Conformational analysis of N→BH3, N→BF3, and N-CH3 + complexes with ibuprofen-derivative amides

Article abstract of DOI:10.1002/hc.21368

The synthesis and structural characterization of novel amine-borane adducts of ibuprofen derivatives are presented. The changes of the electron density on the carbonyl and pyridine ring after formation of N→BH₃, N→BF₃, and N-CH₃ ⁺ have been confirmed by ¹H, ¹¹B, ¹³C, and ¹⁹F NMR, further supported by homonuclear and heteronuclear correlations. Moreover, electrostatic interactions —H⁺···^?F and the nonclassical H⁺···^?H— were identified by NMR spectra. The analysis of the resulting molecular structures offered insights on the 2-aminopyridine N→B adducts. The N→BH₃ adduct formed a single molecular arrangement, both in C₆D₆ and CDCl₃. The same behavior was observed for the N→BF₃ adduct in CDCl₃. However, two conformers of this adduct were detected in C₆D₆. All adduct geometries were corroborated by density functional theory computational calculations.

Full text of DOI:10.1002/hc.21368

Received: 14 June 2016
DOI: 10.1002/hc.21368
Revised: 29 December 2016
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R E S E A R C H A R T I C L E
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Conformational analysis of N→BH3, N→BF3, and N-CH3
complexes with ibuprofen-derivative amides
Maria M. Romero-Chávez
Kayim Pineda-Urbina
Nancy E. Magaña-
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Vergara
Rubén Vázquez-Cárdenas
Zeferino Gómez-Sandoval Ángel
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Ramos-Organillo
Facultad de Ciencias Químicas, Universidad
de Colima, Coquimatlán, Colima, Mexico
Abstract
The synthesis and structural characterization of novel amine-borane adducts of ibu-
profen derivatives are presented. The changes of the electron density on the carbonyl
and pyridine ring after formation of N→BH3, N→BF3, and N-CH3+ have been con-
firmed by 1H, 11B, 13C, and 19F NMR, further supported by homonuclear and hetero-
nuclear correlations. Moreover, electrostatic interactions —H+···−F and the
nonclassical H+···−H— were identified by NMR spectra. The analysis of the result-
ing molecular structures offered insights on the 2-aminopyridine N→B adducts. The
N→BH3 adduct formed a single molecular arrangement, both in C6D6 and CDCl3.
The same behavior was observed for the N→BF3 adduct in CDCl3. However, two
conformers of this adduct were detected in C6D6. All adduct geometries were cor-
roborated by density functional theory computational calculations.
Correspondence
Ángel Ramos-Organillo, Facultad de
Ciencias Químicas, Universidad de Colima,
Coquimatlán, Colima, Mexico.
Emails: mariaromerochavez@ucol.mx;
aaramos@ucol.mx
Funding information
CONACYT-México, Grant/Award Number:
#130381 and #226165
adduct and its bond strength, both of which are influenced
by the functionalization of the boron and nitrogen atoms.[11]
1
INTRODUCTION
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Boron’s chemistry has been of interest to the scientific com-
munity due to its ability to form homonuclear bonds and
coordinate to electron-rich atoms, for example, nitrogen, ox-
ygen, sulfur, and phosphorus.[1,2] Organoboron compounds
are characterized by hydroxyl-boron and amine-boron inter-
actions and are important in many biological processes, for
example, calcium and insulin metabolism, growth and main-
tenance of bones, and some cell signaling mechanisms.[3–10]
Also, these compounds have been applied as reagents in
organometallic and supramolecular chemistry,[11] and as
polymer precursors,[12] reducing agents,[13] catalysts,[14,15] lu-
minescent materials,[16] and hydrogen storage.[17,18]
Boron’s interactions with the elements of group 15 are
classic examples of reactions between Lewis acids and bases.
The vacant p orbital, on the boron atom, is a strong p-electron
acceptor. For example, the N→B interaction shows some ad-
vantages over a C-C bond, like the reversibility of the formed
Differences between N→B adducts and N-C bonds have
also been studied on a range of structures with dithiazinane,
ethanolamine, imine, and imidazole derivatives, where the
electronic properties of nitrogen atom are affected by the pos-
sibility to share its free electron pair.[19,20] This lone electron
pair gives way to discuss an isolobal analogy, which has been
observed in amino-aluminum and amino-boron complexes
before.[21]
Aminopyridines are systems with two nitrogen atoms
with sp2 and sp3 hybridization, where the amine group makes
the pyridine nitrogen more basic than a pyridine’s nitrogen.
Their chemical reactivity depends on the pyridine nitrogen
position with respect to the amine group.[22] Aminopyridines
coupled to ibuprofen have been studied for their participation
in the process of neutrophil chemotaxis, where the amide de-
rivatives of 2-aminopyridine show a better activity compared
to those derived from 3- and 4-aminopyridine.[23]
Dissolved molecular systems’ intramolecular and inter-
molecular interactions are affected by the solvent’s polarity;
polar solvents tend to favor electrostatic interactions, while
Contract grant sponsor: CONACYT-México.
Contract grant number: #130381, #226165.
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Heteroatom Chemistry. 2017;e21368.
https://doi.org/10.1002/hc.21368
wileyonlinelibrary.com/journal/hc
© 2017 Wiley Periodicals, Inc.
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ROMERO-CHÁVEZ Et al.
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nonpolar solvents have a weakening effect on Van der Waals
interactions. Besides any interactions with the medium,
amine-borane adducts exhibit other noncovalent interactions,
like N-Hδ+…−δH-B, which underscore their binding with
biomolecules. Furthermore, these hydride-proton interac-
tions can benefit the structure stability.[24–26]
This work reports the synthesis and structural analysis of
aminopyridines derived from a racemic mixture of ibuprofen,
as well as the formation of N→B adducts under different ex-
perimental conditions. The results of NMR analysis demon-
strate the presence of different structural conformers formed
by the electronic effect of the lone pair of nitrogen atom when
it form adducts with BH3 and BF3 or covalent bonds with
-CH3 in CDCl3 and C6D6. In addition, Density Functional
Theory calculations were performed to further explain the
proposed structures for the adducts by the analysis of NMR
spectra, where N→BF3 adduct in C6D6 showed two different
conformers as well.
on a Varian Excalibur 3100 FT-IR spectrophotometer using
KBr pellets. Elemental analyses were performed on Truspec
Micro elemental analyzer.
2.2
General procedure for the synthesis of
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ibuprofen bencenacetamides 1-3
The amides (Scheme 1) used for the formation of N→BH3,
+
N→BF3, adducts and N-CH3 bond were obtained follow-
ing the reported method by Faisal MM and Najeh AH[27]
There, the carbonyl group is activated by forming an ester
intermediate with N,N′-Dicyclohexylcarbodiimide (DCC) in
the presence of 4-Dimethylaminopyridine (DMAP) which is
acting as catalyst. These systems were reported by Cocco MT
et al. with other synthesis procedures.[28]
In a dry ball flask, the ibuprofen (1000 mg, 4.84 mmol),
aminopyridine (1000 mg, 4.84 mmol), DMAP (60 mg,
0.5 mmol), and dry THF (100 mL) were mixed at room
temperature. This was followed by the dropwise addition of
DCC (1000 mg, 4.84 mmol) during 15 minutes at 0°C. The
reaction was left stirring at room temperature overnight. A
precipitated solid—dicyclohexylurea (DCU)— was filtered,
and the solvent was evaporated under reduced pressure. The
sample was left in ethyl acetate at 5°C for 24 hours, after
which a precipitated solid was removed by filtration and the
solvent was evaporated under reduced pressure. The amides
were purified by column chromatography with a mixture of
hexane:ethyl acetate, 4:1 ratio for 1 and 2, and 1:1 ratio for 3.
