tetrafluoroborate salts, a strong counterion effect was demonstrated by means of theoretical calculations. Through several mechanisms, including short CH F contacts, bifurcation, and long-range dispersion, the counterion promotes considerable structural changes and weakens the NH π interactions from 12-15 kcal mol-1 in "naked"cations to 5-9 kcal mol-1 in the salts. To this end, 8-(2,5-dimethylpyrrol-1-yl)-N,N-dimethylnaphthalene-1-ammonium tetrafluoroborate, with the record linearity and shortness (2.07 ?) of the NH π-centroid bond, was recognized as the most appropriate model with the strongest NH π interaction ever described.

Full text of DOI:10.1021/acs.joc.0c01697

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Article
Modeling Biologically Important NH…#
Interactions Using peri-Disubstituted Naphthalenes
Alexander F. Pozharskii, Olga V. Dyablo, Olga G. Pogosova, Valery A. Ozeryanskii,
Aleksander Filarowski, Kseniya M. Vasilikhina, and Narek A. Dzhangiryan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01697 • Publication Date (Web): 10 Sep 2020
Downloaded from pubs.acs.org on September 12, 2020
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Modeling Biologically Important NH…π Interactions Using peri-Disubstituted
Naphthalenes
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Alexander F. Pozharskii,*а Olga V. Dyablo,а Olga G. Pogosova,а Valery A. Ozeryanskii,а Aleksander
Filarowski,b Kseniya M. Vasilikhina,а Narek A. Dzhangiryan а
8
9
a Department of Organic Chemistry, Southern Federal University, Zorge 7, 344090 Rostov-on-Don, Russian Federation
b Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
Corresponding author. E-mail address: apozharskii@sfedu.ru
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R
Experimental and theoretical screening
H
H
+
N
+
N
Me
Me
Me
Me
N
Me
Me
N–H...

>>
N–H...N(
R = H, OMe, OH, etc.
NH...N(

The first observation of the strong
interaction in uncondensed pyrrole ring

Abstract. For the first time, systematic studies of 8-aryl and 8-pyrrolyl derivatives of 1-
aminonaphthalene as simple, synthetically available and nicely preorganized models were conducted
for a better understanding the properties of NH…π interactions involved in the stabilization of the
secondary and tertiary protein structures as well as the recognition of guest molecules by biological
receptors. It was shown that the NH…π binding is especially effective when the NH-donor is a
positively charged group, e.g. Me2NH+, and the π-donor is an electron-rich aromatic substituent, in
particular, 1-pyrrolyl or 4-hydroxyphenyl groups. Using protonated tetrafluoroborate salts, a strong
counterion effect was demonstrated by means of theoretical calculations. Through several mechanisms,
including short CH...F contacts, bifurcation and long-range dispersion, the counterion promotes
considerable structural changes and weakening the NH...π interactions from 12–15 kcal mol–1 in
“naked” cations to 5–9 kcal mol–1 in the salts. To this end, 8-(2,5-dimethylpyrrol-1-yl)-N,N-
dimethylnaphthalene-1-ammonium tetrafluoroborate, with the record linearity and shortness (2.07 Å)
of the NH…π-centroid bond, was recognized as the most appropriate model with the strongest NH...π
interaction ever described.
Introduction
According to Pauling’s discovery, made in the middle of the last century, the secondary structure of
majority of natural proteins represents the so-called right-handed -helix.1 It is maintained inside each
of its coils mainly by the amide NH…O=C hydrogen bonds (HB). However, after some time,
evidences began to appear that other forms of noncovalent interactions, in particular, the salt ones, as
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well as OH…π and NH…π, are involved in the formation of the secondary and tertiary (crumpled
spiral form) structures.2 Three proteinogenic amino acids containing aromatic nuclei, namely
phenylalanine, tyrosine and tryptophan, play the role of the proton acceptor in the XH…π hydrogen
bonds. It was also established that, in addition to the stabilization of the protein structure, XH…π
interactions are responsible for the recognition of drugs2e and other biologically important molecules
within the “host-guest” and receptor chemistry concepts.2f,g The study of π-interactions on real objects
is rather complicated for various reasons and therefore it is more convenient to simulate them on
simpler synthetic models.2a To date, a lot of efforts have been made in this direction. Most of them are
associated with supramolecular caged ligands like calixarenes, cryptands, podands, metal complexes,
etc.2f,3,4 In them, aromatic nuclei and proton donor groups are normally fixed (preorganized) for
effective XH…π interaction. Given the prevalence of neutral and charged amino groups in proteins, we
were especially interested in modeling NH…π interactions. According to current databases over the
past quarter century, about two dozen reports related to this topic have appeared. Their analysis reveals
the main trends of this approach, as well as its advantages and disadvantages. Primarily, it is not easy to
arrange the internal cavity and receptor part of the caged ligands in such a way that it would be ideally
suited for a particular guest molecule. The cavity may be too narrow or, conversely, have large voids.
In the first case, NH…π interaction often proceeds from the outside and is loose and vulnerable to
external influences, in particular to solvation effects. Indeed, in most of the articles cited, the π-donor
component, benzene as a rule, interacted with the NH receptor from the outside of the host molecule
(ESI, Table S1).3a–f Rarely, the NH component acted as an external guest molecule.3g–i There are quite a
few examples of the effective NH…π interaction inside the molecular framework.2f,4 It is not surprising
that such a variety of situations results in a large spread in the parameters of the NH…π bond. For
example, the distance from the NH proton to the benzene ring centroid (this point is designated in this
work as M) covers the range of 2.17–2.98 Å. Another drawback of this approach is a rather difficult
synthesis of frame structures, often bearing multiple functional groups, that complicates some studies,
especially in solution. Thus, almost in all the cited publications no information is presented concerning
chemical shifts of the NH proton engaged in the NH…π binding. This can be illustrated by one of the
best works of this kind, performed by Steed’s group.4a They synthesized the small tetraazaphane A, in
the inner cavity of which only a proton, but not other Lewis acids, could be placed. However, selective
monoprotonation of the bridging nitrogen atom was not possible, since the external nitrogens were first
protonated. Ultimately, the authors have obtained only tetrahydrochloride, XRD analysis of which
showed the perfect orientation of the internal N–H bond to the benzene centroid with a very short
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NH…M distance of 2.17 Å. Regrettably, in solution no signal of the internal NH proton could be
detected due to its fast exchange with the external protons.
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4 Cl–
+
+
N
H
H2N
+
NH2
+
H2N
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A
In order to improve the above situation, for studying NH…π interactions in the present work we
chose peri-disubstituted naphthalenes 1–8 as simpler and easily accessible models (Figure 1). Another
important advantage of these compounds is the presence of the “proximity effect”5 between proton-
donor and proton-acceptor fragments, which provides the necessary preorganization of the interacting
sites combining with their optimal flexibility. As the proton-acceptors (π-donors), phenyl, p-anisyl, p-
hydroxyphenyl, 2-naphthyl, pyrrol-1-yl and 2,5-dimethylpyrrol-1-yl groups were selected. The
protonated NMe2 group along with NH-pyridinium cation (see also compound 31) and neutral amino
and acetamido groups served as proton donors.6 The choice of these proton donors is explained by a
wide range of their NH-acidity (pKa ≈ 5–27), as well as their abundance in living tissues. It should be
noted that the results of the study of salt 1 and its analogue with the unsubstituted pyrrolyl group
instead of the phenyl one were reported by us in a slightly different context in recent articles.7,8
OMe
OH
–
–
–
–
BF4
BF4
BF4
BF4
H
H
H
H
1'
5
2'
+
+
+
+
NMe2
NMe2
NMe2

