Molecular structure, proton affinity and hydrogen bonds of (2-hydroxyethyl)amine-N-oxides: DFT, MP2 and FTIR study

Article abstract of DOI:10.1016/j.molstruc.2017.09.013

Tris- 1, bis- 2, and mono- 3 (2-hydroxyethyl)amine-N-oxides isomers, their protonated forms, and H-complexes with acids have been studied in gas phase and DMSO solution by the quantum chemical calculations using DFT and MP2 methods. It is found that the proton affinity of the endo isomers 1a–3a, exo isomers 1b–3b and epi isomer 1c depends on the number of the hydroxyethyl groups, steric factors and strengths of the intramolecular H-bonds OH???ON in 1a–3a and OH???OH in 1b–3b. The peculiarities of formation of the hydrogen bonded and proton transfer complexes of tris(2-hydroxyethyl)amine-N-oxide with trifluoroacetic and 2-methylphenyloxyacetic acids are defined by 1 configuration, acid strength and solvent polarity. The structure of 1 and its complexes upon transition to solution was determined using FTIR spectroscopy.

Full text of DOI:10.1016/j.molstruc.2017.09.013

Accepted Manuscript
Molecular structure, proton affinity and hydrogen bonds of (2-hydroxyethyl)amine-N-
oxides: DFT, MP2 and FTIR study
Tamara N. Aksamentova, Nina N. Chipanina, Larisa P. Oznobikhina, Sergei N.
Adamovich, Vladimir I. Smirnov
PII:
S0022-2860(17)31191-2
10.1016/j.molstruc.2017.09.013
MOLSTR 24262
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 16 June 2017
Revised Date: 6 September 2017
Accepted Date: 7 September 2017
Please cite this article as: T.N. Aksamentova, N.N. Chipanina, L.P. Oznobikhina, S.N. Adamovich, V.I.
Smirnov, Molecular structure, proton affinity and hydrogen bonds of (2-hydroxyethyl)amine-N-oxides:
DFT, MP2 and FTIR study, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.09.013.
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ACCEPTED MANUSCRIPT
1c + Acid
HB complex
1a
PT complex
...
Gas, DMSO
DFT
Acid
+
... HO CR
H... O CR
O
O
1b
Gas, DMSO
Acid
DFT
Gas
DFT
Gas, DMSO
CH2Cl2
FTIR
DFT

Molecular structure, proton affinity and hydrogen bonds of (2-
ACCEPTED MANUSCRIPT
hydroxyethyl)amine-N-oxides: DFT, MP2 and FTIR study
Tamara N. Aksamentova*, Nina N. Chipanina, Larisa P. Oznobikhina, Sergei N.
Adamovich, Vladimir I. Smirnov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of Russian Academy of Sciences, 1 Favorsky
Street, 664033, Irkutsk, Russian Federation
A B S T R A C T
Tris- 1, bis- 2, and mono- 3 (2-hydroxyethyl)amine-N-oxides isomers, their protonated forms, and H-
complexes with acids have been studied in gas phase and DMSO solution by the quantum chemical
calculations using DFT and MP2 methods. It is found that the proton affinity of the endo isomers 1a–
3a, exo isomers 1b–3b and epi isomer 1c depends on the number of the hydroxyethyl groups, steric
factors and strengths of the intramolecular H-bonds OH ON in 1a–3a and OH OH in 1b–3b. The
peculiarities of formation of the hydrogen bonded and proton transfer complexes of tris(2-
hydroxyethyl)amine-N-oxide with trifluoroacetic and 2-methylphenyloxyacetic acids are defined by 1
configuration, acid strength and solvent polarity. The structure of 1 and its complexes upon transition
to solution was determined using FTIR spectroscopy.
Keywords: (2-Hydroxyethyl)amine-N-oxides Proton affinity Hydrogen bond Proton transfer
DFT/MP2/FTIR study QTAIM/NBO analysis
1.
Introduction
Amine-N-oxides are employed in organic synthesis as oxidants, catalysts, ligands and find wide
application in pharmacology [1−8]. The nature of the N–O bond in amine-N-oxides has been studied
by theoretical calculations (including QTAIM and NBO approaches) and the statistical analyses of the
database crystal structure content [9, 10]. It is revealed that the hydrogen- and halogen-bonded
complexes of N-oxides possess a strong Lewis basicity of the N-oxide group [9, 11]. Pyridine-N-
oxides are more fully studied by physicochemical methods using quantum chemical calculations. An
effect of the substituent nature on the geometry and redox properties of compounds as well as on the
parameters of the semipolar N→O bond has been analyzed using DFT (B3LYP and PBE0) and MP2
approximations [12]. The complexes of substituted pyridines and pyridine-N-oxides with carboxylic
1
and mineral acids were studied in various organic solvents by spectroscopic (IR, H, NMR),
conductometric, potentiometric, and vapor pressure osmometry methods [13]. Competition
_______
* Corresponding author.
E-mail address: aksamentova@irioch.irk.ru (T.N. Aksamentova).