2
2.1
EXPERIMENTAL
General information
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Ibuprofen was supplied by the Alfadelta S. A. de C. V. as
racemic mixture and it was not further purified. Other rea-
gents were obtained from Sigma-Aldrich, USA, and they
were used without further purification. Thin-layer chro-
matography (TLC) was run on silica gel (60Å) (Sigma-
Aldrich). The NMR spectra were obtained by dissolving
compounds in CDCl3 or C6D6 and analyzed with a Bruker
400 MHz NMR spectrometer for 1H (400.13 247 MHz),
13C (100.62 282 MHz), 11B (128.37 760 MHz), and 19F
(376.46 071 MHz). NMR of 15N was obtained by INEPT
and HSQC with NH4NO3 utilized as reference (δ=0.0 ppm),
where only the amide nitrogen was observed. Chemical shifts
(δ) are reported in ppm and coupling constants in Hz (see
Supporting Information). The infrared spectra were recorded
2.2.1
2-[4-(2-methylpropyl)phenyl]-N-
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(pyridin-2-yl)propanamide (1)
1
Yellow, wax-like product, 90% yield. H NMR (400 MHz,
3
CDCl3) δ 8.25 (s, 1H, -NH), 8.22 (d, J=8.4 Hz, 1H, H14),
3
8.14 (m, 1H, H17), 7.21 (d, J=7.7 Hz, 1H, H2), 7.21 (d,
3J=7.7 Hz, 1H, H6), 7.17 (d, J=8.0 Hz, 1H, H3), 7.17 (d,
3
3J=8.0 Hz, 1H, H5), 7.13 (ddd, 3J=1.8 Hz, 3J=1.8 Hz,
SCHEME 1 Synthetic pathway of 1-3
amides ibuprofen derivatives

ROMERO-CHÁVEZ Et al.
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4J=0.5 Hz, 1H, H15), 6.13 (m, 1H, H16), 3.64 (q, 3J=7.2 Hz,
3
1H, H7), 2.45 (d, J=7.1 Hz, 2H, H9), 1.84 (m, 1H, H10),
3
3
1.53 (d, J=7.1 Hz, 3H, H8), 0.81 (d, J=6.6 Hz, 6H,11H).
15N NMR (400 MHz, CDCl3) δ 141.3 (-NH). 13C NMR δ
(400 MHz, CDCl3) δ 173.1 (C12), 151.4 (C13), 146.1 (C17),
141.0 (C4), 139.7 (C1), 139.3 (C15), 129.8 (C2, C6), 127.2
(C3, C5), 119.4 (C16), 114.1 (C14), 47.9 (C7), 45.2 (C9),
30.1 (C10), 22.7 (C11), 17.8 (C8).
2.2.2
2-[4-(2-methylpropyl)phenyl]-N-
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(pyridin-3-yl)propanamide (2)
1
Brown, wax-like product, 88% yield. H NMR (400 MHz,
CDCl3) δ 8.09 (s, 1H, H14), 8.53 (s, 1H, -NH), 8.22 (d,
3J=4.5 Hz, 1H, H17), 8.11 (d, 3J=8.5 Hz, 1H, H15), 7.31 (d,
3J=8.0 Hz, 1H, H2), 7.16 (d, J=7.9 Hz, 1H, H3), 7.16 (d,
3
SCHEME 2 Synthesis of N→BH3, N→BF3 adducts (i: CDCl3,
Et2O·BF3, or DMS·BH3; ii: C6D6, Et2O·BF3 or DMS·BH3) and N-
CH3 + salt with ibuprofen-derived amides
3J=7.9 Hz, 1H, H5), 7.16 (d, J=8.0 Hz, 1H, H6), 7.10 (m,
3
3
3
1H, H16), 3.74 (q, J=7.0 Hz 1H, H7), 2.56 (d, J=8.5 Hz,
3
2H, H9), 1.86 (m, 1H, H10), 1.64 (d, J=7.1 Hz, 3H, H8),
0.92 (d, J=6.6 Hz, 6H, H11). 15N NMR (400 MHz, CDCl3)
For 1b-3b, Et2O·BF3 was substituted by borane dimethyl sul-
fide complex (DMS·BH3) (0.17 mL, 1.77 mmol) following
the above method. The products were isolated by vacuum-
assisted solvent evaporation and were immediately analyzed
by FT-IR and elemental analysis. The resulting compounds
had tendency to react with the ambient humidity, effectively
destroying the N→B interaction.
To make their NMR analysis viable, the products were
synthesized inside a NMR tube. The synthesis followed the
previously described method, substituting the CHCl3 for
CDCl3 and downscaling the used quantities from 1.77 mmol
to 0.18 mmol. In addition, the adducts were also synthesized
using C6D6 as solvent to explore the solvent effect on the
structure (Method ii).
The synthesis of 3c followed the next process. Methyl io-
dide (0.28 mL, 4.42 mmol) was added to 5 mL of an amide 3
(0.5 g, 1.77 mmol) solution in acetone. The reaction was left
12 h to reflux. This was followed by the removal of the sol-
vent and the excess of CH3I by vacuum-assisted evaporation.
The aromatic nitrogen methylation was carried out only for
the amide 3, as the methylation for amides 1 and 2 failed in
all of the conditions presented in Table 1.[29–31]
3
δ 125.2 (-NH). 13C NMR (400 MHz, CDCl3) δ 173.6 (C12),
144.4 (C17), 141.2 (C14), 140.7 (C4), 137.9 (C1), 135.3
(C13), 129.8 (C2, C6), 127.5 (C3, C5), 127.5 (C15), 123.7
(C16), 47.5 (C7), 45.0 (C9), 30.2 (C10), 22.4 (C11), 18.6 (C8).