NMe2



1
2
8
7
6
3
4
1
2
3
4
OMe
–
–
BF4
BF4
Ha
Me
H
Hb
2
H
H COMe
N
1
+
+
Me
3
4
N
NMe2
N
N
10
9
8
5
7
6
7
5
6
8
Figure 1. Compounds for which NH…π interactions were studied.
The main methods for studying the NH… hydrogen bonds in this work were XRD measurements
1
for the solid state, H NMR and IR spectroscopy for solutions and quantum-chemical calculations for
MeCN solution and the gas phase.
Results and discussion
Synthesis
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The synthetic approaches to compounds 1–4, as well as 7 and 8, are shown in Scheme 1. In most cases,
the starting material was 1-bromo-8-acetamidonaphthalene 9,9 which was subjected into the Suzuki
reaction to introduce an aryl substituent with the following deacylation and exhaustive methylation of
the amino group. It should be noted that the reaction of 9 with naphthyl-1-boronic acid, to obtain
compound 12, could not be carried out under a wide range of conditions. However, the same reaction
with naphthyl-2-boronic acid proceeded without complications, leading to compounds 11, 14 and 18 in
good yields. Phenol 17 was obtained by demethylation of 4-methoxyphenyl derivative 16 with
hydrobromic acid. Initially, we also intended to study the salts of monomethyl derivatives 21. For this,
by methylation of the acetamido group in compounds 8 and 10, we obtained compounds 19, 20.
However, all attempts to carry out their deacetylation failed; the difficulties of carrying out such
reactions for some other peri-substituted naphthalenes were reported previously.10
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Scheme 1. Synthesis of Compounds 1–4, 7 and 8
NH2
R
AcHN
Br
AcHN
R
ii
i
13
7
14
8
10
11
12
R = Ph
R = 4-MeOC6H4 (96%)
R = 2-naphthyl (80%)
9
R = Ph
R = 4-MeOC6H4 (54%)
R = 2-naphthyl (65%)
R = 1-naphthyl (0%)
iii
vi
Me2N
R
MeHN
R
Ac(Me)N
R
15
R = Ph
16
17
18
R = 4-MeOC6H4 (66%)
R = 4-HOC6H4 (42%)
R = 2-naphthyl (80%)
iv
R = 4-MeOC6H4 (50%)
21
19
20
R = Ph (35%)
v
+
Me2HN
R
–
i RB(OH)2, Pd(OAc)2, PPh3,
Na2CO3, n-PrOH, H2O, Ar , 6 h
ii HCl, EtOH, , 3 h
BF4
iii Me2SO4, Na2CO3, H2O, rt, 24 h
iv HBr, , 1 h
1
R = Ph
v HBF4, MeCN
2
3
4
R = 4-MeOC6H4 (73%)
R = 4-HOC6H4 (83%)
R = 2-naphthyl (88%)
vi MeI, KOH, DMSO, rt, 24 h
10-Phenylbenzo[h]quinoline (22) used to generate salt 6 was prepared by direct phenylation of
benzo[h]quinoline as described earlier11 while for the preparation of 1-(2,5-dimethylpyrrol-1-yl)-8-
dimethylaminonaphthalene (24) the interaction of peri-diamine 23 with 2,5-hexanedione was employed
(Scheme 2). The target salts 1–6 were obtained on addition of equimolar amount of aqueous
tetrafluoroboric acid to a solution of the corresponding base in acetonitrile or ethyl acetate.
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Scheme 2. Preparation of Protonated Models 5 and 6
4
5
N
6
7
8
9
HBF4
6
MeCN
22
Me
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O
Me
NH2 NMe2
N
NMe2
HBF4
O
5
MeCN
, 3 h
23
24
Solid State Structures
As the main parameters indicating the formation and peculiarities of the NH…π hydrogen bonding in
the crystalline state of the studied substances, we considered the NH…M and NH…C1 distances, the
NHM angle, the rotation angle of the aryl (pyrrolyl) substituent relative to the naphthalene ring and the
HNC1C2 torsion angle, showing the directionality of the NH bond to the plane of the aromatic π-
system. In addition, we were interested in the degree of deformation of the naphthalene ring, in
particular, the so-called “twisting”  (torsion angle between the C2–C3/C6–C7 bonds which are
highlighted in structure 1 in bold lines) and the angles , β and  (see structure 2). It should be noted
that the distortions of the naphthalene ring as a whole turned out to be small and little variable;
therefore less attention was paid to them. At the same time, for salts 1–6, useful information was
obtained from the minimum distances between the chelated NH proton and the nearest fluorine atom in
–
the counterion, NH…FBF3 . All this and a number of other information are depicted in Table 1 and in
Figures 2, 4–6.
Table 1. Selected Bond Lengths, Distances (Å) and Angles () for Compounds 1–8
(with indicated uncertainties; all XRD measurements were performed at 120 K except 100 K for salt 4)
Parameter
Compound
5
1
83.8
(84.1)
178(2)
2
3a
4
6
7
76.1
(74.3)
145(6)d
167(4)e
8
48.5
(45.1)
60(4)
b
78.7
86.1
73.5
(70.3)
177(2)
88.1
(86.9)
174(2)
62.8
(57.4)
177(2)c
(76.4)
171(2)
(84.3)
178(4)
HNC1C2
N–H
0.91(2) 0.89(2) 0.91(3) 0.89(4)
2.39(2) 2.41(2) 2.45(3) 2.56(4)
0.90(2)
0.90(2)
0.85(7)d 0.87(2)
1.07(4)e
NH…Mf
2.07(2)
171(2)
2.84(2)
153(2)
2.70(4)d 3.66(2)
173(2)
165(2)
172(3)
167(3)
144(5)d
126(4)e
2.30(4)
75(2)
NHMf
NH…C1'
2.06(2) 2.06(2) 2.05(3) 2.08(4)
2.07(2)
2.29(2)
2.84(2)
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NHC1g
h
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9
146(2)
0.6(3)
148(2)
1.3(3)
151(4)
1.0(4)
147(3)
2.8(3)
144.1(11) 118.1(12)
0.5(2) 3.7(2)
125(4) 118.2(11)
1.4(4) 11.8(2)
, β, i
123.0(2) 123.2(2) 124.0(2) 124.4(2) 120.97(12) 125.95(12) 124.4(2) 124.1(2)
127.0(2) 127.2(2) 126.8(2) 126.1(3) 127.36(12) 125.74(12) 125.3(2) 125.8(2)
121.0(2) 120.6(2) 120.9(2) 120.0(2) 121.99(13) 122.60(12) 122.7(2) 122.3(2)
NН…FBF3 3.67(2) 3.55(2) 3.30(3)j 3.14(4)
4.21(2)
2.19(2)
–
–
–
a
b
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Average values for 4 independent cations; Rotation angle of the aryl (pyrrolyl) substituent relatively the average
naphthalene ring plane. Estimation of the same parameter via torsion angle С7С8С1'C2' is given in brackets. c Torsion angle
HNC1aC4a (atom numbering corresponds to the IUPAC rules). d For Ha atom of NH2 group (see Figure 1). e For Hb atom of
NH2 group. f M – centroid of the phenyl (pyrrolyl) substituent; in case of 4, the M refers to the lower benzene ring. g NHC2
and NHN for compounds 4 and 5, respectively. h Torsion angle C2–C3/C6–C7. i The values of these angles are given from
top to bottom, respectively. Average value for two of four independent molecules; two others form dimer pairs due to
NH…ОН binding, in which the BF4– counterions are located outside the cations at the NН…FBF3– distances of 4.37(3) and
j
4.95(3) Å.
2
3
4
5
Figure 2. Representative solid state molecular structures of compounds 2–5 showing general
arrangement of the peri-substituents directed to the viewer (capped stick models, hydrogen atoms,
except the NH proton, and BF4 anions are ommited for clarity).
–
Obviously, the main sign of the NH…π interaction is the strict orientation of the N–H bond onto
the aromatic ring face. Ideally, this should be manifested in the rotation of the latter relative to the
naphthalene ring plane by angle  = 90° (see structure 1 in Figure 1). At the same time, the N–H bond
should lie in the plane of the naphthalene system or close to it, which can be expressed through the
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torsion angle HNC1C2 or alternatively through the angle between the planes of the naphthalene ring
and HNC1.
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7
8
According to the Cambridge Structural Database (CCDC), aromatic nuclei in the solid diphenyl
and 2,2'-binaphthyl are coplanar ( = 0°). In contrast, in 1,1'-binaphthyl  = 68.5° while information on
1,2'-binaphthyl, 1-phenyl-, 1-p-anisyl-, 1-p-hydroxyphenyl- and 1-(pyrrol-1-yl) naphthalenes in the
CCDC is absent. There is little doubt that in the last five compounds the bi-nuclear systems should be
noncoplanar due to peri-interaction with the proton in position 8. Therefore, it seems logical to count
the rotation angle  of the aryl substituent in compounds 1–5 not from the hypothetical planar structure
with  = 0°, but from the value of  in compounds 25–29. In this case, the corresponding difference,
, should better reflect the stimulus of the aromatic substituent to the NH…π interaction. Following
these considerations, we performed a DFT calculation of the angle  in molecules 25–29 for the gas
phase, and for the first three substances also for the solution in acetonitrile. The B3LYP/6-311++G**
level of theory was used, since previously for proton sponges it gave good agreement between
theoretically calculated and experimental structural characteristics.12 The obtained  values are shown
in Figure 3.
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OH
OMe



27
25
26

calc. = 60.0 (gas)

calc. = 61.7 (gas)


calc. = 59.1 (gas)
calc. = 59.1 (MeCN)

calc. = 58.9 (MeCN)

calc. = 60.4 (MeCN)

aver. = 59.5

aver. = 61.0

aver. = 59.1
PicO–
N

Me
Me
N


+
H
Me2N
29
28
30


= 90 (gas)