2
experiments between the pyridyl and pyridyl-N-oxide groups have been carried out to find out which
ACCEPTED MANUSCRIPT
of these two groups is a better acceptor in the hydrogen bonding with the carboxylic acid group [14].
An ability of amine-N-oxides to act as proton acceptor in the formation of HB complex has
been theoretically evaluated on the example of ammonium oxide and trimethylamine-oxide [15]. In
some cases, they form strong H-bonds with an energy exceeding 12 Kcal.mol−1. Notably, for strong
acids in gaseous phase the spontaneous proton transfer takes place. The interaction between
trimethylamine-N-oxide and urea is studied experimentally using broadband (100 MHz-1.6 THz)
dielectric spectroscopy in the presence of water [16]. It is shown that H-bonds of three water
molecules with hydrophilic N–O moiety of N-oxide remain intact at any urea concentration. The
complexes of alkylamine-N-oxides with phenols, which are used for the phenol extraction from water,
were investigated by isothermal titration calorimetry and quantum chemical modeling [17].
The reactions of amine-N-oxides with acids lead to hydroxyammonium complexes (salts),
which possess potential anti-cancer and growth-stimulating activity [6, 18 and references cited
therein]. Tris(2-hydroxyethyl)amine-N-oxide O−N(CH2CH2OH)3 1 can be obtained via biodegradation
[19] or catalytic oxidation of triethanolamine [20, 21]. In contrast to these methods, we have managed
to synthesize N-oxide 1 under non-catalytic conditions. This compound is found to react with
arylchalcogenylacetic and other acids to afford a number of tris(2-hydroxyethyl)hydroxyammonium
complexes (salts and ionic liquids) [22]. These compounds are of interest as potentially
pharmacologically active substances and drug precursors. Among the essential properties of drugs is
bioavailability, which is defined by structure of the precursors, in particular, by their H-bonds. It has
been established that different pharmacologically active complexes, hydrogen bonded (HB) and proton
transfer (PT) ones, show different mode of penetration into cell membranes [23]. Some 2-
hydroxyethylammonium complexes (ionic liquids) are characterized by rapid intermolecular proton
transfer between OH moieties and acid molecules HX [24]. Various acid-dependent H-bonds can also
be formed in the complexes synthesized by us.
Earlier, we used unoxidized forms of biogenic tris-, bis-, mono(2-hydroxyethyl)amine N(Ме)3-
n(CH2CH2OH)n (n = 1−3) and biologically active 2-methylphenyloxyacetic acid 2-Me-Ph-O-
CH2COOH (and other arylchalcogenylacetic acids) to synthesize a wide range of (2-
.
hydroxyethyl)ammonium salts and ionic liquids of the formula (НОСН2СН2)n(Me)3-nN+H
−OOCCH2YAr. Some of them were found to possess pharma-cological activity with immunotropic,
antiallergenic, antitumor, antimetastatic, protecting, growth and enzyme promoting action [25−28].
According to X-ray data, N-oxide oxygen atom of compound 1 forms intermolecular H-bonds
with the hydroxyl groups of its three identical molecules [29]. Analogous four-centered H-bonds are
observed in the complex of tris(2-hydroxyethyl)amine-N-oxide with tris(2-hydroxyethyl)amine [30].
Amine-oxide O atom of this complex is trifurcated by a trigonal “cap” of hydrogen bonds to the
hydroxyl H atoms of the triethanolamine lying on the same threefold axis. The amine-oxide hydroxyl

