Hydrogen bonds determine the signal arrangement in 13C NMR spectra of nicotinate

Article abstract of DOI:10.1016/j.molstruc.2017.10.086

Present work reports on studies of sodium nicotinate solutions in water and aqueous ethanol by means of ¹H, ¹³C, ¹⁵N NMR spectroscopy. The H(2) nucleus was observed to be the least shielded among pyridine ring protons whil

Full text of DOI:10.1016/j.molstruc.2017.10.086

Accepted Manuscript
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Hydrogen bonds determine the signal arrangement in C NMR spectra of nicotinate
G.A. Gamov, N.N. Kuranova, A.E. Pogonin, V.V. Aleksandriiskii, V.A. Sharnin
PII:
S0022-2860(17)31432-1
10.1016/j.molstruc.2017.10.086
MOLSTR 24457
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 August 2017
Revised Date: 20 October 2017
Accepted Date: 24 October 2017
Please cite this article as: G.A. Gamov, N.N. Kuranova, A.E. Pogonin, V.V. Aleksandriiskii, V.A. Sharnin,
13
Hydrogen bonds determine the signal arrangement in C NMR spectra of nicotinate, Journal of
Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.10.086.
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13C-1H HSQC spectrum of nicotinate (0.25 mol kg-1, aqueous)

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Hydrogen bonds determine the signal arrangement in 13C NMR
spectra of nicotinate
Gamov G.A.1, Kuranova N.N.1, Pogonin A.E.1, Aleksandriiskii V.V.1, 2,
Sharnin V.A.1
1Research Institute of Thermodynamics and Kinetics of Chemical
Processes, Ivanovo State University of Chemistry and Technology
2Institute of Solution Chemistry, Russian Academy of Sciences
oxt705@isuct.ru
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Present work reports on studies of sodium nicotinate solutions in water and aqueous ethanol by
1
means of H, 13C, 15N NMR spectroscopy. The H(2) nucleus was observed to be the least
shielded among pyridine ring protons whilst C(6) signal placed in the lowest field in relation to
the other pyridine carbons. The hydrogen bonds formation between nicotinate and water
molecules was shown to be probable reason of signal arrangement in 13C NMR spectra of
nicotinate. The heteronitrogen of nicotinate is less prone to the hydrogen bonding with water
molecules than that of nicotinamide. The data on the change in the Gibbs energy of the nicotinate
transfer and the results of the 13C NMR experiment are compared.
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20 Keywords: nicotinate, HMBC N-1H, HSQC C-1H, NMR, hydrogen
21 bond, aqueous ethanol
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1. Introduction
Pyridine-3-carboxylic acid (nicotinic acid, PP or B3 vitamin) is a vitamin of
25 B group and drug used as pellagra treating, preventing remedy, and lipid-lowering
26 agent, which could be used in complex therapy of atherosclerosis, hyperlipidemia,
27 insulin resistance [1-3]. Nicotinic acid acts as precursor of nicotinamide adenine
28 dinucleotide (NAD) coenzyme in living organisms [4].
29
Moderately soluble in water [5], nicotinic acid could be administered as
30 calcium or sodium salts [6]. At the physiological pH value of 7.4, the anionic
31 species of nicotinic acid could only exist [7]. Due to that, nicotinate solvation in

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water or in water mixtures with ethanol, a solvent, widely used in medicine, is of
interest for researchers.
Recently, a number of papers describing the behavior of different aqueous
solutions of nicotinic acid had appeared. For example, authors [8] found that either
nicotinic acid or nicotinate keeps primary solvation sphere in aqueous solutions of
sodium gluconate. The hydrophobic hydration is the predominant interactions type
in such a system [8]. B. Sinha’s group noted the nicotinic acid in aqueous solutions
of sodium malonate to act as structure-promoting agent [9]. Analogous conclusions
had been made in report [10] describing the aqueous solutions of nicotinic acid and
10 some other vitamins. The complex character of solute-solvent and solute-solute
11 interactions in the systems containing nicotinic acid was observed [11]. The
12 standard molar enthalpies of nicotinic acid dissolution and nicotinate formation in
13 water were determined [12].