= 61.8 (gas)
= 49.7 (solid)
Figure 3. Compounds used for estimation of rotation angle  () when NH…π interactions are absent
(theoretically calculated values for 25–29, XRD data for 30, see ref. 7).
As can be seen, the  values for compounds 25–27 differ little for the gas phase and the solution.
Therefore, when evaluating the parameter  for them, we were guided by the average values of the
calculated rotation angle aver. Only in the case of dimethylpyrrolylnaphthalene 29 both nuclei are
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perfectly orthogonal, which reflects the strong steric repulsion of the -methyl groups and the H-8/H-2
protons. A weighty argument in favor of such repulsion is the fact that in 1-pyrrolylnaphthalene 30, for
which XRD data are available, the angle  is only near 50° (see also ESI, p. S28).7 Clearly, a sharp
difference between the latter value and 90°, like between  for 25–28 and 90o, reflects a compromise
among the steric repulsion of the two nuclei and their tendency to conjugate with each other.
The obtained  values, which, we believe, result from the tendency of the aryl nuclei to
participate in the NH…π interaction, for compounds 1–4 are 22.8, 19.6, 26.6, and 11.7°, respectively.
As for compound 5, it is preorganized for the NH…π interaction with the peri-HN+Me2 group from the
very beginning. Nevertheless, it seemed yet interesting to apply the above approach to 5 assuming that,
by analogy with 30 the angle of rotation  in reference compound 29 is also close to 50°. A purely
hypothetical value of  for 5 estimated by this way is ~38°. Thus, in any case, the 2,5-dimethyl-1-
pyrrolyl group, followed by the p-hydroxyphenyl, phenyl, p-anisyl and 2-naphthyl groups, manifests
the largest degree of NH…π interaction in the solid tetrafluoroborates 1–5. Common in biochemical
practice,2c the analysis of the N–H…M hydrogen bond linearity, estimated via the angle between the
normal to the aromatic centroid and the N–H bond, leads to a close conclusion (Figure 4). As can be
seen, for compound 5 (17°) the HB linearity is half as much as for 1–4 (31–37°). Apparently this
geometrical circumstance along with the higher π-donating ability of the pyrrolyl group in 5 recalls
with the relative contribution of tryptophan, tyrosine and phenylalanine in stabilisation of protein
structures changing in proportion 5 : 1.5 : 1.2c
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Naph
Naph
+N
H
Me2
+N
Me2
H
31.7o
30.9o
29.8o
M
M
30.3o
2
1
OMe
+N
Me2
Naph
Naph
+N
H
Me2
H
36.5o
33.8o
32.1o
45.0o
M
M
3
4
OH
Naph
Naph
N
2.07 A
Me
16.5o
N
H
H
34.9o
+N
H
Me
Me2
17.3o
31.8o
M
M
7
5
OMe
Figure 4. Schematic illustration of relative NH…π hydrogen bond linearity in compounds 1–5 and 7.
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Important structural feature of salts 1–5 is that the NH proton in their cations is hidden into a tight
hydrophobic pocket formed, on the one side, by an aryl group (a kind of specific wall), and by the
NMe2 group on the other side. In the case of 5 the NH proton is additionally shielded by the ortho-
methyl groups of the pyrrole ring. This is supported by the values of the shortest distances between the
–
chelated NH proton and the BF4 anion. Those noticeably exceed 3 Å what should prevent the NH…π
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hydrogen bond from bifurcation and therefore from distortion (Table 1). For comparison, in the
tetrafluoroborate of protonated 1,8-bis(dimethylamino)naphthalene (proton sponge), the NH…F
distance is 2.91 Å, while in the tetrafluoroborates of such compounds as 2,2'-dipyridyl and o-
phenanthroline, called pseudo-proton sponges,13 the NH…F contact falls down to 1.9–2.3 Å and the
intramolecular HB in them becomes strongly bifurcated. The tetrafluoroborate of 10-
phenylbenzo[h]quinolinium 6, for which the NH…F distance is 2.19 Å, definitely also belongs to this
–
class of compounds. Since there is no steric shielding of the NH proton in 6, the BF4 anion is able to
approach it closer and enter into the bifurcation interaction. This causes a considerable weakening of
IHB in 6 what is clearly seen in Figure 5a and the corresponding parameters given in Table 1. For the
same reason, two NH…π hydrogen bonds in the structurally related bis(tetrafluoroborate) 31 are even
more weakened (Figure 5b). Indeed, the NH…M distances in 31 are near 3.1 Å versus 2.8 Å for its
monomeric analogue 6 and 2.4 Å for salts 1–4, not to mention salt 5 (2.1 Å). Note that the base of
10,10'-dibenzo[h]quinoline was described previously14a but its bis(tetrafluoroborate) was obtained and
studied by us for the first time.14b
(a)
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5
6
7
8
9
–
2 BF4
10
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14
15
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17
18
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20
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23
24
25
26
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30
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49
50
51
52
53
54
55
56
57
58
59
60
H
+
N
+
N
H
31
(b)
Figure 5. Molecular structures of (a) salt 6 (P = 50%, short contacts between the interacting atoms are
shown by dashed lines) and (b) bis(tetrafluoroborate) of 10,10'-dibenzo[h]quinolinium monohydrate
(31) (with indication of short contacts around both the NH protons).
Although the non-protonated forms of salts 1–6 are still not structurally characterized (mainly due
to the fact that bases 15–18 and 22 are liquid at room temperature or fusible as 24), the contraction of
the N…M distance upon protonation might serve as another measure of NH… binding. There is a
single example when such estimation can be done. Thus, when going from neutral 1-dimethylamino-8-
(pyrrolyl-1)naphthalene7 to salt 5 (here, however, two C–Me groups are added, but they have little
effect on the pyrrole cycle geometry), the distance to the pyrrole centroid N…M decreases from 3.354
to 2.960 Å, that is by 12%, and the repulsive interaction of peri-substituents becomes attractive. In
general, taking into account the smallest angle alpha ( = 120.97°, Table 1) and the striking equality15
of the NH…M and NH…N distances (both 2.07 Å) in 5, the NH… interaction in this salt should be
considered the strongest in this and related series. Simultaneously, this is the first observation of the
NH…N() interaction in uncondensed pyrrole ring.
We now turn to compound 7, which contains a neutral amino group with the substantially less
acidic N–H bonds than in salts 1–6. The first thing that attracts attention in the structure of 7 (Figure 6)
is a considerable pyramidalization of the nitrogen atom (N = 338.3°) sharply contrasting with the
completely flat and coplanar with the ring NH2 group in 1-aminonaphthalene (N = 360.0°).16 The
second peculiarity of the amino group in 7 is the notable shortening of the N–H bond facing the p-
anisyl substituent (0.85 Å) if compared with the external N–H bond (1.07 Å). Apparently, this may be
due to a small interpenetration of the van der Waals spheres of the benzene ring and the internal NH2
hydrogen atom, what breaks the planarity and symmetry of the NH2 group. Indeed, the van der Waals
radius of the hydrogen atom is 1.20 Å, and the half-width of the benzene ring is 1.70 Å.17 Their sum
(2.90 Å) somewhat exceeds the NH…M distance (2.70 Å) in amine 7. At the same time, in salts 1–5,
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the NH…M contacts are markedly shorter (2.07–2.45 Å), meaning much stronger interpenetration of
the electron shells of the NH proton and the benzene (pyrrole) ring. With such characteristics, the
NH…π hydrogen bond in salts 1–5 should have a significant covalent component unlike 7 in which the
hydrogen bond is considerably weaker due to predominantly electrostatic nature. Additional signs of
this are a reduced rotation angle ( = 17°) of the p-anisyl group in 7 relative to reference compound
26, as well as a slightly lower linearity of the hydrogen bond than in salts 1–3 and 5 (Figure 4).
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Molecular structure of amine 7 with the indication of key parameters (P = 50%).
Given the higher NH-acidity of carboxamides (pKa ~14–15) compared with arylamines (pKa
~27),18 we assumed that the NH…π binding would also be possible in compound 8. However, XRD
measurements showed that crystal lattice of 8 is formed exclusively by the intermolecular amide bonds
NH…O=C (ESI, Figure S42).
Solution Structures
Based on the classical example of the CH…π hydrogen bond between chloroform and benzene, which
manifests itself in notable shielding (СH = –1.56 ppm)19 of the CHCl3 proton (Figure 7, structure
32),20,21 we reasoned that a similar effect can be used to estimate the NH…π chelation in the
compounds under study. The corresponding data on the chemical shifts, NH, and the paramagnetic
shift, NH, relative to a reference compound not bearing an aromatic substituent in the adjacent peri-
position are depicted in Table 2. As reference compounds there were taken 1-aminonaphthalene 33, 1-
acetamidonaphthalene 34 and tetrafluoroborates of dimethyl(naphth-1-yl)ammonium 35 and
benzo[h]quinolinium 36 (Figure 7). Acetonitrile served as a solvent for salts of types B and C, and
chloroform for neutral amines D and carboxamides E.
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Cl
Cl
120o
C
H
Cl
COMe
H
H
N
N
 = 0o
H
5
6
32
7
8
9
34
33