2.2.3
2-[4-(2-methylpropyl)phenyl]-N-
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(pyridin-4-yl)propanamide (3)
1
Yellow, wax-like product, 93% yield. H NMR (400 MHz,
3
CDCl3) δ 8.43 (s, 1H, -NH), 8.36 (d, J=5.5 Hz, 1H, 15H),
3
3
8.36 (d, J=5.5 Hz, 1H, H16), 7.51 (d, J=5.8 Hz, 1H, H14),
3
3
7.51 (d, J=5.8 Hz, 1H, H17), 7.22 (d, J=8.0 Hz, 1H, H2),
7.16 (d, 3J=8.0 Hz, 1H, H3), 7.16 (d, 3J=8.0 Hz, 1H, H5), 7.16
(d, 3J=8.0 Hz, 1H, H6), 3.67 (q, 3J=7.0 Hz, 1H, H7), 2.53 (d,
3J=7.2 Hz, 2H, H9), 1.87 (m, J=6.7 Hz, 1H, H10), 1.51 (d,
3
3J=7.0 Hz, 3H, H8), 0.91 (d, 3J=6.6 Hz, 6H, H11). 15N NMR
(400 MHz, CDCl3) δ 137.2 (-NH). 13C NMR (400 MHz,
CDCl3) δ 174.0 (C12), 149.6 (C15, C16), 146.2 (C13), 141.1
(C4), 137.7 (C1), 129.8 (C2, C6), 127.5 (C3, C5), 113.8 (C14,
C17), 47.6 (C7), 45.0 (C9), 30.1 (C10), 22.4 (C11), 18.7 (C8).
2.3
Synthesis of adducts N→Boron with
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BH3, BF3, and CH3I
2.3.1
Trifluoro(2-(2-(4-isobutylphenyl)
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propanamido)pyridin-1-ium-1-yl)borate (1a*)
The synthesis of 1a-3a and 1b-3b adducts was carried out
under the same conditions of time and temperature, varying
only the type of deuterated solvent (CDCl3 and C6D6) to find
structural differences (Scheme 2).
1a-3a and 1b-3b were synthesized following the Schlenk
technique under a nitrogen atmosphere. For 1a-3a, boron tri-
fluoride diethyl etherate (Et2O·BF3) (0.22 mL, 1.77 mmol)
was added to 5 mL of the corresponding amide (0.50 g,
1.77 mmol) solution in dry CHCl3 in an ice bath (Method i).
Yellow sticky wax-like product, 88% yield. 1H NMR
(400 MHz, CDCl3) δ 10.24 (s, 1H, -NH), 8.21 (d, 3J=8.8 Hz,
1H, H14), 8.16 (m, 1H, H17), 7.56 (dd, 3J=6.1 Hz, 3J=6.1 Hz,
3
1H, H15), 7.38 (m, 1H, H16), 7.24 (d, J=7.9 Hz, 1H, H2),
7.24 (d, 3J=8.1 Hz, 1H, H6), 6.97 (d, 3J=8.1 Hz, 1H, H3), 6.97
(d, 3J=8.1 Hz, 1H, H5), 3.93 (q, 3J=7.1 Hz, 1H, H7), 2.31 (d,
3J=7.2 Hz, 2H, H9), 1.71 (m, 1H, H10), 1.45 (d, J=7.0 Hz,
3
3H, H8), 0.72 (d, 3J=6.6 Hz, 6H, H11). 15N (400 MHz, CDCl3)

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ROMERO-CHÁVEZ Et al.
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TABLE 1 Reaction conditions tested
Amide
CH3I
Solvent
Time/Temperature
Product
for methylation
1 eq
1 eq
1 eq
1 eq
2.5 eq
4 eq
4 eq
Acetone
Acetone
Toluene
Ethanol
4 h in reflux
18 h in reflux
4 h in reflux
1 h on ice, then 72 h at room
temperature
3c
N/A
N/A
N/A
4 eq
1 eq
4 eq
Ethanol
1 h on ice, then 12 h in reflux
N/A
N/A, not available.
δ 131.9 (-NH). 13C NMR (400 MHz, CDCl3) δ 178.8 (C12),
148.4 (C13), 147.1 (C17), 141.4 (C4), 139.8 (C1), 136.8
(C15), 130.0 (C2, C6), 129.2 (C3, C5), 121.0 (C16), 116.8
(C14), 46.9 (C7), 45.2 (C9), 30.1 (C10), 22.6 (C11), 18.4 (C8).
11B NMR (400 MHz, CDCl3) δ −1.0. 19F NMR (400 MHz,
CDCl3) δ −147.8. Anal. (C18H22N2O BF3): Calcd. C, 61.74;
H, 6.33; B, 3.09; F, 16.28; N, 8.00; O, 4.57; found: C, 61.39;
H, 6.29; N, 7.95. (*for cyclic conformer).
δ 126.3 (-NH). 13C NMR (400 MHz, CDCl3) δ 175.7
(C12), 141.1 (C4), 137.0 (C1), 136.9 (C14), 136.5 (C15),
136.2 (C13), 132.5 (C16), 129.7 (C2, C6), 127.5 (C3, C5),
127.7 (C17), 46.9 (C7), 45.0 (C9), 30.1 (C10), 22.3 (C11),
18.2 (C8). 11B NMR (400 MHz, CDCl3) δ −0.8. 19F NMR
(400 MHz, CDCl3) δ −147.3. Anal. (C18H22N2OBF3): Calcd.
C, 61.74; H, 6.33; B, 3.09; F, 16.28; N, 8.00; O, 4.57; found
C, 61.35; H 6.27; N 7.70.
2.3.2
(2-(2-(4-isobutylphenyl)
2.3.4
(3-(2-(4-isobutylphenyl)
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propanamido)pyridin-1-ium-1-yl)
trihydroborate (1b*)
propanamido)pyridin-1-ium-1-yl)
trihydroborate (2b)
1
Colorless sticky wax-like product, 80% yield. H NMR
(400 MHz, CDCl3) δ 9.28 (s, 1H, -NH), 8.51 (d, 3J=8.6 Hz,
1H, H14), 8.28 (d, 3J=5.8 Hz, 1H, H17) 7.82 (dd, 3J=7.8 Hz,
Colorless sticky wax-like product, 78% yield. 1H NMR
3
(400 MHz, CDCl3) δ 8.60 (s, 1H, H14), 8.34 (d, J=8.3 Hz,
3
1H, H15), 8.23 (d, J=5.0 Hz, 1H, H17), 8.05 (s, 1H, -NH),
3J=7.8 Hz,1H, H15), 7.31 (d, J=7.9 Hz, 1H, H2), 7.31 (d,
7.39 (m, 1H, H16), 7.28 (d, J=7.9 Hz, 1H, H2), 7.28 (d,
3
3
3J=8.1 Hz, 1H, H6), 7.08 (d, J=8.1 Hz, 1H, H3), 7.08 (d,
3J=7.9 Hz, 1H, H6), 7.05 (d, J=7.8 Hz, 1H, H3), 7.05 (d,
3
3
3J=8.1 Hz, 1H, H5), 7.02 (m, 1H, H16), 3.55 (q, 3J=7.1 Hz,
3J=7.8 Hz, 1H, H5), 3.71 (q, J=7.1 Hz, 1H, H7), 2.37 (d,
3
3
3
1H, H7), 2.39 (d, J=7.3 Hz, 2H, H9), 1.82 (m, 1H, H10),
3J=7.1 Hz, 2H, H9), 1.83 (m, 1H, H10), 1.48 (d, J=7.0 Hz,
3
3
1.56 (d, J=7.0 Hz, 3H, H8), 0.82 (d, J=6.5 Hz, 6H, H11).