14
The solvation state of nicotinic acid vitamer, nicotinamide, in mixed
15 aqueous-organic solvents had being studied [13, 14]. The authors [15] focused on
16 the study of the hydrogen bonds (H-bonds) between nicotinamide and water and π-
17 π stacking between nicotinamide molecules.
18
The present work reports on the influence of the aqueous ethanol solvent
19 composition on 13C NMR spectrum of nicotinate (NA-). 1H, 15N NMR experiments
20 are also discussed. We focus on the reasons determining the signal arrangement in
21 NMR spectra combining both experimental and quantum chemical methods.
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23
2. Experimental
Nicotinic acid (Merck Millipore, Germany) was used without additional
24 purification. The purity of the reagent claimed by manufacturer was >99.9 %
25 (weight). The aqueous or aqueous ethanol solutions of sodium nicotinate for NMR
26 studies were prepared by adding the exact quantity of preliminarily standardized
27 NaOH solution to the 0.249-0.251 mol kg-1 nicotinic acid solution. The bidistilled
28 water (pH = 6.6, κ = 1.7 µSm cm-1) was used for every solution preparation. The
29 ethanol was distilled under atmospheric pressure. Water content in the ethanol was
2

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controlled densimetrically (4.56 weight %) and was taken into account when the
binary solvents were made by the weighting of the accurate amounts of water and
organic solvent with inaccuracy 0.0002 g.
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The H-15N HMBC, H-13C HSQC, C NMR spectra of sodium nicotinate
solutions (0.249-0.251 mol kg-1) in water and aqueous ethanol were recorded on
Avance III Bruker 500 NMR spectrometer with operating frequencies of 500.17,
125.77, 50.701 MHz (1H, 13C, 15N nuclei respectively) at the temperature of 298.2
K. A 5 mm 1H/31P/D-BBz-GRD triple resonance broad band probe (TBI) was
employed. Nitromethane and hexamethyldisiloxane were used as external
15
1
13
10 standards for N and H, C nuclei respectively. An experimental error of
13
15
11 chemical shift measuring did not exceed 0.005 ppm for C, and 0.1 ppm for N.
12 The accuracy of temperature maintaining using temperature unit BVT-3000 was
13 ±0.1 K. Some spectra are given (Figs. S1-S6).
14
Quantum chemical calculations were performed using Firefly QC package
15 [16], which is partially based on the GAMESS (US) source code [17]. The
16 functional B3LYP [18] (DFT method) with basis set 6-311++G(d,p) [19] was
17 chosen to optimize the geometry of nicotinate H-complexes. The basis set choice is
18 justified by its successful application towards analogous compounds in previous
19 studies [20-22]. The suggested ground states were verified by frequency analysis
20 after optimization. NMR chemical shifts (GIAO [23]) were calculated at the same
21 theory level and referenced to the preliminarily calculated chemical shifts of
22 benzene [24] as proposed in [25]. The solvent (water) was set within the
23 framework of CPCM approach in all cases.
24
25
3. Results and Discussion
In the 1H NMR spectrum of aqueous solution of sodium nicotinate, there are
26 four signals referring to the studied compound. They could be assigned uniquely
27 using spin-spin coupling constants (Fig. S1).
28
The proton of site 2 has no neighboring C-H groups, therefore its signal is
29 slightly split (dd, 4J2,4 = 1.72 Hz, 5J2,5 = 0.96 Hz). The H(6) resonance is split more
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(dd, 3J6,5 = 4.98 Hz, 4J6,4 = 1.72 Hz). The rest hydrogen peaks are also significantly
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split (H(4): dt, J4,5 = 7.85 Hz, J4,6 = 1.72 Hz; H(5): ddd, J5,4 = 7.85 Hz,
5
3J5,6 = 4.98 Hz, J2,5 = 0.96 Hz). As expected, H(2) signal is shifted towards lower
field in relation to the other protons of aromatic system.
13
The carbon signals in the C NMR spectrum could be anticipated to follow
in the same order. However, it is the C(6) nucleus that is the least shielded one
13
among the pyridine ring carbons as it follows from C-1H HSQC experiment
results (Fig. S2). Nicotinamide was also reported to possess the same order of
13
signals in the C NMR spectrum (δC6> δC2> δC4> δC5) [13, 14], however, to the
10 best of our knowledge, no explanation had been given yet.