CH = 7.27 ppm (cyclohexane)
–

CH = 5.71 ppm (benzene)
BF4
Me
Me
N
Me
–
–
BF4
BF4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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50
51
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60
H
H
N
H
+
+
+
NMe2
N
NMe2
N
Me
35
36
37
38
Figure 7. Auxiliary compounds and interacting systems used in the discussion.
Table 2. Changes in the NH Proton Chemical Shifts in Compounds B–E Induced by Paramagnetic
Component of Ring Current of Aryl and Pyrrolyl Groups
–
–
BF4
BF4
H
+
H
+
R
NH2
R
N
R
NHAc
R
NMe2
D
C
E
B
Type of
compd.
R
H
No Solvent
Ref.
NH,
ppm
35 CD3CN 9.47
NH,
ppm
a
b
a
a
a
a
B
B
B
B
B
B
–
Ph
1
2
3
4
5
CD3CN 8.09
CD3CN 8.45
CD3CN 8.57
CD3CN 8.30
CD3CN 6.20
–1.38
–1.02
–0.90
–1.17
–3.27
4-MeOC6H4
4-HOC6H4
naphth-2-yl
2,5-dimethyl-
pyrrol-1-yl
pyrrol-1-yl
H
c
a
a
a
B
C
C
C
37 CD3CN 6.40
36 CD3CN 13.92
–3.07
–
Ph
6
CD3CN 12.35 –1.57
31 CD3CN 12.50 –1.42
+
H
N
–
BF4
d
a
a
a
a
e
D
D
D
D
E
E
E
H
32 CDCl3 4.04
13 CDCl3 3.72
CDCl3 3.69
14 CDCl3 3.70
34 CDCl3 7.96
CDCl3 7.03
10 CDCl3 7.19
11 CDCl3 6.97
–
Ph
–0.32
–0.35
–0.34
–
–0.93
–0.77
–0.99
4-MeOC6H4
naphth-2-yl
H
7
Ph
8
a
a
4-MeOC6H4
naphth-2-yl
E
a
b
c
d
This work. Ref. 7. Ref. 8. Spectral database of organic compounds (SDBS № 1171); Internet resource:
(http://sdbs.db.aist.go.jp/sdbs/cgi-bin/cre_index.cgi). e Ref. 9.
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From Table 2 it follows that the largest paramagnetic shifts, NH, are observed for salts 5 and 37
with 1-pyrrolyl group, 3.27 and 3.07 ppm respectively, whereas for their aryl analogues 1–4 such
values are 2.5–3 times less (0.90–1.38 ppm), and for neutral amine 7 even 0.35 ppm. It seemed
reasonable to assume that there could be some correlation between the magnitudes of NH and the
NH...M distances. To test this idea we built the corresponding plot for cations 1–6, 31, 37 having the
charge-assisted NH…π hydrogen bonds and included in it also amine 7 (Figure 8). As expected, the
points for benzo[h]quinolinium cations 6 and 31 and amine 7 (red circles) strongly dropped out of the
graph, apparently due to the bifurcation of IHB in two first salts and the absence of IHB in solution of 7
(see below). At the same time, the observed linear relationship for cations 1–5 and 37 is quite
satisfactory with the correlation coefficient R2 = 0.9682. Interestingly, that a certain correlation with R2
= 0.9535 exists for all salts, including 6 and 31, when using the chemical shift values, NH, instead of
the NH parameter (ESI, Figure S43).
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3,3
y = -0,149x + 2,5923
31
3,1
2,9
2,7
2,5
2,3
2,1
1,9
R 2
= 0,9682
6
7
4
3
2
1
37
5
0
0,5
1
1,5
2
2,5
3
3,5
(NH), ppm