15N NMR (400 MHz, CDCl3) δ 136.8 (-NH). 13C NMR
(400 MHz, CDCl3) δ 172.9 (C12), 148.8 (C13), 146.5 (C17),
141.5 (C4), 141.5 (C15), 136.5 (C1), 130.0 (C2, C6), 127.5
(C3, C5), 118.8 (C16), 115.5 (C14), 48.4 (C7), 45.0 (C9),
30.2 (C10), 25.8 (C11), 22.3 (C8). 13C NMR (400 MHz,
3H, H8), 0.88 (d, 3J=6.5 Hz, 6H, H11). 15N NMR (400 MHz,
CDCl3) δ 124.6 (-NH). 13C NMR (400 MHz, CDCl3) δ 173.5
(C12), 142.2 (C17), 141.4 (C4), 138.7 (C14), 137.0 (C1), 136.9
(C13), 129.4 (C15), 129.9 (C2, C6), 127.3 (C3, C5), 125.4
(C16), 47.5 (C7), 45.0 (C9), 30.1 (C10), 22.9 (C11), 18.5 (C8).
11B NMR (400 MHz, CDCl3) δ −20.3 (q, J(B-H)=106.3 Hz,
1
1
CDCl3) δ −20.2 (q, J(B-H)=105.5 Hz, -BH3). Anal. (C18
C18H22N2OBH3): Calcd. C, 72.99; H, 8.51; B, 3.65; N, 9.46;
O, 5.40; found C, 72.43; H, 8.42; N, 9.36.
-BH3). Anal. (C18H22N2OBH3): Calcd. C, 72.99; H, 8.51; B,
3.65; N, 9.46; O, 5.40; found C, 72.94; H, 8.36; N, 9.30.
2.3.5
1-(difluoroboryl)-4-(2-(4-
|
2.3.3
1-(difluoroboryl)-3-(2-(4-
isobutylphenyl)propanamido)pyridin-1-ium
fluoride (3a)
|
isobutylphenyl)propanamido)pyridin-1-ium
fluoride (2a)
Yellow sticky wax-like product, 78% yield. 1H NMR
(400 MHz, CDCl3) δ 9.31 (s, 1H, -NH), 8.27 (d,3J= 5.9 Hz,
1H, H16), 8.27 (d, 3J= 5.9 Hz, 1H, H15), 8.01 (d, 3J= 6.2 Hz,
1H, H17), 8.01 (d, 3J= 6.2 Hz, 1H, H14), 7.28 (d, 3J= 7.2 Hz,
1H, H2), 7.28 (d, 3J= 7.2 Hz, 1H, H6), 7.04 (d, 3J= 8.0 Hz,
Yellow sticky wax-like product, 82% yield. 1H NMR
(400 MHz, CDCl3) δ 9.11 (s, 1H, -NH), 9.11 (d, 3J=5.1 Hz,
1H, H14), 8.47 (d, 3J=7.7 Hz, 1H, H17), 8.27 (m, 1H, H15),
3
7.78 (m, 1H, H16), 7.27 (d, J=8.3 Hz, 1H, H2), 7.27 (d,
3
3
3
3J=8.3 Hz, 1H, H6), 7.01 (d, J=7.6 Hz, 1H, H3), 7.01 (d,
1H, H5), 7.04 (d, J=8.0 Hz, 1H, H3), 3.88 (q, J= 6.8 Hz,
3
3J=7.6 Hz, 1H, H5), 3.87 (m, 1H, 7H), 2.32 (d,3J=6.2 Hz,
1H, H7), 2.36 (d, J= 7.1 Hz, 2H, H9), 1.76 (m, 1H, H10),
3
2H, H9), 1.89 (m, 1H, 10H), 1.48 (d, J=6.1 Hz, 3H, H8),
1.52 (d, 3J= 7.0 Hz, 3H, H8), 0.87 (d, 3J= 6.6 Hz, 6H, H11).
0.81 (d, 3J=6.4 Hz, 6H, H11). 15N NMR (400 MHz, CDCl3)
15N NMR (400 MHz, CDCl3) δ 137.9 (-NH). 13C NMR

ROMERO-CHÁVEZ Et al.
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3
3
(400 MHz, CDCl3) δ 174.0 (C12), 153.8 (C15, C16), 141.8
(C13), 141.7 (C4), 137.4 (C1), 129.9 (C2, C6), 127.4 (C3,
C5), 115.0 (C14, C17), 47.8 (C7), 18.1 (C8), 45.1 (C9), 30.1
1H, H5), 6.21 (dd, J=6.6 Hz, J=6.6 Hz, 1H, H16), 3.32
3
3
(q, J=7.0 Hz, 1H, H7), 2.12 (d, J=7.2 Hz, 2H, H9), 1.51
(m, 1H, H10), 0.61 (d, J=6.6 Hz, 6H, H11). 13C NMR
3
(C10), 22.3 (C11). 11B NMR (400 MHz, CDCl3) δ −0.9. 19
F
(400 MHz, C6D6) δ 172.4 (C12), 148.4 (C13), 143.6 (C17),
141.3 (C4), 136.4 (C1), 136.4 (C15), 130.0 (C2, C6), 127.8
(C3, C5), 119.0 (C16), 117.0 (C14), 48.3 (C7), 44.9 (C9),
30.0 (C10), 21.9 (C11), 17.1 (C8). 11B NMR (400 MHz,
C6D6) δ 0.4. 19F NMR (400 MHz, C6D6) δ −144.7.
NMR (400 MHz, CDCl3) δ −147.2. Anal. (C18H22N2O BF3):
Calcd. C, 61.74; H, 6.33; B, 3.09; F, 16.28; N, 8.00; O, 4.57;
found C, 61.52; H, 6.79; N, 8.04.
2.3.6
(4-(2-(4-isobutylphenyl)
|
propanamido)pyridin-1-ium-1-yl)
trihydroborate (3b)
2.3.9
1b*′
|
1H NMR (400 MHz, C6D6) δ 9.25 (s, 1H, -NH), 8.17 (d,
1
3
Colorless sticky wax-like product, 85% yield. H NMR
(400 MHz, CDCl3) δ 8.24 (s, 1H, -NH), 8.29 (d, 3J=7.0 Hz,
1H, H16), 8.29 (d,3J=7.1 Hz, 1H, H15), 7.62 (d, 3J=7.0 Hz,
1H, H17), 7.62 (d, 3J=7.0 Hz, 1H, H14), 7.22 (d, 3J=8.0 Hz,
3J=8.5 Hz, 1H, H14), 7.08 (d, J=8.0 Hz, 1H, H2), 7.08 (d,
3J=8.0 Hz, 1H, H6), 7.81 (d, 3J=5.3 Hz, 1H, H17), 6.77 (m,
3
3
1H, H15), 6.77 (d, J=8.0 Hz, 1H, H3), 6.77 (d, J=8.0 Hz,
3
1H, H5), 5.98 (m,1H, H16), 3.31 (q, J=7.2 Hz, 1H, H7),
3
3
3
1H, H6), 7.22 (d, J=8.0 Hz, 1H, H2), 7.13 (d, J= 8.0 Hz,
2.12 (d, J=6.6 Hz, 2H, H9), 1.51 (m, 1H, H10), 1.25 (d,
3
3
1H, H5), 7.13 (d, J=8.0 Hz, 1H, H3), 3.80 (q, J=7.0 Hz,
1H, H7), 2.43 (d,3J=7.2 Hz, 2H, H9), 1.84 (m, 1H, H10),
3J=6.8 Hz, 3H, H8), 0.61 (d, 3J=6.5 Hz, 6H, H11). 13C NMR
(400 MHz, C6D6) δ 172.3 (C12), 148.7 (C13), 146.1 (C17),
141.5 (C4), 140.6 (C15), 136.9 (C1), 129.9 (C2, C6), 127.5
(C3, C5), 118.1 (C16), 114.9 (C14), 48.3 (C7), 44.8 (C9),
30.1 (C10), 22.6 (C8), 22.6 (C11). 11B NMR (400 MHz,
C6D6) δ −19.7 (q, 1J(B-H)=106.0 Hz, -BH3).