Unlike the experiment, the quantum chemical calculations of NMR spectrum
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12 of nicotinate taking into account the solvent, water (PCM), show C(2) as the least
13 shielded nucleus (See Figs. S8-S15 and Table 1) in all cases except for S15
14 (nicotinate+40 water molecules).
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16 Table 1. Calculated NMR spectra of models S8-S15 (nicotinate + n water
17 molecules), MAE (Mean Absolute Error*) values and correlation coefficients
18 between calculated and experimental chemical shifts
Model
Number
of water
molecules
H(2)
S8
S9
S10
S11
S12
S13
S14
S15
Exp.
0
1
1a
2
3
6
8
40
8.84
8.16
7.98
6.90
0.46
8.88
8.11
8.06
7.00
0.50
8.86
8.23
8.01
6.94
0.50
8.75
8.17
8.06
6.82
0.44
8.81
8.21
8.08
7.04
0.53
8.95
8.21
8.11
7.03
0.57
8.85
8.21
8.13
7.05
0.55
8.87
8.60
8.25
6.97
0.66
8.12
7.79
7.43
6.70
H(6)
H(4)
H(5)
MAE
**
R2
0.9617 0.9193 0.9725 0.9451 0.9556 0.9380 0.9399 0.9544
adj.
Model
Nucleus
C(7)
C(6)
C(2)
C(4)
C(3)
C(5)
S8
0
S9
1
S10
1a
S11
2
S12
3
S13
6
S14
8
S15
40
Exp.
169.10 168.74 170.14 169.20 169.90 170.88 170.29 177.69
151.09 148.75 151.59 149.57 149.98 150.49 150.44 152.11
152.39 150.83 152.50 150.42 150.65 151.03 150.89 153.33
137.05 138.11 137.35 138.88 139.06 138.82 139.15 142.43
134.79 134.88 133.80 134.68 134.03 133.15 133.22 129.63
122.33 123.00 122.63 123.25 123.25 123.55 123.32 123.45
172.16
149.40
148.02
136.65
131.26
122.90
-1.38
δC(2)-δC(6)
1.30
2.08
0.91
0.85
0.67
0.54
0.45
-1.22
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MAE
2.27
2.01
2.03
1.92
1.83
1.68
1.78
3.31
**
R2
0.9705 0.9812 0.9785 0.9864 0.9891 0.9926 0.9903 0.9840
adj.
n
δ
−δcalc
i
∑
exp
* MAE =
i=1
1
n
2
3
4
**R2adj. - adjusted R-squared (number of variables = 1)
Adding the water molecules forming hydrogen bonds (H-bonds) with
nicotinate results in the change of difference between C(2) and C(6) chemical
shifts. Water specifically interacts with nicotinate nitrogen and causes the
increasing of δC2-δC6, thus, increasing the difference between experimental and
calculated NMR spectra. On the contrary, water binding with –COO- group
decreases the difference of δC2-δC6 (See Table 1). The greater the number of water
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6
7
8
9
10 molecules added to the nicotinate in the model, the closer the calculated values of
11 C(2) and C(6) chemical shifts become. Eight water molecules added to the
12 nicotinate decreases the difference of δC2-δC6 to 0.45 ppm (see Table 1). Finally, 40
13
13 water molecules added to the nicotinate makes the calculated C NMR signals
14 order to be in agreement with experimental results (Table 1). Suggesting the model
15 S15, which contains 40 water molecules, we aimed to form the first solvation shell
16 surrounding uniformly the nicotinate.
17
The geometry of pyridine residue of nicotinate is slightly disturbed by water
18 molecules added. In the S8 structure (CPCM only) the bond lengths values are
19 indicative of conjugated structure (C-C distances of 1.39-1.40 Å, C-N distances of
20 1.34 Å) [26]. Adding from 1 to 8 molecules changes the bond lengths in the
21 heterocycle by 0.001-0.002 Å, while the transfer from S14 to S15 structure gives
22 also 0.001-0.002 Å variation to bond lengths. The C3-C7 undergoes the most
23 significant shortening: from 1.533 Å in S7 to 1.503 Å (40 water molecules added).