Figure 8. Correlation of the (NH) values versus the XRD NH…M distances for the
tetrafluoroborates 1–5 and 37. Since for pyrrole derivative 37 diffraction measurements could not be
performed (ref. 8) the DFT gas-phase distance was used in this case.
As for amine 7, all the data indicate that, unlike the solid state, the intramolecular NH…π binding
1
is absent in its solutions. Indeed, in the H NMR spectrum of 7 in CDCl3, the NH protons give a one
two-proton signal at  3.69 ppm. Their equivalence is maintained upon cooling to –90 °C, indicating
the low barrier rotation of the amino group in the given temperature range (ESI, Figure S4). An
insignificant paramagnetic shift of the NH2 signal relative to 1-aminonaphthalene (NH = –0.35 ppm)
as well as in spectra of amines 13 and 14 can be a reflection of both different hybridization of the
nitrogen atoms in 33 and 7, and a short-term alternate staying of each NH proton in the paramagnetic
field of the adjacent aromatic ring. The absence of a stable NH…π hydrogen bond in 7 is also
confirmed by IR spectroscopy. Indeed, the bands of symmetric and antisymmetric stretching vibrations
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of the NH2 group in a solution of 7 in CCl4 (s = 3401; as = 3495 cm–1) as compared with amine 33 (s
= 3395; as = 3476 cm–1) are moved not to the red region as normally occurs at the hydrogen bonding
(including NH…π one), but to the blue one (ESI, Table S2, Figures S44 and S45).22
2
3
4
5
6
7
8
9
The situation for carboxamides 8, 10 and 11 looks ambiguously. In their 1H NMR spectra in CDCl3
a relatively small paramagnetic shift is observed for NH proton (NH = –0.77…–0.99 ppm) as
compared with 1-acetamidonaphthalene 34 (Table 2). At the same time, in the IR spectra of 8 and 10,
the NH band undergoes a strong shift to the high-frequency region of the spectrum (Table 3). In our
opinion, the IR data, indicating the absence of NH… interaction in amides 8 and 10, are more reliable.
The blue shift of the NH band, as well as increase of the СО frequency and the paramagnetic shift of
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13
14
15
16
17
18
19
20
21
22
23
24
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26
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31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
the NH signal in H NMR spectra can be interpreted as a result of the destruction of the carboxamide
associates (see ESI, Figure S42).
Table 3. IR Spectra of 1-Acetamido-8-arylnaphthalenes
(NH and С=О groups region, 0.1 M solutions in CCl4)
NH, cm–1 СО, cm–1 NH, cm–1 СО, cm–1
Compd.
8
10
34
3426
3437
3269
1701
1704
1651
+157
+169
–
+50
+53
–
NH…π Bond Energy
Finally, we wished to estimate, at least roughly, the energy of NH...π interactions in the compounds
studied. For this, salts 1–3 and 5 were selected. It should be emphasized that there are still no reliable
experimental methods for estimating the energy of intramolecular noncovalent interactions. What
concerns theoretical approaches they also differ by insufficient accuracy and various limitations. For
example, we have recently shown7 that the so-called “isodesmic” calculation method23 does not work
in the case of salts of type 1–5, and in the present work, the NBO (natural bond orbital) method24 also
failed. In this regard, we focused on the “rotational” approach,7,25 according to which the EHB energy is
defined as a difference between the total energies of two optimized structures, the close (chelated) and
open (non-chelated) one (Figure 9). To achieve the goal, we performed the DFT calculations of the
IHB energies, EHB, using the B3LYP method with the 6-311++G(d,p) basis set. The calculations were
conducted for the gas phase and acetonitrile solution. Besides, we also performed calculation of EHB
values using the Grimme's D3 dispersion correction.26 It comes from an idea that quantification of
intramolecular phenomena can be more accurate if to take into account the long-range electron
correlation (London dispersion interactions).
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F
B
F
F
R
R
F
B
F
F
F
Me
N
Me
F
Me
H
H
+
Me
+
N
1
2
3
(R = H)
(R = OMe)
(R = OH)
9
10
11
12
13
14
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19
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22
23
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F
F
B
F
F
F
B
Me
Me
F
Me
H +
F
Me
N
Me
Me
F
H
Me
Me
N
N
+
N
5
E1 (close)
E2 (open)
EHB = E1 – E2
Figure 9. Structures with close and open IHBs used for calculation of EHB values (at calculation of the
–
“naked” cations, the BF4 anion was omitted).
When considering salts like 1–3 and 5, the main drawback of the “rotational” approach is the
existence of hydrogen bonds between the anion Х– (BF4 in our case) and acidic protons, not only in
–
the close, but also in the open forms. Even more important is the fact that character of the hydrogen
bonding in both forms is essentially different. In the close forms, the NH proton is strongly shielded by
both peri-substituents, which keeps it at a considerable distance from the anion and thus minimizes the
NH...X– bifurcation interactions (see above discussion concerning solid state XRD measurements).
Instead, as it was shown for proton sponge salts, the CH...X– hydrogen bonds between the anion and
the H-atoms play a significant role since up to 40% of the positive charge is concentrated on the N-
methyl groups due to dispersion.27 According to XRD studies and the theoretical calculations, the
CH...X– interactions are also important in salts 1–3, 5 (Table 4). This is evidenced by both the location
–
–
of the BF4 anion over the N-methyl groups and the distances CH...FBF3 , which are noticeably shorter
than the sum of the van der Waals radii of the hydrogen and fluorine atoms. In fact, the situation is
–
complicated even more owing to interactions of the BF4 anion with the CH bonds of the aromatic rings
(compound 1), methoxy (2) and C–CH3 groups (5), as well as the OH proton (3).
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Table 4. General Views and the Shortest NH…F and CH…F Distances in Tetrafluoroborates of 1-
Dimethylammonio-8-arylnaphthalenes [B3LYP/6-311++G(d,p); full version of this Table with the
Grimme's D3 dispersion correction is given in ESI as Table S3]
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 (XRD)
2 (XRD)
3 (XRD)
5 (XRD)
1 (DFT)
2 (DFT)
3 (DFT)
5 (DFT)
–
Salt NH…F, Å
CH…F, Å
Position of BF4 against
peri-substituents
XRD
XRD
Calc. in XRD
Calc. in
MeCN
Calc. in
MeCN
Aside and between
both subst.
Above H+NMe2
MeCN
4.26
Above H+NMe2
Above H+NMe2
1
2
3.67
3.55
2.27
2.25; 2.35a
3.51
3.58
4.01
2.52; 2.57; 2.34; 2.35;
2.59b 4.03b
2.34; 2.39; 2.32; 2.33;
2.44d 4.03d
2.60; 2.37e 2.25; 2.25
Above H+NMe2
Above H+NMe2
3
5
3.26
(3.30)c
4.21
Aside of the both, Above H+NMe2
closer to H+NMe2
a
b
c
For ortho-hydrogen atom of the C6H5 group. For CH3O. Average value for two of four independent molecules (see
Table 1). d For OH…F. e For C–Me.
Unlike chelated forms, in the open ones the NH proton is not sterically shielded, so its bond with
the anion becomes much shorter and rather strong. As a result, the difference E = E1 – E2 characterizes
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not so much the hydrogen bond energy in the chelated cation as the difference in the energy of all
noncovalent interactions in the two forms. Obviously, this circumstance should manifest itself in an
underestimation of the EHB values and make the latter less reliable, especially for the gas-phase state.
The data in Table 5 confirm this assumption, and for salt 5, the calculation even predicts greater
stability of the open form. In addition, the sequence of salts with respect to the EHB values is not
consistent with XRD data and looks very irrational. Indeed, at the end of the row given below is salt 5,
although the 2,5-dimethyl-1-pyrrolyl group is a stronger -donor than p-hydroxyphenyl, p-anisyl, and
especially phenyl.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Calculated gas-phase hydrogen bond energies, EHB
Without Grimme’s correction: 1 > 3 > 2 > 5
With Grimme’s correction: 3 > 2 > 1 > 5
Table 5. Calculated NH…π Bond Energies in Tetrafluoroborates 1–3 and 5 [B3LYP/6-311++G(d,p)
and B3LYP-D3/6-311++G(d,p)]
–
Salt Medium
EHB, kcal mol–1
B3LYP/6- B3LYP-D3/6- B3LYP/6-
NH…FBF3 distance, Å
B3LYP-D3/6-
311++G(d,p)
Close Open
311++G(d,p) 311++G(d,p)
311++G(d,p)
Close Open
1
1
2
2
3
3
5
5
Gas phase –6.53
–4.49
–4.30 ZPE
–5.71
–5.95 ZPE
–4.96
–4.69 ZPE
–6.79
–6.81 ZPE
–5.13