1.55 (d, J=7.0 Hz, 3H, H8), 0.90 (d,3J=6.6 Hz, 1H, H11).
3
1H NMR (400 MHz, CDCl3) δ 133.7 (-NH). 13C NMR
(400 MHz, CDCl3) δ 174.0 (C12), 148.0 (C15, C16), 147.6
(C13), 141.6 (C4), 137.0 (C1), 130.0 (C2, C6), 127.3 (C3,
C5), 114.2 (C14, C17), 47.8 (C7), 45.0 (C9), 30.1 (C10), 22.4
(C11), 18.1 (C8). 11B NMR (400 MHz, CDCl3) δ −12.7 (m,
-BH3). Anal. (C18H22N2OBH3): Calcd. C, 72.99; H, 8.51; B,
3.65; N, 9.46; O, 5.40; found C, 72.96; H, 8.74; N, 9.28.
2.3.10
2a′
|
1H NMR (400 MHz, C6D6) δ 9.07 (d, 3J=5.1 Hz, 1H, H14),
3
9.07 (s, 1H, -NH), 8.23 (d, J=7.7 Hz, 1H, H17), 8.01 (m,
3
3
1H, H15), 7.58 (d, J=8.1 Hz, 1H, H2), 7.58 (d, J=8.1 Hz,
2.3.7
4-(2-(4-isobutylphenyl)
|
3
1H, H6), 7.26 (m, 1H, H16), 7.07 (d, J=8.1 Hz, 1H, H3),
propanamido)-1-methylpyridin-1-ium iodide
(3c)
3
3
7.07 (d, J=8.1 Hz, 1H, H5), 4.11 (q, J=6.4 Hz, 1H, H7),
2.27 (d,3J=6.2 Hz, 2H, H9), 1.72 (m, 1H, 10H), 1.65 (d,
3J=6.9 Hz, 3H, H8), 0.75 (d, 3J=6.6 Hz, 6H, H11). 13C NMR
δ (400 MHz, C6D6) 175.9 (C12), 141.1 (C4), 138.2 (C1),
137.3 (C13), 136.3 (C14), 135.8 (C15), 132.2 (C16), 129.7
(C2, C6), 127.6 (C3, C5), 127.4 (C17), 47.0 (C7), 44.8 (C9),
30.0 (C10), 22.0 (C11), 17.9 (C8). 11B NMR (400 MHz,
C6D6) δ −0.2. 19F NMR (400 MHz, C6D6) δ −146.5.
1
Yellow liquid, 92% yield. H NMR (400 MHz, CDCl3)
3
δ 10.91 (-NH), 8.48 (d, J=7.2 Hz, 1H, H15), 8.39 (d,
3J=7.2 Hz, 1H, H14), 7.39 (3d, J =7.6 Hz, 1H, H2), 7.39
3
(d, 3J=7.6 Hz, 1H, H6), 7.0 (d, 3J=7.6 Hz, 1H, H3), 7.04 (d,
3J=7.6 Hz, 1H, H5), 4.31 (q, J=6.4 Hz, 1H, H7), 4.20 (s,
3
1H, -CH3), 2.33 (d, 3J=7.2 Hz, 2H, H9), 1.72 (m, 1H, H10),
1.43 (d, 3J=6.8 Hz, 3H, H8), 0.77 (d, 3J =6.8 Hz, 6H, H11).
15N NMR (400 MHz, CDCl3) δ 142.6 (-NH). 13C NMR
(400 MHz, CDCl3) δ 174.7 (C12), 151.8 (C13), 143.9 (C15,
C16), 140.0 (C4), 136.5 (C1), 128.5 (C2, C6), 126.8 (C3,
C5), 114.4 (C14, C17), 46.7 (C7), 45.6 (N-CH3+), 44.0 (C9),
29.1 (C10), 21.4 (C11), 17.8 (C8). Anal. ([C18H22N2OCH3]
+[OH]−): Calcd. C, 72.58; H, 8.33; N, 8.91; O, 10.18; found
C, 72.49; H, 8.33; N, 8.90.
2.3.11
2b′
|
1H NMR (400 MHz, C6D6) δ 8.44 (s, 1H, H14), 7.66 (d,
3J=5.7 Hz, 1H, H17), 7.61 (d, 3J=8.6 Hz, 1H, H15), 7.54 (s,
3
3
1H, -NH), 7.11 (d, J=8.0 Hz, 1H, H2), 7.11 (d, J=8.0 Hz,
1H, H6), 6.83 (d, 3J=8.0 Hz, 1H, H3), 6.83 (d, 3J=8.0 Hz, 1H,
H5), 6.25 (m, 1H, H16), 3.38 (q, 3J=7.1 Hz, 1H, H7), 2.09 (d,
3J=7.1 Hz, 2H, H9), 1.51 (m, 1H, H10), 1.32 (d, 3J=7.0 Hz,
3H, H8), 0.61 (d, 3J=6.6 Hz, 6H, H11). 13C NMR (400 MHz,
C6D6) δ 172.8 (C12), 141.5 (C14), 140.9 (C4), 138.0 (C1),
138.8 (C15), 136.8 (C13), 129.7 (C2, C6), 128.5 (C16), 127.0
(C3, C5), 124.9 (C17), 49.7 (C7), 44.9 (C9), 30.1 (C10), 22.6
(C11), 18.8 (C8). 11B NMR (400 MHz, C6D6) δ −19.7 (q,
1J(B-H)=105.4 Hz, BH3).