24 The C-O bond lengths also change noticeably. Being equivalent in the S8 model
25 (1.258 Å), they become slightly unequal and longer in S15 structure (1.266 Å and
26 1.269 Å). The hydrogen bond between nitrogen and water proton elongates from
27 1.839 Å (S9) to 1.850 Å (S15), while the quantity of water molecules increases. In
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the models S10-S14, carboxylate oxygens form two H-bonds with water with bond
lengths of 1.7-1.8 Å. When 40 water molecules are added to nicotinate, a number
of H-bonds between COO- group and solvent molecules could be suggested basing
on the interatomic distances range of 1.8-2.0 Å.
The H-bonds formed between water and nicotinate nitrogen are probably
weaker than in case of nicotinamide heteronitrogen. This suggestion could be
confirmed either using quantum chemical calculations of 13C NMR spectra (adding
the water molecule H-bonded with nitrogen increases difference between
calculated and experimental spectra) or comparing the 15N-1H HMBC spectrum of
10 aqueous solution of nicotinate with that of nicotinate dissolved in aqueous ethanol
11 (XEtOH = 0.7). The difference between nitrogen chemical shifts of nicotinate in two
12 solvents (δN = -85.2 ppm at XEtOH = 0, δN = -83.4 ppm at XEtOH = 0.7) is less than
13 that of nicotinamide (δN = -78.5 ppm at XEtOH = 0, δN = -74.1 ppm at XEtOH = 0.7
14 [13]).
15
Taking all above into account, the order of signals in experimental 13C NMR
16 spectrum of nicotinate (aqueous solution) could be concluded to be determined by
17 H-bond formation between –COO- group of solute and the large quantity of water
18 molecules surrounding the nicotinate.
19
The analysis of dependencies of C(2) and C(6) chemical shifts on ethanol
20 concentration in the binary solvent confirms that suggestion (Fig. 1).
21
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172,5
172,0
171,5
171,0
170,5
170,0
169,5
δ
, ppm
C7
150,0
149,5
149,0
148,5
148,0
C2
C6
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
XEtOH, m.f.
1
2
Figure 1. Dependencies of C(2), C(6) and C(7) chemical shifts on aqueous
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6
7
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ethanol solvent composition
Alcohol content growth leads to the decreasing of water molecules quantity
capable of H-bonding the nicotinate (either nitrogen and ionized carboxylic group).
By this reason, the signals of C(2) and C(6) become closer until ethanol
concentration ca. 0.47 mole fraction and, being swapped, diverge at higher alcohol
13
content (Fig. S3). It is worth noting that the same order of C NMR peaks (δC2>
10 δC6> δC4> δC5) is observed also in aqueous DMSO and aqueous DMF (both XH2O
=
11 0.3, see Figs. S4, S5), which also could confirm the influence of H-bonds with
12 water on the signal arrangement in the 13C NMR spectrum of nicotinate.
13
The tendency of C(2) and C(6) carbons to converge at the increasing of
14 ethanol concentration was observed also in case of nicotinamide [27]. However,
15 the C(2) and C(6) peaks of nicotinamide had never swapped due to higher distance
16 between resonances (>4 ppm in water) and their unidirectional shift.
17
All the dependencies of nicotinate carbon chemical shifts on ethanol content
18 presented bend slightly at XEtOH = 0.2-0.35 m.f. (Fig. 1). The most significant
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changes of nicotinate solvation state probably occurs in that interval of binary
solvent composition.
The significant growth of Gibbs energy change of nicotinate transfer
accompanies the decreasing of water molecules quantity capable of H-bonding the
solute (Fig. 2).
ꢀtrG(NA-), kJ mol-1
12
10
8
6
4
2
0
0
0.1
0.2
0.3
0.4
0.5
XEtOH
7
8
Figure 2. The Gibbs energy changes of nicotinate transfer from water to
aqueous ethanol
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10
11
The Gibbs energy change of nicotinate transfer from water to ethanol
12 ꢀtrG(NA-) is defined as follows:
13
ꢀtrG(NA-)= ꢀG(NA-)H2O-EtOH - ꢀG(NA-)H2O
(1);
14
where ꢀG(NA-)H2O-EtOH is the Gibbs energy change of nicotinate solvation in
15 the binary solvent of water-ethanol; ꢀG(NA-)H2O is the Gibbs energy change of
16 nicotinate solvation in water.