–4.85 ZPE
–9.76
–9.55 ZPE
0.39
–0.16 ZPE
–6.24
1.906 1.667 2.079 1.731
4.259 1.782 4.576 1.754
1.927 1.619 2.107 1.619
3.510 1.775 2.987 1.774
1.925 1.617 2.100 1.616
3.582 1.771 3.384 1.753
2.078 1.637 2.010 1.698
4.014 1.780 3.481 1.749
–6.24 ZPEa
–8.56
MeCN
–8.53 ZPE
Gas phase –2.57
–2.48 ZPE
–7.34
–7.32 ZPE
Gas phase –2.74
–2.62 ZPE
–7.29
–7.41 ZPE
Gas phase 0.93
0.43 ZPE
–7.47
–7.84 ZPE
MeCN
MeCN
MeCN
–6.39 ZPE
a Energy values corrected for zero-point energy and taken as (Е0 + Еzpe)close – (Е0 + Еzpe)open.
In terms of the absolute values of EHB, the calculation for acetonitrile solutions turned out to be
more reliable, what can be assigned to the ionic associates and hydrogen bonds loosening, especially in
the open forms. Such calculations rank the studied compounds with regard to the NH…π hydrogen
bond strength in the following order (ZPE):
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Calculated hydrogen bond energies, EHB, in MeCN medium
Without Grimme’s correction: 1 > 5 > 3 > 2
With Grimme’s correction: 3 > 2 > 5 > 1
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The first place of salt 1 in the upper sequence is doubtful since a phenyl group is the weakest π-
donor among all. Calculations with the Grimme’s correction provide more reliable sequence (lower
line) though the third position of salt 5 is still questionable. To exemplify the manifestation of the
Grimme's dispersion correction let us consider tetrafluoroborate salt 3. Its optimized structure in MeCN
obtained with the B3LYP/6-311++G(d,p) method demonstrates only two short CH…F contacts (Table
4 and Figure 10). In contrast, the B3LYP-D3/6-311++G(d,p) approach allows the proton donor
substituent HN+Me2 to “see” the oxygen atoms of the OH and OMe groups at a longer distances,
having entered into the dispersion interaction that stabilizes the closed form. In addition, the p-
hydroxyphenyl group in 3, already as a proton donor, can stabilize this form via a long-distant OH...F
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–
contact with the BF4 anion (Figure 10). The combination of all these interactions well explains why
salts 3 and 2 come to the top when using the Grimme’s correction for acetonitrile solutions.
Figure 10. Optimized structures of salt 3 (in MeCN) obtained by B3LYP/6-311++G(d,p) (above) and
B3LYP-D3/6-311++G(d,p) (below) methods.
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To rule out the severe complications caused by anion-cation interactions on the NH…π hydrogen
bonds, the theoretical calculations of the “naked” cations of salts 1–3 and 5 were performed. From the
results obtained (Table 6) it follows that their ranking in terms of the ЕНВ values (ZPE) in the gas phase
and acetonitrile solution is exactly the same and, what is even more important, closely consistent with
the relative electron donating ability of the aryl and pyrrolyl nuclei: gas phase, 5 > 2 > 3 > 1; MeCN
solution, 5 > 2 > 3 > 1.
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Table 6. Comparison of NH…π bond energies in "naked" cations calculated by B3LYP/6-311++G(d,p)
and B3LYP-D3/6-311++G(d,p)*
Cation
Medium EHB, kcal mol–1 EHB, kcal mol–1*
1
1
2
2
3
3
5
5
Gas phase –13.69
–13.77 ZPE
–11.73
–11.83 ZPE
Gas phase –14.10
–14.28 ZPE
–12.03
–12.28 ZPE
Gas phase –13.93
–14.10 ZPE
–11.95
–12.19 ZPE
Gas phase –14.98
–15.34 ZPE
–12.07
–12.29 ZPE
–13.19
–13.48 ZPE
–11.10
–11.24 ZPE
–13.62
–13.90 ZPE
–11.41
–11.52 ZPE
–13.43
–13.70 ZPE
–11.31
–11.55 ZPE
–15.28
–15.55 ZPE
–11.95
MeCN
MeCN
MeCN
MeCN
–12.28 ZPE
As expected, the EHB values in the “naked” cations in acetonitrile are significantly larger than in
tetrafluoroborate salts. This fact seems to be important as it underlines how large can be the influence
of the environment on the NH…π binding in living tissues. One can think that when the NH…π
binding is realized in a hydrophobic environment, charged proton donors such as ammonium groups
behave similar to “naked” cations. In such a case, according to our calculations, the energy of the
NH…π interactions can reach 12–15 kcal mol–1, while in the polar environment (water and various
anions) it decreases by at least 4–5 kcal mol–1. As can be seen from Table 6 (right column), in the case
of “naked” cations, the inclusion of the dispersion factor does not bring any changes to their
arrangement in terms of ЕНВ values (5 > 2 > 3 > 1). The only difference is a slight decrease in the
hydrogen bond strength (by 0.2–0.7 kcal mol–1) for cations 1–3 (a slight increase was obtained only for
cation 5 in the gas phase).
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Conclusions
On the whole, in order to simulate NH…π interactions involved in the stabilization of the secondary
and tertiary structure of proteins, the molecular structures of nine representatives of peri-disubstituted
naphthalenes were examined in the solid state and MeCN solution. According to both the XRD and 1H
NMR measurements, the -donor activity of the studied substituents decreases in the following
sequence: 2,5-dimethyl-1-pyrrolyl > 4-hydroxyphenyl > phenyl > p-anisyl > 2-naphthyl, while the
largest proton donor ability is characterized by the Me2NH+ group, which significantly exceeds those of
the neutral NH2 group and pyridinium N–H+ bond. No NH...π interaction has been observed in 1-
acetamido-8-phenylnapathalene. DFT calculations of the energy of the NH... hydrogen bond, ЕНВ, in
tetrafluoroborates 1–3 and 5 revealed a strong distorting effect caused by the counterion. At the same
time, the ЕНВ values for "naked" cations, lying between 13.5–15.5 (in the gas phase) and 11.2–12.3
kcal mol–1 (for MeCN solution) look quite reasonable, agreeing with the XRD and NMR sequences.
The dominant position of the 2,5-dimethyl-1-pyrrolyl group reflects the ideal pre-organization of the
latter for NH... interaction, the highest linearity of the NH...π bond and the record short NH…N and
NH...centroid distances (2.07 Å).
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Experimental Section
1
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General. Solution H and C NMR experiments were performed with a 600 MHz, 300 MHz or 250
MHz spectrometers. Mass spectra were obtained from Finnigan MAT INCOS 50 instrument (electron
impact, 70 eV). The HR-ESI mass-spectra were obtained on a BRUKER maXis spectrometer equipped
with an electrospray ionization (ESI) source; methanol was used as the solvent (Chemical Analysis and
Materials Research Centre, St. Petersburg State University). The instrument was operated in positive
mode using an m/z range of 50–1200. The capillary voltage of the ion source was set at 4000 V. The
nebulizer gas pressure was 1.0 bar, and the drying gas flow was set to 4.0 L/min. IR spectra were
recorded on an FT FSM-1202 spectrometer. All reagents and starting materials were obtained from
commercial sources and used without further purification. Tetrafluoroborate 1 and N,N-dimethyl-8-
phenylnaphthalen-1-amine (13) were synthesized as described previously.7
N-(8-(4-Methoxyphenyl)naphthalene-1-yl)acetamide (10): A solution of Na2CO3·10H2O (2.05 g, 7
mmol) in water (10 mL) was added under argon to a solution of N-(8-bromonaphthalen-1-yl)acetamide
(9)9 (1.27 g, 4.8 mmol), 4-methoxyphenylboronic acid (0.9 g, 6 mmol), palladium acetate (23 mg, 0.1
mmol) and triphenylphosphane (75 mg, 0.3 mmol) in propanol (25 mL). The resulting mixture was
heated on a silicone oil bath at reflux for 6 h. The solvent was evaporated in vacuum and water was
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added to the residue. The mixture was extracted with CHCl3 and the crude product obtained after
solvent evaporation was purified by column chromatography (Al2O3/CHCl3) (Rf 0.6) to give 10 (0.76 g;
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54%) as beige crystals; m.p. 141–142 °C. Н NMR (250 MHz, CDCl3): δ = 1.51 (s, 3H, Ac), 3.87 (s,
7
8
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3H, OMe), 7.02 (d, J = 8.6 Hz, 2H), 7.19 (s, 1H, NH), 7.25 (s, J = 6.2 Hz, 1H), 7.34 (d, J = 8.5 Hz,
2H), 7.40–7.50 (m, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H).
13С{1H} NMR (62.9 MHz, CDCl3): δ = 24.3, 55.6, 114.1, 121.3, 124.1, 124.7, 125.8, 125.9, 128.9,
130.1, 130.2, 133.2, 135.3, 135.5, 136.4, 159.3, 167.8 ppm. IR (nujol, cm–1): 3246 (NH), 1700 (C=O).
MS: m/z (%) = 291 (100) [M]+, 249 (99), 234 (35), 217 (26), 204 (78). Anal. calcd: C 78.33, H 5.88, N
4.81; C19H17NO2; found: C 78.53, H 5.69, N 4.60.
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8-(4-Methoxyphenyl)naphthalene-1-amine (7): A mixture of compound 10 (690 mg, 2.4 mmol),