3
H atoms are hydrogen bonded to three adjacent triethanolaIPmine O atoms, thus completing a three-
ACCEPTED MANUSCR T
dimensional polymeric network.
The problems, related to the effect of intra- and intermolecular H-bonds on the conformational
structure of nitrogen- and oxygen-containing molecules are successfully solved at the combined use of
quantum chemical calculations and spectral methods of the investigation [31−34]. The present work is
aimed at theoretical estimation of geometric, energetic, and electronic characteristics and basicity of
tris-, bis-, and mono(2-hydroxyethyl)amine-N-oxides, O-N(Me)3-n(CH2CH2OH)n (n = 1−3), in the
endo 1a−3a, exo 1b−3b and epi 1c configurations, trimethylamine-N-oxide 4 (Chart 1), their
protonated forms, as well as HB and PT complexes with trifluoroacetic (CF3COOH) 5 and 2-
methylphenyloxy-acetic (2-Me-Ph-O-CH2COOH) 6 acids in gas phase and polar medium. The
structures of 1−3 and their complexes with acids upon transition to solution was determined using
NMR and FTIR spectroscopy.
The number of hydroxyethyl groups in molecules 1−3 determines the presence of
intramolecular H-bonds of various types, which stability of molecules and their basicity depend on
them. The conformational endo and exo isomers of amine-N-oxides are chosen as the most stable, due
to the presence of intramolecular NO HO and HO HO bonds. The epi conformer 1c is realized in the
crystal, does not contain intramolecular hydrogen bonds, and is structured between endo and exo
forms. Acid 6 is used because its complexes with tris-, bis(2-hydroxyethyl)amine have showed the
high biological activity [25, 28]. The stronger acid 5 is selected as able to form PT complexes with
heteroatomic molecules. The compounds 2 and 3 and the complexes of 1−3 with acid 6 are synthesized
and characterized by NMR and IR spectroscopy. The structure of 1 and its complexes upon transition
to solution was determined using FTIR spectroscopy. It is expected that the results obtained will be
helpful in design of the most effective pharmaceuticals.
OH
OH
OH
OH
OH
OH
OH
O
N
N O
O
N
OH
OH
OH
OH
O
N
Me
N O
Me
OH
OH
1a
1b
1c
2a
2b
Tris(2-hydroxyethyl)amine-N-oxide
N-methyl-bis(2-hydroxyethyl)amine-N-oxide
Me
Me
Me
N O
Me
Me
N O
Me
N
Me
O
OH
OH
3a
3b
4
N,N-dimethyl-mono(2-hydroxyethyl)amine-N-oxide
Trimethylamine-N-oxide

4
C rt 1. Amine-N-oxides
ACCEPThaED MANUSCRIPT
DFT and MP2 methods were used for quantum chemical calculations of investigated
compounds. A special attention is focused on hydrogen bonds formed by the hydroxyl groups and N-
oxides oxygen atom of the isomers 1 and their HB and PT complexes. The results are compared with
the data of previous study of HB and PT complexes of tri-, di-, and monoethanolamines [35]. The
quantum theory of atoms in molecules (QTAIM) and the natural bond orbital (NBO) analysis have
been used to evaluate strength of the hydrogen bonds OH ON, OH OH and NOH+ O− and estimate
the energies of orbital interactions in the studied molecules and their complexes.
2.
Experimental
2.1. Material and instruments
The chemicals were of reagent grade, purchased from Aldrich and were used without any further
purification. NMR spectra (D2O) were recorded on a Bruker DPX-400 spectrometer (1H, 400.13 MHz;
15
13C, 101.62 MHz; N, 40.53 MHz, relative to MeNO2), using HMDS as an internal standard. Signals
1
1
in the NMR spectra were assigned using 2D experiments H-13C HSQC and H-13C HMBC. FTIR
spectra were taken for solid compounds and for their solutions in CH2Cl2 on a ATR-FTIR Varian 3100
spectrometer.
2.2. Synthesis and characterization
2.2.1 Synthesis of compounds 1, 2 and 3.
Tris(2-hydroxyethyl)amine-N-oxide, O−N(CH2CH2OH)3 1, was synthesized via oxidation of
triethanolamine with hydrogen peroxide by the procedure described in [22]. Compounds 2 and 3 are
obtained similarly.
N-methyl-bis(2-hydroxyethyl)amine-N-oxide (2).
The yield 96%. Colorless oil.
1H NMR (D2O, 400 MHz), δ: 3.78 (t, 4 H, OCH2, J = 5.0 Hz), 3.29 (t, 4 H, NCH2, J = 5.0 Hz), 3.00 (s,
3 H, Me).
1
1
13C NMR (D2O, 100 MHz), δ: 69.78 (NCH2, JC,H = 142.6 Hz); 56.07 (Me); 55.69 (OCH2, JC,H
=
145.5 Hz).
15N NMR (D2O, 40 MHz), δ: -265.1 (unoxidized form -353.1).
Anal. calcd. for C5H13NO3: C 44.43, H 9.69, N 10.36; found: C 44.70, H 9.90, N 10.55.
N,N-dimethyl-mono(2-hydroxyethyl)amine-N-oxide (3).