2.3.8
1a′
|
1H NMR (400 MHz, C6D6) δ 9.63 (s, 1H, -NH), 7.40 (d,
3J=8.7 Hz, 1H, H14), 7.26 (d, J=5.8 Hz 1H, H17),7.05 (d,
3
3J=8.7 Hz, 1H, H2), 7.05 (d, J=8.7 Hz, 1H, H6), 6.94 (m,
3
3
3
1H, H15), 6.88 (d, J=8.7 Hz, 1H, H3), 6.88 (d, J=8.7 Hz,

6 of 12
ROMERO-CHÁVEZ Et al.
|
3
3.1
RESULTS AND DISCUSSION
|
2.3.12
3a′
|
NMR analysis of 1H and 13C
1H NMR (400 MHz, C6D6) δ 9.74 (s, 1H, -NH), 8.06 (w, 1H,
H15), 8.06 (w, 1H, H16), 7.78 (w, 1H, H17), 7.78 (w, 1H,
|
The chemical shifts for positions 7, 14-17, and -NH were af-
fected by the adducts formation in both CDCl3 and C6D6. The
NMR data for 1H and 13C are shown in Tables 2-4. In CDCl3,
the amide proton signal in 1a* and 1b* is shifted to higher
frequencies compared to the raw material (δ-NH 1: 8.1 ppm;
1a*: 10.24 ppm; 1b*: 9.26 ppm). This change is due to the
amide proton’s interaction with fluorine and hydride, re-
spectively (Figure 1). Both 1a* and 1b* shared a trend in
the chemical shifts for 14-17 protons, moving to higher fre-
quencies respect to the raw materials. This is caused by the
decrease of electron density on these positions due to the co-
ordination between the pyridine nitrogen and the boron atom.
Additionally, the C12 signal in 1a* appears at higher frequen-
cies (178.8 ppm) than C12 (172.9 ppm) in 1b*. This effect is
the result of the noncovalent interaction between the amidic
proton and one of the fluorine atoms in 1a*, which allows the
carbonyl’s electron density to flow to the amide’s nitrogen.
This is further supported by the 15N NMR data (Table 5).
During the N→BF3 adduct formation in C6D6, two different
conformers were observed (1a*′ and 1a′). The doubling of the
3
3
H14), 7.41 (d, J=8.5 Hz, 1H, H2), 7.41 (d, J=8.5 Hz, 1H,
3
3
H6), 6.95 (d, J=7.7 Hz, 1H, H3), 6.95 (d, J=7.7 Hz, 1H,
H5), 3.96 (m, 1H, H7), 2.11 (d, 3J=6.6 Hz, 2H, H9), 1.53 (m,
3
3
1H, H10), 1.36 (d, J=6.7 Hz, 3H, H8), 0.58 (d, J=6.2 Hz,
6H, H11). 13C NMR (400 MHz, C6D6) δ 174.1 (C12), 153.2
(C13), 152.3 (C15, C16), 141.1 (C4), 136.9 (C1), 128.9 (C2,
C6), 127.1 (C3, C5), 113.8 (C14, C17), 46.6 (C7), 44.1 (C9),
29.2 (C10), 21.3 (C11), 17.2 (C8). 11B NMR (400 MHz,
C6D6) δ −0.1. 19F NMR (400 MHz, C6D6) δ −147.1.
2.3.13
3b′
|
1H NMR (400 MHz, C6D6) δ 7.99 (d, 3J=6.2 Hz, 1H, H15),
7.99 (d, 3J=6.2 Hz, 1H, H16), 7.63 (-NH), 7.24 (d, 3J=7.9 Hz,
3
3
1H, H6), 7.24 (d, J=7.9 Hz, 1H, H2), 7.09 (d, J=6.2 Hz,
1H, H14), 7.09 (d, 3J=6.2 Hz, 1H, H17), 7.01 (d, 3J=7.9 Hz,
3
3
1H, H3), 7.01 (d, J=7.9 Hz, 1H, H3), 3.68 (q, J=6.5 Hz,
3
1H, H7), 2.29 (d, J=6.4 Hz, 2H, H9), 1.74 (m, 1H, H10),
1.51 (w, 3H, H8), 0.84 (d, J=6.5 Hz, 1H, H11). 13C NMR
3
signals in the H and 13C NMR spectra confirmed the coex-
1
(400 MHz, C6D6) δ 172.9 (C12), 147.1 (C13), 141.2 (C4),
137.6 (C1), 129.8 (C2, C6), 127.3 (C3, C5), 113.7 (C14,
C17), 47.6 (C7), 44.8 (C9), 30.0 (C10), 22.1 (C11), 18.6
(C8), 147.6 (C15, C16). 11B NMR (400 MHz, C6D6) δ −19.7
(q, 1J(B-H)=106.2 Hz, -BH3).
istence of two conformers (see Supporting Information). The
second structure differs from 1a* in the relative position of the
BF3 moiety, which is oriented toward the carbonyl’s oxygen
(Figure 1, 1a′). The chemical shifts of the carbonyl group (C12)
appear at 172.4 and 178.2 ppm for 1a′ and 1a*′, respectively.
Furthermore, two amide protons were observed at 9.63 ppm
and 10.45 ppm for 1a′ and 1a*′, respectively (Table 2).
While structurally similar, the N→BH3 adduct chemical
shifts differ in CDCl3 (1b*) and C6D6 (1b*′). For compound
1b*′, the signals corresponding to protons H14-H17 were
shifted to lower frequencies with respect to 1b*. This effect is
attributed to weaker Van der Waals interactions between the
solvent and the compound, because benzene does not favor
these interactions as well as CDCl3. The electronic effects on
the C13-C17 positions are similar to those reported for 1a*′,
indicating the formation of the structures shown in Figure 1
(1b* and 1b*′).
2.3.14
3c′
|
1H NMR (400 MHz, C6D6) δ 11.38 (-NH), 8.35 (s,1H, H15),
8.30 (s,1H, H14), 8.35 (s,1H, H16), 8.30 (s,1H, H16), 7.85
3
3
(d, J=7.6 Hz, 1H, H2), 7.85 (d, J=7.6 Hz, 1H, H6), 7.12
(d, 3J=8.0 Hz, 1H, H3), 7.12 (d, 3J=8.0 Hz, 1H, H5), 4.75 (q,
3J=6.4 Hz, 1H, H7), 2.31 (d, J=8.0 Hz, 2H, H9), 1.73 (m,
3
3
1H, H10), 1.59 (d, J=6.4 Hz, 3H, H8), 4.13 (s, 3H, -CH3),
0.82 (d, J=6.4 Hz, 6H, H11). 13C NMR (400 MHz, C6D6)
3
δ 175.3 (C12), 152.2 (C13), 145.1 (C15, C16), 140.8 (C4),
137.9 (C1), 129.6 (C2, C6), 127.4 (C3, C5), 114.8 (C14,
C17), 46.7 (C7), 44.9 (C9), 30.0 (C10), 22.2 (C11), 18.9 (C8).
Theformationoftheadductsderivedfrom3-aminopyridine
(2) was evidenced by 1H and 13C NMR spectra in CDCl3 and
C6D6 (Table 3). In general, the most significant changes in 1H
NMR spectra are for the amide proton and the H14 position.
In all the adducts (2a, 2a′, 2b, and 2b′), the H14 signal was
shifted to higher frequencies when the aromatic nitrogen’s
lone electron pair interacts with the boron atom (Figure 2).
The amide proton showed a deshielding effect on the N→BF3
derivatives, an effect that was not observed on the N→BH3
adducts, where the acidic proton (-NH) was shifted to lower
frequencies. On the 13C NMR spectra, all the adducts exhibit
2.4
Computational details
|
Full geometry optimizations were carried out at a density func-
tional theory level using the exchange-correlation hybrid func-
tional B3LYP[32–36] along with the 6-31++G**[37–48] basis set
as is implemented in Gaussian 09.[49] A vibrational analysis
was performed to discriminate between minima and transi-
tion state structures. All calculations were performed using
the solvation model based on density, SMD.[50] Computed
structures were rendered as images using Chemcraft.[51]

ROMERO-CHÁVEZ Et al.