17
ꢀtrG(NA-) (Fig. 2) is calculated basing the data on Gibbs energy change of
18 transfer of dissociation reaction (ꢀtrGr) of nicotinic acid (HNA):
19
ꢀtrG(NA-) = ꢀtrGr - ꢀtrG(HNA) - ꢀtrG(H+)
(2);
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The values of ꢀtrGr and ꢀtrG(H+) are taken from papers [7] and [28]
respectively. ꢀtrG(HNA) is calculated using report [29] data considering the
tautomeric equilibria of nicotinic acid:
ꢀtrG(HNA) = X±ꢁ ꢀtrG(HNA±) + X0ꢁ ꢀtrG(HNA0)
(3);
where X±, X0 are the mole fractions of zwitterionic and neutral species of
nicotinic acid, ꢀtrG(HNA±), ꢀtrG(HNA0) are Gibbs energy changes of zwitterionic
and neutral species transfer.
Therefore, the increasing of ethanol concentration in the binary solvent leads
to H-bonds breaking between water and nicotinate, and nicotinate is solvated less
10 efficiently.
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12
4. Conclusions
There are four signals referred to pyridine residue in the H NMR spectrum
1
13 of aqueous solution of sodium nicotinate. They are placed in the following order:
13
14 δH2>δH6>δH4>δH5. The different order of signals is observed in C NMR spectrum
15 of nicotinate (δC6>δC2>δC4>δC5). Hydrogen bonds formed between water molecules
16 and –COO- group of solute are the most probable reason for C(6) carbon peaks
17 shifted towards lower field in relation to other nuclei of pyridine ring. From the
18 one hand, this suggestion is confirmed by quantum chemical calculations results
19 showing the tendency of C(2) and C(6) resonances to converge at water molecules
20 adding to the model. Accounting the solvation shells of solutes is important for
21 obtaining the correspondence between calculated and experimental data. Modelling
22 the solvation shell of nicotinate using 40 water molecules (model S15) leads to
23 agreement between experimental and calculated signals order. From the other
13
24 hand, C NMR study of aqueous ethanol solutions of sodium nicotinate show the
25 C(2) and C(6) signals swapped at the ethanol concentration of 0.4-0.45 m.f., which
26 makes the order to be δC2>δC6>δC4>δC5. The same signal arrangement is also
27 observed in the solutions of nicotinate in aqueous DMSO (XDMSO = 0.7) and
28 aqueous DMF (XDMF = 0.7).
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The dependencies of C(7), C(6), C(2) nuclei chemical shifts on aqueous
ethanol solvent composition bend slightly at XEtOH = 0.2-0.35 m.f. Probably, the
most significant changes of solvation state of nicotinate occur within this range of
ethanol concentrations.
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Nicotinate heteronitrogen is probably less H-bonded with water molecules
than that of nicotinamide. Adding the water molecule H-bonded with nitrogen of
6
13
7
nicotinate increases the difference between calculated and experimental C NMR
15
8
spectra. Small changes of N chemical shift (ca. 1.4 ppm) while nicotinate
9
transfers from water to aqueous ethanol (XEtOH = 0.7) also confirm this suggestion.
Decreasing the water molecules quantity capable of H-bonding the
10
11 nicotinate is accompanied by the increasing of Gibbs energy change of nicotinate
12 transfer from water to aqueous ethanol.
13
14
Acknowledgements
The study was carried out as a part of State Task of the Ministry of
15 Education and Science of the Russian Federation (basic part project
16 4.7104.2017/8.9.) with financial support of Council on grants of the President of
17 the Russian Federation (project 14.Z56.16.5118-MK). The equipment of Joint
18 Research Center "Upper Volga Regional Center of Physical and Chemical
19 Research" was used to perform NMR experiment. We also thank Prof. G. V.
20 Girichev for his help in conducting the quantum chemical calculations on
21 computing resources of the department of physics of Ivanovo State University of
22 Chemistry and Technology.
23
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ACCEPTED MANUSCRIPT
Highlights
- Signals order in 1H, 13C NMR spectra of nicotinate is different;
- It is caused by hydrogen bonds formation between water and –COO-
group;
- H-bonds between nicotinate nitrogen and water are weak;
- Aqueous ethanol solvent composition influence on nicotinate NMR is
studied.