5
The yield 95%. Colorless oil. ACCEPTED MANUSCRIPT
1H NMR (D2O, 400 MHz), δ: 3.81 (t, 2 H, OCH2, J = 5.0 Hz), 3.34 (t, 2 H, NCH2, J = 5.0 Hz), 3.09 (s,
6 H, Me).
1
1
13C NMR (D2O, 100 MHz), δ: 70.77 (NCH2, JC,H = 142.0 Hz); 57.75 (Me); 55.72 (OCH2, JC,H
=
145.7 Hz).
15N NMR (D2O, 40 MHz), δ: -269.6 (unoxidized form -357.2).
Anal. calcd. for С4Н11NO2: C 45.69, H 10.54, N 13.32; found: C 45.47, H 10.40, N 13.36.
2.2.2 Synthesis of compounds 1 5, 1 6, 2 6 and 3 6 (general procedure).
Synthesis of the parent (2-methylphenyloxyacetic) acid 6 and tris(2-hydroxyethyl)hydroxyammonium
trifluoroacetate (1 5) was described earlier [22].
A mixture of corresponding 2-hydroxyethylamine-N-oxide 1, 2 or 3 (0.01 mol) and 2-
methylphenoxyacetic acid 6 (the ratio 1 : 1) in H2O or methanol (30-70 mL) was stirred for 1-3 h at
20-45 °C. The solvent was evaporated, the residue was repeatedly washed with diethyl ether, dried in
vacuo (0.5 Torr, over P2O5, 24 h) to obtain colorless powder or waxy substance.
Tris(2-hydroxyethyl)hydroxyammonium (2-methylphenyloxy)acetate (1 6).
The yield was 89% (45 °C, 3 h, MeOH), yellow waxy substance.
3
1H NMR (D2O, 400 MHz), δ: 7.01 (d, 1 H, C(3)HC6H4, 4J H,H = 1.8 Hz), 6.98 (dd, 1 H, C(5)HC6H4 JH,H
= 7.8 Hz, 4JH,H = 1.8 Hz), 6.57 (d, 1 H, C(6)HC6H4, 3JH,H = 7.8 Hz), 4.33 (s, 2 H, C6H4OCH2), 3.71 (t, 6
H, OCH2, J = 5.0 Hz), 3.21 (t, 6 H, NCH2, J = 5.0 Hz), 2.07 (s, 3 H, Me). 13C NMR (D2O, 100 MHz),
δ: 174.55 (C=O); 154.94 (CC6H4 (1)), 130.02 (CC6H4 (3)), 128.65 (CC6H4 (4)), 126.06 (CC6H4 (2)), 124.65
(CC6H4 (5)), 112.92 (CC6H4 (6)); 67.55 (C6H4OCH2); 58.55 (NCH2); 54.75 (OCH2); 15.45 (Me).
15N NMR (D2O, 40 MHz), δ: -260.60 (unoxidized form -338.6 ).
Anal. calcd. for C15H25NO7: C 54.37, H 7.60, N 4.22; found: C 54.67, H 7.40, N 4.21.
N-methyl-bis(2-hydroxyethyl)hydroxyammonium (2-methylphenyloxy)acetate (2 6).
Yield 76% (45 °C, 1 h, H2O). Yellow waxy substance.
3
1H NMR (D2O, 400 MHz), δ: 6.72 (d, 1 H, C(3)HC6H4, 4J H,H = 1.8 Hz), 6.69 (dd, 1 H, C(5)HC6H4 JH,H
= 7.8 Hz, 4JH,H = 1.8 Hz), 6.31 (d, 1 H, C(6)HC6H4, 3JH,H = 7.8 Hz), 4.12 (s, 2 H, C6H4OCH2), 3.80 (t, 4
H, OCH2, J = 5.0 Hz), 3.48 (t, 4 H, NCH2, J = 5.0 Hz), 3.12 (s, 3H, NMe), 1.85 (s, 3 H, Me).
13C NMR (D2O, 100 MHz), δ: 175.82 (C=O), 154.70 (CC6H4 (1)), 130.20 (CC6H4 (3)), 128.76 (CC6H4
(4)), 126.20 (CC6H4 (2)), 124.91 (CC6H4 (5)), 112.45 (CC6H4 (6)), 69.54 (NCH2), 66.88 (C6H4OCH2),
55.29 (OCH2), 55.05 (NMe), 15.40 (Me).
15N NMR (D2O, 40 MHz), δ: -262.20 (unoxidized form -340.43).
Anal. calcd. for C14H23NO6: C 55.80, H 7.69, N 4.64; found: C 56.09, H 7.51, N 4.35.