7 of 12
|
TABLE 2 Selected 1H and 13C NMR shifts (ppm) of 1a-1b adducts in CDCl3 and C6D6 (see Figure 1 for numbering sequence)
1a*
1b*
1a′
1a*′
1b*′
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
7
3.93
—
—
8.21
7.56
7.38
8.16
10.24
46.9
178.8
148.4
116.8
136.8
121.0
147.1
—
3.55
—
—
8.51
7.82
7.02
8.28
9.28
48.4
172.9
148.8
115.5
141.5
118.8
146.5
—
3.32
—
—
7.40
6.94
6.21
7.26
9.63
48.3
172.4
148.4
117.0
136.4
119.0
143.6
—
4.03
—
—
8.19
7.15
6.37
7.92
10.45
46.3
178.2
148.0
116.3
136.3
119.7
146.2
—
3.31
—
—
8.17
6.77
5.98
7.81
9.25
48.3
172.3
148.7
114.9
140.6
118.1
146.1
—
12
13
14
15
16
17
-NH
(′) Compounds in benzene; (*for cyclic conformer).
TABLE 3 Chemical shifts δ (ppm) of
2a
1H
2a′
1H
2b
1H
2b′
1H
characteristic peaks in the 1H and 13
C
13C
13C
13C
13C
spectra of meta adducts in CDCl3 andC6D6
7
3.87
—
—
9.11
8.27
7.78
8.47
9.11
46.9
175.7
136.2
136.9
136.5
132.5
127.7
—
4.11
—
—
9.07
8.01
7.26
8.23
9.05
47.0
175.9
137.3
136.3
135.8
132.2
127.4
—
3.71
—
—
8.60
8.34
7.39
8.23
8.05
47.5
173.5
136.9
138.7
129.4
125.4
142.2
—
3.38
—
—
8.44
7.61
6.25
7.66
7.54
49.7
172.8
136.8
141.5
138.8
128.5
124.9
—
12
13
14
15
16
17
-NH
(′)Compounds in benzene.
TABLE 4 Selected chemical shifts δ (ppm) of 1H and 13C spectra of para adducts in CDCl3 and C6D6
3a
3a′
3b
3b′
3c
3c′
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
7
3.88
—
—
8.01
8.27
8.27
8.01
9.31
47.4
175.5
141.8
115.0
153.8
153.8
115.0
—
3.96
—
—
7.78
8.06
8.06
7.78
9.74
46.6
174.1
153.2
113.8
152.3
152.3
113.8
—
3.80
—
—
7.62
8.29
8.29
7.62
8.24
47.8
174.0
147.6
114.2
148.0
148.0
114.2
—
3.52
—
—
7.09
7.99
7.99
7.09
7.63
47.6
172.9
147.1
113.7
147.6
147.6
113.7
—
4.31
—
—
8.39
8.48
8.48
8.39
10.91
46.6
174.7
151.8
114.4
143.9
143.9
114.4
—
4.75
—
—
8.30
8.35
8.35
8.30
11.38
47.8
175.3
152.2
114.8
145.1
145.1
114.8
—
12
13
14
15
16
17
-NH
(′)Compounds in benzene.
a deshielding effect for C15 and C16, while C14 and C17
presented a shielding effect because of the activation of the
ortho and para positions of the aromatic ring by the N→B
adduct formation (see Supporting Information).
In general, the 4-aminopyridine derivatives of NMR of
1H and 13C spectra showed the same trends for positions 13-
17 in both solvents. The formation of the N→BF3, N→BH3
+
adducts, and the covalent bond N-CH3 with the pyridine’s

8 of 12
ROMERO-CHÁVEZ Et al.
|
FIGURE 1 Adducts of amide 1 with
BF3 and BH3 in CDCl3 and C6D6
TABLE 5 Chemical shifts (δ) in ppm
11B
15N
19F
No.
11B
15N
No.
3c
15N
for 11B, 15N, and 19F in CDCl3
1a*
2a
3a
−1.0
−0.8
−0.9
131.9
126.3
137.9
−147.8
−147.3
−147.2
1b*
2b
3b
−20.2
−20.3
−12.7
136.8
130.6
133.7
142.6
NMR of 15N was obtained by INEPT. 15N: 1, 141.3; 2, 125.2; 3, 137.2.
FIGURE 2 Adducts of the amide 2
with BF3 and BH3 in CDCl3 and C6D6. The
same structure was observed in C6D6
nitrogen protects the 15 and 16 positions of the pyridine ring
while deshielding the positions 14 and 17 (Table 3). Although
the electron distribution trends are the same for 3a, 3b, and
3c, the latter system showed the most significant changes due
to the presence of a covalent bond with an electron density
donor group. The proposed structures for 3 derivatives are
shown in Figure 3. There is an isolobal analogy between
these systems, that is, they are isoelectronic because all of
them presented the same electronic changes on the pyridine
ring, either in the presence of N→B adducts or with the N-C
covalent bond.
on the amide’s nitrogen on the 2-aminopyridine derivatives
(1a* and 1b*). This results from an increased electron den-
sity around the amide nitrogen due to the formation of addi-
tional cycles (see Figure 3). For 3-aminopyridine derivatives,
a slight deshielding effect on the amide’s nitrogen was ob-
served on 2b. This indicates that the adduct formation on this
position does not affect the electron density around this atom.
A completely different behavior was observed on 3a, 3b, and
3c, where the signal of 15N was shifted to higher frequencies
because the pyridine nitrogen is at a para position respect to
the amide moiety.
The 11B NMR signals were analyzed and compared with
other reported systems, expecting the BF3 and BH3 chemical
shifts in the range of −0.9 to −11.5 ppm, for the compounds
where the boron atom is coordinated with the pyridine’s
nitrogen.[52] The 1b* compound shows a quartet signal at
−20.2 ppm with a coupling constant 1J(B-H)=105.5 Hz, char-
acteristic of an N→BH3 coordination. In the case of 1b*′,
3.2
NMR analysis of 11B, 15N and 19F
|
The analysis of the chemical shifts for the heteroatoms cor-
roborates the behavior of the amides in the adducts formation,
and also provides important information about their chemi-
cal environment (Table 5). A shielding effect was observed

ROMERO-CHÁVEZ Et al.
9 of 12
|
FIGURE 3 Adducts of 3 with BF3, BH3, and CH3I in CDCl3. The same structure was observed in C6D6
the 11B signal appears at −19.7 ppm, confirming the adduct
formation. For the 2b adduct, a quartet signal was observed
at −20.3 ppm with a 1J(B-H)=106.3 Hz, confirming the forma-
tion of the N→B adduct with the pyridine nitrogen. Finally, a
quartet signal at −20.1 ppm for 2b′.
corresponding proton (Figure 6). This structural arrangement
supports the chemical shifts discussed in the NMR section.