ethanol (2.5 mL) and conc. hydrochloric acid (1.2 mL) was heated on a silicone oil bath at reflux for 3
h. After evaporation of the solvents, the residue was stirred with Et2O (3 mL) and a solution of KOH
(300 mg) in water (2 mL) until the solid was completely dissolved. The organic layer was separated
and the aqueous layer was extracted with Et2O (3 x 2 mL). The combined organic layers were
evaporated to afford 7 (568 mg, 96%) as beige crystals; m.p. 98–99 C. 1Н NMR (250 MHz, CDCl3): δ
= 3.52 (s, 2H, NH2), 3.87 (s, 3H, OMe), 6.63 (dd, J = 7.1, 1.5 Hz, 1H), 6.96–6.99 (m, 2H), 7.15 (dd, J =
7.0, 1.2 Hz, 1H), 7.27–7.41 (m, 5H), 7.77 (dd, J = 8.2, 1.1 Hz, 1H). 13С{1H} NMR (62.9 MHz, CDCl3):
δ = 55.4, 111.2, 113.5, 119.0, 121.0, 124.7, 126.6, 128.5, 128.6, 130.4, 135.7, 136.0, 138.0, 143.9,
159.1 ppm. IR (nujol, cm–1): 3456, 3357 (NH2). MS: m/z (%) = 249 (100) [M]+, 234 (30), 217 (16), 204
(43). Anal. calcd: C 81.90, H 6.06, N 5.62; C17H15NO; found: C 82.13, H 6.29, N 5.33.
.
N-(1,2'-Binaphthyl-8-yl)acetamide (11): A solution of Na2CO3 10H2O (130 mg, 0.45 mmol) in water
(1 mL) was added under argon to a solution of N-(8-bromonaphthalen-1-yl)acetamide (9) (100 mg,
0.38 mmol), 2-naphthylboronic acid (65 mg, 0.38 mmol), palladium acetate (1 mg, 0.004 mmol) and
triphenylphosphane (4 mg, 0.015 mmol) in propanol (3 mL). The resulting mixture was heated on a
silicone oil bath at reflux for 6 h. The solvent was evaporated in vacuum and water was added to the
residue. The mixture was extracted with CHCl3 and the crude product obtained after solvent
evaporation was purified by column chromatography (Al2O3/CHCl3) to obtain 11 (Rf 0.6) (77 mg;
65%) as a yellow oil. 1Н NMR (250 MHz, CDCl3): δ = 1.03 (s, 3H, Ac), 6.97 (s, 1Н, NH), 7.36 (dd, J =
6.9, 0.9 Hz, 1Н), 7.47–7.57 (m, 5Н), 7.76 (d, J = 8.0 Hz, 1Н), 7.84–7.99 (m, 6Н). 13С{1H} NMR
(CDCl3, 62.9 MHz): δ = 23.7, 122.5, 124.6, 124.8, 126.1, 126.3, 126.7, 127.2, 127.5, 127.8, 128.0,
128.1, 129.2, 130.1, 132.5, 133.0, 133.2, 135.4, 136.9, 141.0, 167.9. HRMS m/z: calc. for C22H17NO+H
312.1383, found 312.1380.
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1,2'-Binaphthyl-8-amine (14): A mixture of compound 11 (77 mg, 0.25 mmol), ethanol (2.5 mL) and
conc. hydrochloric acid (0.15 mL) was heated on a silicone oil bath at reflux for 4 h. After evaporation
of the solvents, the residue was stirred with CH2Cl2 (1 mL) and 0.1 M KOH (1 mL) until the solid was
completely dissolved. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3
x 2 mL). The combined organic layers were evaporated to afford 14 (54 mg, 80%) as a dark green oil.
1Н NMR (250 MHz, CDCl3): δ = 3.70 (s, 2H, NH2), 6.62 (dd, J = 7.1, 1.5 Hz, 1Н), 7.21–7.24 (m, 1Н),
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7.26–7.44 (m, 3Н), 7.52–7.60 (m, 3Н), 7.81 (dd, J = 8.2, 1.1 Hz, 1Н), 7.85–7.93 (m, 4Н). С{1H}
NMR (CDCl3, 62.9 MHz): δ =111.2, 119.0, 120.8, 124.6, 126.3, 126.6, 126.7, 127.5, 127.8, 128.0,
128.2, 128.6, 128.8, 132.5, 132.9, 136.0, 138.3, 141.2, 143.9. HRMS m/z: calc. for C20H15N+H
270.1277, found 270.1274.
8-(4-Methoxyphenyl)-N,N-dimethylnaphthalen-1-amine (16): A mixture of compound 7 (100 mg,
0.4 mmol), dimethyl sulfate (1.3 mL, 14 mmol), Na2CO3·10H2O (1.14 g, 4 mmol) and water (0.5 mL)
was stirred at the ambient temperature for 20 h. Then the mixture was diluted with water (3 mL),
extracted with CH2Cl2 (3 x 2 mL), concentrated and purified by column chromatography
(Al2O3/CH2Cl2) to afford 16 (Rf 0.9) (73 mg; 66%) as a light-brown oil. 1Н NMR (CDCl3, 250 MHz): δ
= 2.26 (s, 6H, NMe2), 3.86 (s, 3H, OMe), 6.81–6.87 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 7.29–7.47 (m,
5H), 7.54 (dd, J = 8.1, 1.1 Hz, 1Н), 7.77 (dd, J = 8.1, 1.3 Hz, 1H). 13С{1H} NMR (CDCl3, 62.9 MHz):
δ = 43.4, 55.3, 111.4, 115.1, 123.0, 125.0, 125.6, 125.7, 127.9, 129.6, 130.3, 136.5, 136.6, 139.3, 150.9,
157.9 ppm. MS: m/z (%) = 277 (62) [M]+, 262 (8), 245 (14), 234 (8), 218 (9), 203 (8), 189 (12), 57
(100), 43 (99). Anal. calcd: C 82.28, H 6.90, N 5.05; C19H19NO; found: C 82.47, H 7.19, N 5.31.
4-(8-(Dimethylamino)naphthalen-1-yl)phenol (17): A solution of compound 16 (100 mg, 0.36 mmol)
in conc. aqueous HBr (5 mL) was heated on a silicone oil bath at reflux for 1 h, then neutralized with
ammonia and extracted with CH2Cl2 (3 x 5 mL). The resulting product was purified by column
chromatography (Al2O3/CH2Cl2) to collect 17 (Rf 0.4) (40 mg, 42%) as a grey oil. 1Н NMR (250 MHz,
CDCl3): δ = 2.26 (s, 6H, NMe2), 5.29 (d, J = 1.5 Hz, 1Н), 6.79 (d, J = 8.5 Hz, 2Н), 7.03 (d, J = 6.7 Hz,
1Н), 7.23–7.31 (m, 3Н), 7.36–7.45 (m, 2Н), 7.54 (d, J = 7.4 Hz, 1Н), 7.77 (dd, J = 8.0, 1.0 Hz, 1Н).
13С{1H} NMR (CDCl3, 62.9 MHz): δ = 43.4, 113.0, 115.1, 122.9, 125.0, 125.6, 125.7, 128.0, 129.5,
130.5, 136.6, 136.7, 139.3, 150.9, 153.9. HRMS m/z: calc. for C18H17NO 264.1383, found 264.1384. IR
(CCl4, cm–1): 3611 (ОН).
N,N-Dimethyl-1,2'-binaphthyl-8-amine (18): A mixture of compound 14 (53 mg, 0.2 mmol),
dimethyl sulfate (0.66 mL, 7 mmol), Na2CO3·10H2O (572 mg, 2 mmol) and water (1 mL) was stirred at
room temperature for 24 h. The crude mixture was neutralized with ammonia and extracted with
CH2Cl2 (3 x 2 mL). Purification by column chromatography (Al2O3/CH2Cl2) afforded amine 18 (Rf 0.9)
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(47 mg; 80%) as a brown oil. 1Н NMR (250 MHz, CDCl3): δ = 1.99 (br. s, 3H, N-Mea), 2.38 (br. s, 3H,
N-Meb), 7.08 (d, 1Н), 7.42–7.49 (m, 6Н), 7.60 (d, J = 8.0 Hz, 1Н), 7.66 (d, J = 8.5 Hz, 1Н), 7.82–7.89
(m, 3Н), 7.95 (s, 1Н). 13С{1H} NMR (CDCl3, 62.9 MHz): δ = 115.8, 123.4, 124.0, 125.2, 125.3, 125.3,
125.5, 125.9, 126.3, 127.4, 127.9, 128.4, 129.9, 130.0, 132.1, 132.9, 136.5, 139.6, 142.5, 151.1. HRMS
m/z: calc. for C20H15N+H 298.1590, found 298.1590.
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N-Methyl-N-(8-phenylnaphthalen-1-yl)acetamide (19): Potassium hydroxide (112 mg, 2 mmol) was
stirred in dimethyl sulfoxide (3 mL) until dissolution, then N-(8-phenylnaphthalen-1-yl)acetamide (8)8
(464 mg, 1,8 mmol) and methyl iodide (0.4 mL, 6.4 mmol) were added and the reaction mixture was
stirred at room temperature for 24 h. The resulting product was separated on addition of water (50 mL),
filtered off and purified by column chromatography (Al2O3/CH2Cl2) to give colorless crystals of 19
(170 mg, 35%). M.p. 170–170.2 C; 1Н NMR (250 MHz, CDCl3): δ = 1.50 (s, 0.5H, CH3), 1.70 (s, 3H,
CH3), 2.63 (s, 3H, CH3), 2.78 (s, 0.5H, CH3), 7.18–7.20 (m, 1.7Н), 7.26–7.29 (m, 1.2H), 7.33–7.38 (m,
13
5H), 7.45–7.55 (m, 2.6H), 7.85–7.94 (m, 2.3Н). С{1H} NMR (CDCl3, 62.9 MHz): δ = 22.0, 23.1,
37.8, 40.5, 125.1, 125.6, 125.8, 125.9, 126.5, 127.0, 127.1, 127.5, 127.6, 127.8, 128.1, 128.3, 128.4,
128.9, 129.2, 129.6, 130.7, 131.3, 136.0, 138.4, 140.9, 142.6, 170.6, 171.6 ppm. MS: m/z (%) = 275
(45) [M]+, 233 (40), 216 (56), 202 (15), 189 (11), 56 (100), 43 (74). Anal. calcd: C 82.88, H 6.22, N
5.09. C19H17NO; found: C 83.09, H 6.02, N 5.30.
N-(8-(4-Methoxyphenyl)naphthalen-1-yl)-N-methylacetamide (20): Potassium hydroxide (100 mg,
1.8 mmol) was stirred in dimethyl sulfoxide (3 mL) until dissolution, then N-(8-(4-
methoxyphenyl)naphthalen-1-yl)acetamide (10) (450 mg, 1.55 mmol) and methyl iodide (0.5 mL, 8
mmol) were added and the reaction mixture was stirred at room temperature for 24 h. The resulting
product was separated on addition of water (50 mL), filtered off and purified by column
chromatography (Al2O3/CH2Cl2) to afford 20 (238 mg, 50%) as colorless crystals. M.p. 191–193.5 C;
1Н NMR (250 MHz, CDCl3): δ = 1.59 (s, 0.6H, CH3), 1.70 (s, 3H, CH3), 2.64 (s, 3H, CH3), 2.77 (s,
0.6H, CH3), 3.82 (s, 3H, OCH3), 3.83 (s, 0.6H, OCH3), 6.87–6.90 (m, 2.2H), 7.12–7.19 (m, 3H), 7.22–
7.25 (m, 0.4H), 7.28–7.32 (m, 1.4H), 7.40–7.52 (m 2.4H), 7.82–7.92 (m, 2.4H). 13С{1H} NMR (CDCl3,
62.9 MHz): δ = 22.2, 23.0, 37.8, 40.4, 55.3, 55.4, 112.5, 112.8, 112.9, 113.2, 125.1, 125.6, 125.7,
125.8, 127.5, 128.4, 128.8, 128.8, 129.0, 129.1, 129.5, 129.6, 130.4, 131.0, 131.7, 134.9, 135.7, 136.0,
137.6, 138.2, 140.5, 141.0, 158.4, 158.6, 170.5, 171.5 ppm. MS: m/z (%) = 305 (94) [M]+, 291 (16),
263 (40), 248 (35), 231 (17), 216 (30), 204 (57), 189 (24), 56 (89), 43 (100). Anal. calcd: C 78.66, H
6.27, N 4.59; C20H19NO2; found: C 78.29, H 6.47, N 4.29.
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8-(2,5-Dimethyl-1H-pyrrol-1-yl)-N,N-dimethylnaphthalen-1-amine (24). A mixture of N,N-
dimethylnaphthalene-1,8-diamine (23) (44 mg, 0.24 mmol) and 2,5-hexanedione (70 µL, 0.6 mmol)