6
ACCEPTED MANUSCRIPT
N,N-dimethyl-mono(2-hydroxyethyl)hydroxyammonium (2-methylphenyloxy)acetate (3 6).
Yield 94% (25°C, 1 h, MeOH). Colorless waxy substance.
3
1H NMR (D2O, 400 MHz), δ: 7.13 (d, 1 H, C(3)HC6H4, 4J H,H = 1.8 Hz), 7.10 (dd, 1 H, C(5)HC6H4 JH,H
= 7.8 Hz, 4JH,H = 1.8 Hz), 6.65 (d, 1 H, C(6)HC6H4, 3JH,H = 7.8 Hz), 4.40 (s, 2 H, C6H4OCH2), 4.00 (t, 2
H, OCH2, J = 5.0 Hz), 3.64 (t, 2 H, NCH2, J = 5.0 Hz), 3.38 (s, 6H, Me), 2.15 (s, 3 H, Me).
13C NMR (D2O, 100 MHz), δ: 176.43 (C=O); 154.70 (CC6H4 (1)), 130.18 (CC6H4 (3)), 128.45 (CC6H4
(4)), 126.00 (CC6H4 (2)), 124.60 (CC6H4 (5)), 112.54 (CC6H4 (6)), 70.49 (NCH2), 67.04 (C6H4OCH2),
57.06 (Me2N), 55.37 (OCH2), 15.32 (Me).
15N NMR (D2O, 40 MHz), δ: -269.60 (unoxidized form -344.01).
Anal. calcd. for C13H21NO5: C 57.55, H 7.80, N 5.16; found: C 55.81, H 7.53, N 5.21.
2.3. Quantum chemical calculations
The calculations were performed at B3LYP/6-311+G(d,p), M06-2X/6-311G(d,p) and MP2/6-
311+G(d,p)//B3LYP/6-311+G(d,p) levels of theory with full geometry optimization by DFT method
using Gaussian 09 program suite [36]. Despite the deficiencies of B3LYP method it is successfully
used for the molecular systems with hydrogen bonding and proton transfer [7, 37−40]. In addition, the
use of this functional has allowed us to compare the results of the calculations with the previously
performed ones for unoxidized ethanolamines and their complexes with acids [35]. All calculated
structures correspond to minima on the potential energy surface (PES) as proved by positive
eigenvalues of the corresponding Hessian matrices. The energies were calculated by all methods with
ZPE correction of DFT method. The proton affinity of basic (PA1) and acid centers (PA2) was
calculated as the enthalpy difference (∆H298) between corresponding neutral and charged molecules. A
formation energies Е1(В АН) of HB and E2(BH+ A−) of PT complexes were defined by subtracting the
sum of neutral acid and base or their conjugation species total energies from the total energy E(ZPE)
of the complexes. The calculations in the polar medium (DMSO, ε = 46.7) were performed with
Onsager self-consistent reaction field (SCRF) method [41] at DFT levels of theory with full geometry
optimization. The NBO analysis [42, 43] as implemented into Gaussian package was performed at
B3LYP/6-311+G(d,p) level of theory using the structures optimized by this method. The QTAIM
analysis was performed by the use of AIM2000 program (version 2.0) [44] with the wave function
taken from MP2/6-311++G** calculations on the previously B3LYP/6-311+G(d,p) optimized
structures.
3.
Results and discussion