3.4
Infrared analysis
|
The signal for 19F appears at lower frequencies with re-
spect to the reagent (Et2O·BF3, −127 ppm), due to the ex-
change of the oxygen for the nitrogen on the boron atom.
The characteristic bands of stretching for amide carbonyl
group ν(C=O) appear between 1695 and 1620 cm−1, near
of C=N stretching bands (1590-1510 cm−1). In the amide
bands, stretching for C-N bond is a strong signal around
1480-1410 cm−1 and N-H asymmetric and symmetric stretch-
ing appear a broad signal at 3350-3150 cm−1. Stretching N-H
band gives us important information about the chemical envi-
ronment surrounding to the acid proton. Selected IR stretch-
3.3
Conformational analysis of the amide
|
1a in chloroform and benzene
To further explain the proposed structures for N→BF3 and
N→BH3 adducts in chloroform and benzene, quantum chem-
ical calculations were performed. A conformational search
for the above compounds using Gaussian09 code was per-
formed. The geometry optimization of molecule 1a* under
the solvent effect of chloroform only identified one conformer
(Figure 4) as a minimum on the potential energy surface.
In contrast to chloroform, two conformers were found
for the same molecule using benzene as solvent (Figure 5).
The Gibbs free energy difference between the structures was
9.624 kcal/mol. This finding together with the rotational
pathway between both conformers supports their coexis-
tence, as observed in the NMR data.
For 1b*, a similar structure was found, where the amide
and pyridine orientations were analogous to those observed
on 1a*. The main difference between 1a* and 1b* is the ori-
entation of the boron’s substituents. While in 1a*, a single
fluorine interacts with the amide’s proton, 1b* has two hy-
drides forming an asymmetric bifurcate interaction with the
+
ing bands for the amine-borane adducts and N-CH3 bond
are presented in Table 6.
The difference between the asymmetric and symmetric
stretching of the N-H bonds for 1a is 18 cm−1, while it is
69 cm−1 for 2a and 37 cm−1 for 3a. This phenomenon is re-
lated to the proton-fluorine (N-H+···−F-B) interaction in 1a.
The splitting of signals in 2a was attributed to the distance
between the proton and fluorine in addition to the steric hin-
drance that apparently inhibits any intermolecular interaction
for the amide’s proton. Contrastingly, this splitting disappears
in 1b, 3b, and 3c, where a single broad band was observed.
Changes in N-H stretching vibrations are related with the
coordination of this proton with electron donor atoms. This
changes are attributed to hydride-proton interactions which
inhibit the splitting of the bands in 1b, which generates en-
hanced structural stability (N-H+···−H-B). This is further sup-
ported by the movement of the chemical shift for the N-H
proton at higher frequencies in NMR. The formation of the
FIGURE 4 Structural rearrangement
of amide 1a* in chloroform

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ROMERO-CHÁVEZ Et al.
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FIGURE 5 Structural rearrangements of the amide 1 with BF3 in benzene
of medium intensity, where higher frequencies correspond
to the free hydride (N→BH3) and the lower frequencies are
caused by the hydrides coordinated with the amide proton
(N-H+···−H-B).[56,57]
4
CONCLUSIONS
|
Amine-borane adducts ibuprofen derivatives have been suc-
cessfully developed. The analyses of IR, NMR (1H, 11B, 13C,
15N, and 19F) data, and DFT calculations demonstrated that
N→BX3 adducts were formed on pyridine ring.
The 2-aminopyridine derivatives (1a* and 1b*) formed
cycles between the amide proton and the hydride and flu-
orine, which acted as donors in the N-H+···−X-B intramo-
lecular interactions. Another cycle was observed on these
structures, formed by the interaction of the carbonyl’s oxygen
and a pyridine’s hydrogen. The duplication of the carbonyl
chemical shift in the NMR spectrum for the N→BF3 com-
plex in benzene indicates the presence of a second coexisting
structure (1a′), where the previously discussed cycles were
not formed.
FIGURE 6 Structural rearrangements of the amide 1b
N→BX3 adducts is supported by the appearance of a strong
band at 1160-1140 cm−1 due to the N-B stretching for these
ligands.[53,54] The 1a, 2a, and 3a adducts exhibited a broad
and strong band at 1100-1000 cm−1, because of the B-F
symmetric and asymmetric stretching.[55] As it is known, the
B-H stretching appears at 2400-2200 cm−1, as a broad band
DFT calculations showed a connecting path between struc-
tures 1a*′ and 1a′, through the rotation of the amide-pyridine
TABLE 6 Characteristic infrared bands of ibuprofen amides in N→BH3, N→BF3 adducts, and N-CH3+ bond
Wavenumber (cm−1
)
νa(B-X) (X=H or
F)
νs(B-X) (X=H or
F)
No.
ν(C=O)
ν(C=N) (pyridine)
ν(C-N) (amide)
νa(N-H)
νs(N-H)
ν(B-N)
1a
2a
3a
1b
2b
3b
3c
1652 (s)
1630 (w)
1639 (m)
1623 (m)
1628 (m)
1674 (m)
1641 (m)
1572 (s)
1544 (s)
1506 (s)
1511 (s)
1508 (s)
1538 (s)
1517 (s)
1439 (s)
1459 (s)
1477 (s)
1438 (s)
1432 (s)
1428 (s)
1432 (m)
3270(b)
3343 (b)
3322 (b)
3311 (b)
3322 (b)
3311 (b)
3422 (b)
3252 (b)
3274 (b)
3285 (b)
1155 (s)
1160 (m)
1142 (m)
1148 (m)
1149 (s)
1154 (s)
1090 (b,s)
1056 (b,s)
1051 (b,s)
2397 (m), 2310 (m)
2359 (m), 2308 (m), 2276 (m)
2368 (m), 2267 (m)
999 (b,s)
1020 (b,s)
1020 (b,s)
3290 (b)
a, X=H; b, X= F; s, strong; m, medium; w, weak; b, broad.

ROMERO-CHÁVEZ Et al.
11 of 12
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[20] J. C. Gálvez-Ruiz, E. Solano-Ruiz, S. A. Sánchez-Ruiz, R.
Contreras, A. Flores-Parra, ARKIVOC 2008, 81.
bond. The calculated Gibbs free energies showed a difference
of 9.624 kcal/mol between the structures, with 1a* having
the lower energy. These computational results support the
coexistence of both conformers.
The NMR analyses of the 3a, 3b, and 3c systems in both
solvents present the same chemical shift trend between them,
where the ortho and para positions were shielding, while that
meta was deshielding. This confirms an isolobal analogy be-
tween the N-C and N→B interactions in these compounds.
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ACKNOWLEDGMENTS
Maria Romero-Chávez is grateful for the scholarship 289752
from CONACYT-México and partial funding support by
grant #130381 and grant #226165 provided by CONACYT
are also acknowledged. Magaña-Vergara Nancy E. and the
University of Colima are thankful for the scholarship to
SEP-PRODEP.
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How to cite this article: Romero-Chávez MM,
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Cárdenas R, Gómez-Sandoval Z, Ramos-Organillo Á.
Conformational analysis of N→BH3, N→BF3, and
N-CH3+ complexes with ibuprofen-derivative amides.
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