was heated on a silicone oil bath at 145–150 C for 3 h. Then the reaction mixture was cooled down to
the ambient temperature, diluted with CH2Cl2 (2 mL) and subjected to column chromatography
(Al2O3/CHCl3–hexane, 1:3) to afford compound 24 (Rf 0.4) (20 mg; 32%) as light brown crystals with
m.p. 41–43 C. 1Н NMR (CD3CN, 600 MHz): δ = 1.89 (s, 6H), 2.40 (s, 6H), 5.79 (s, 2H), 7.15 (dd, J =
7.24, 1.33 Hz, 1H), 7.20 (dd, J = 7.47, 1.15 Hz, 1H), 7.43–7.45 (m, 1H), 7.51 (dd, J = 8.17, 7.25 Hz,
1H), 8.64–8.65 (m, 1H), 7.91–7.92 (m, 1H). 13С{1H} NMR (CD3CN, 150 MHz): δ = 12.78, 44.89,
105.39, 117.31, 124.14, 125.49, 126.29, 126.61, 129.03, 129.42, 129.78, 135.09, 137.47, 151.52 ppm.
HRMS m/z: calc. for C18H20N2+H 256.1699, found 265.1704.
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General Procedure for Preparation of Proton Complexes With Tetrafluoroboric Acid (Hydrogen
Tetrafluoroborates) (2–6, 31). These were prepared by mixing equimolar amounts of appropriate
bases and 40% aqueous HBF4 in a minimum volume of EtOAc followed by 3-fold dilution with Et2O.
The residue thus formed was washed with Et2O and vacuum-dried to give the desired salts in high
yield.
8-(4-Methoxyphenyl)-N,N-dimethylnaphthalen-1-aminium Tetrafluoroborate (2). Obtained from
compound 16 (92 mg, 0.33 mmol) according to general procedure. Colorless crystals of 2 (89 mg,
1
73%) with m.p. 127–129 C. Н NMR (CD3CN, 300 MHz): δ = 3.08 (d, J = 5.3 Hz, 6H, NMe2), 3.97
(s, 3H, OMe), 7.28 (d, J = 8.7 Hz, 2H), 7.52 (dd, J = 7.1, 1.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.71–
7.80 (m, 2H), 7.93 (d, J = 7.3 Hz, 1H), 8.16 (dd, J = 8.3, 0.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.45 (s,
1H, NH). 13С{1H} NMR (CD3CN, 75.5 MHz): δ = 47.9, 55.9, 116.7, 121.0, 123.2, 126.5, 127.3, 130.2,
130.8, 131.0, 132.7, 133.0, 134.4, 135.9, 139.7, 162.1. Anal. calcd: C 62.49, H 5.52, N 3.84;
C19H20BF4NO; found: C 62.72, H 5.28, N 3.52.
8-(4-Hydroxyphenyl)-N,N-dimethylnaphthalen-1-aminium Tetrafluoroborate (3): Obtained from
compound 17 (26 mg, 0.1 mmol) according to general procedure. Colorless crystals of 3 (29 mg, 83%)
1
with m.p. 169–170 C. Н NMR (CD3CN, 300 MHz): δ = 3.08 (d, J = 5.3 Hz, 6H, NMe2), 7.15–7.18
(m, 2H), 7.50–7.54 (m, 3H), 7.70–7.79 (m, 3H), 7.91 (dd, J = 7.7, 0.8 Hz, 1H), 8.15 (dd, J = 8.3, 1.1
Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.57 (br. s, 1H, NH). 13С{1H} NMR (CD3CN, 75.5 MHz): δ = 47.8,
120.9, 123.1, 126.5, 127.3, 129.9, 130.1, 131.1, 132.7, 133.0, 134.5, 135.8, 139.6, 159.7. Anal. calcd: C
61.57, H 5.17, N 3.99; C18H18BF4NO; found: C 61.80, H 5.32, N 3.70.
N,N-Dimethyl-1,2'-binaphthyl-8-aminium Tetrafluoroborate (4): Obtained from compound 18 (30
mg, 0.1 mmol) according to general procedure. Light-brown crystals of 4 (34 mg, 88%) with m.p. 194–
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195 C. 1Н NMR (CD3CN, 250 MHz): δ = 3.00 (d, J = 5.2 Hz, 3H, N-Mea), 3.07 (d, J = 5.2 Hz, 3H, N-
Meb), 7.66 (dd, J = 7.1, 1.1 Hz, 1H), 7.73–7.86 (m, 5H), 7.98 (d, J = 7.6 Hz, 1H), 8.08–8.11 (m, 1H),
8.15–8.19 (m, 1H), 8.23–8.34 (m, 4H). 13С{1H} NMR (CD3CN, 62.9 MHz): δ = 47.4, 47.4, 120.6,
122.3, 125.7, 126.1, 126.8, 128.0, 128.1, 128.3, 128.3, 128.6, 129.9, 131.1, 132.3, 132.8, 133.6, 134.0,
134.1, 135.4, 136.3, 139.0 ppm. Anal. calcd: C 68.60, H 5.23, N 3.64; C22H20BF4N; found: C 68.41, H
5.55, N 3.36.
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8-(2,5-Dimethyl-1H-pyrrol-1-yl)-N,N-dimethylnaphthalen-1-aminium Tetrafluoroborate (5):
Obtained from compound 25 (23 mg, 0.09 mmol) according to general procedure. Brown crystals of 5
(27 mg, 87%) with m.p. 168–171C. 1Н NMR (CD3CN, 600 MHz): δ = 1.96 (s, 6H, 2C-Me), 3.16 (d, J
= 5.09 Hz, 6H, NMe2), 6.21 (br. s, 1H, NH), 6.30 (s, 2H), 7.71 (dd, J = 7.26, 1.30 Hz, 1H), 7.78–7.84
(m, 2H), 8.01 (dd, J = 7.82, 1.01 Hz, 1H), 8.27 (ddd, J = 8.35, 1.29, 0.43 Hz, 1H), 7.29 (dd, J = 8.22,
13
1.04 Hz, 1H). С{1H} NMR (CD3CN, 150 MHz): δ = 11.87, 50.45, 110.28, 122.29, 122.39, 127.07,
127.67, 129.93, 130.32, 131.69, 131.83, 132.84, 136.53, 138.25 ppm. Anal. calcd: C 61.39, H 6.01, N
7.95; C18H21BF4N2; found: C 61.11, H 6.25, N 8.09.
10-Phenylbenzo[h]quinolinium Tetrafluoroborate (6): Obtained from compound 22 (33 mg, 0.13
mmol) according to general procedure. Yellowish crystals of 6 (36 mg, 82%) with m.p. 216–218 C. 1Н
NMR (CD3CN, 300 MHz): δ = 7.64–7.66 (m, 2H), 7.72–7.75 (m, 3H), 7.77 (dd, J = 7.4, 1.3 Hz, 1H),
8.02–8.12 (m, 2H), 8.17 (d, J = 8.9 Hz, 1H), 8.27 (dd, J = 8.1, 1.2 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H),
13
8.60 (dd, J = 5.7, 1.6 Hz, 1H), 9.18 (dd, J = 8.2, 1.6 Hz, 1H), 12.35 (br. s, 1H, NH). С{1H} NMR
(CD3CN, 75.5 MHz): δ = 119.7, 123.0, 125.1, 129.7, 129.8, 130.1, 130.3, 130.6, 131.4, 132.3, 133.6,
136.5, 137.4, 138.7, 139.2, 141.2, 147.6. Anal. calcd: C 66.51, H 4.11, N 4.08; C19H14BF4N; found: C
66.43, H 4.09, N 3.98.
10,10'-Dibenzo[h]quinolinium
Bis(tetrafluoroborate)
(31):
Obtained
from
10,10'-
dibenzo[h]quinoline14 (44 mg, 0.12 mmol) according to general procedure. Yellowish crystals of 31 (52
mg, 81%) not melting up to 290 C. 1Н NMR (CD3CN, 300 MHz): δ = 7.75 (dd, J = 7.5, 1.3 Hz, 2H),
8.05 (t, J = 7.5 Hz, 2H), 8.11 (dd, J = 8.4, 5.7 Hz, 2H), 8.33 (d, J = 8.9 Hz, 2H), 8.51–8.54 (m, 4H),
8.57 (dd, J = 5.7, 1.5 Hz, 2H), 9.25 (dd, J = 8.4, 1.5 Hz, 2H), 12.50 (very br. s, 2H, NH). Anal. calcd: C
58.70, H 3.41, N 5.27; C26H18B2F8N2; found: C 58.64, H 3.52, N 5.39.
Crystal Structure Determination. XRD measurements were conducted with Bruker APEX-II CCD
diffractometer and four-circle diffractometer SuperNova, Single source at offset/far, HyPix3000. The
structures were solved by direct methods and refined by the full-matrix least-squares against F2 in
anisotropic (for non-hydrogen atoms) approximation. All hydrogen atoms were placed in geometrically
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calculated positions and were refined in isotropic approximation in the riding model with the Uiso(H)
parameters equal to n·Ueq(Ci) (n = 1.2 for CH and CH2 groups and n = 1.5 for CH3 groups), where
U(Ci) are respectively the equivalent thermal parameters of the atoms to which corresponding H atoms
are bonded. The H(N) and H(O) hydrogen atoms were found in the difference Fourier synthesis and
refined in isotropic approximation. Atomic coordinates, bond lengths, bond angles and thermal
parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC).
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CCDC 1978186 (for 2, from MeCN), 1978191 (for 3, from MeCN), 1978190 (for 4, from
CH2Cl2/Et2O), 1978193 (for 5, from MeCN/Et2O), 1978192 (for 6, from MeCN), 1978189 (for 7, from
MeOH), 1978187 (for 8, from MeCN) and 1978188 (for 31, from CH2Cl2/acetone) contain the
supplementary crystallographic data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Theoretical Calculations. Quantum-mechanical calculations using the B3LYP functional (DFT, the
three-parameter exchange hybrid functional of Becke,28 and gradient-corrected correlation functional of
Lee, Yang, and Parr29) with the 6-311++G(d,p) basis set30 were performed for the full geometry
optimizations with the GAUSSIAN 16 program.31 The associated force constants were calculated at the
same level to evaluate harmonic frequencies and their zero-point energy (ZPE) corrections. The atom
pair-wise correction method (DFT-D3) was also used.32 Solvent effects were taken into account with
the polarizable continuum model (PCM).33–35
Supporting Information
XRD data, spectral data, additional comments and computational details (PDF). The Supporting
Information (ESI) is available free of charge on the ACS Publications website at DOI: ...
Conflicts of Interest
There are no conflicts of interest to declare.
Acknowledgements
This work was supported by the Russian Foundation for Basic Research (projects No 17-03-00035 and
No 20-03-00112). XRD studies were performed by Drs. Kyrill Y. Suponitsky (A. N. Nesmeyanov
Institute of Organoelement Compounds, Moscow) and Olesya V. Khoroshilova (Center for X-Ray
Diffraction Studies, St. Petersburg State University Research Park). We also thank Drs. Anna V.
Tkachuk and Oleg N. Burov (Scientific and Educational Laboratory of Resonance Spectroscopy,
Department of Natural and High Molecular Compounds Chemistry, Southern Federal University) for
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NMR measurements. The authors gratefully acknowledge the Wroclaw Centre for Networking and
Supercomputing (WCSS) for computational facilities.
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