7
3.1. Energetic and geometric characteristics, andUSproton affinity (PA) of (2-hydroxyethyl)amine-
ACCEPTED MAN CRIPT
N-oxides
The values of relative electron energies ∆E(ZPE), enthalpies ∆H298, Gibbs free energies ∆G298 and
entropies ∆S298 of the (2-hydroxyethyl)amine-N-oxides isomers 1a,b,c, 2a,b and 3a,b are given in
Table S1 (hereinafter is given in Supplementary Information). In the all calculation methods, these
values are changed according to each other. Amine-N-oxides 1a−3a are more stable configurations.
The highest difference in stability is observed for isomers 1, especially in polar medium. For instance,
isomers 1b and 1c are less stable than 1a by 12.48 and 15.33 Kcal.mol−1 in gas phase and 16.51 and
19.62 Kcal.mol−1 in DMSO (ε = 46.7) at B3LYP/6-311+G(d,p) method. The stabilities of 1b and 1c
decrease by 1−2 Kcal.mol−1 at MP2 method. The differences of stability remain unchanged for 1b and
increase by 5 Kcal.mol−1 for 1c with M06-2X method. Values of ∆H298 and ∆G298 vary in the same
way, but ∆S298 values are low for 1a and 1b and increase by 10 eu for a less stable 1c. However, it is
the most unstable isomer 1c in the gas and solution that forms the crystal structure of the compound 1,
determined by the X-ray diffraction method. The energies of intermolecular interactions in the
structure 1d, formed by four single molecules 1c through three OH ON and three OH OH bonds,
(Fig. S1) are calculated in the gas at B3LYP/6-311G(d,p) to determine the cause of this phenomenon.
The structure 1d is the fragment of the crystal structure 1. At this calculation the stability of 1a in the
gas is higher than 1c at 19.29 Kcal.mol−1. Accordingly the average electronic energy E(ZPE)av of
single molecule 1c in the structure 1d, this isomer is more stable than 1a by 0.03 Kcal.mol−1. Hence
the energy of intermolecular interactions in 1d overcomes energy necessary for reorganization of the
most stable conformer 1a in 1c.
The nature of the N−O bonds and intramolecular OH ON, OH OH bonds in 1a–3a, 1b–3b,
1c and 4 was analyzed by QTAIM approach [45] (Table S2). Bond critical points (BCP) were found
and the topological properties of the electron density ρ(rc), its Laplacian 2ρ(rc), the local potential
energy densities Vc, the local kinetic energy densities Gc, and the total energy densities H(rc) were
evaluated. The critical points (3, −1) were identified as the bond critical and H-bond critical points.
The binding energies E were calculated by equations E = ½Vc; Vc = ¼ 2ρ(rc) – 2Gc [46]. The energy
values of H-bonding E both between N-oxide oxygen atom and hydroxyl groups in 1a–3a and between
hydroxyl groups in 1b–3b are 6–11 Kcal.mol−1.
The molecular structures of 1a–3a, 1b–3b, 1c and 4 are given in Figure 1 and their geometric
parameters and QTAIM energies E in Tables S2, S3. The intramolecular OH ON bonds are formed in
1a−3a, while the intramolecular OH OH bonds are observed in 1b−3b. The shortest (l 1.809 Å) two-
centered H-bond NO HO with the most values of the electron density ρ(rc) 0.0383 au and energy E
11.09 Kcal.mol−1 is expectedly formed in 3a. The components of the N-oxide oxygen atom bifurcation
bond in 2a become longer (l 1.823 and 1.897 Å) with decreasing electron densities (ρ(rc) 0.0371,

8
0.0324 au) and energies (E 10.68, 9.01 Kcal ). Simultaneously the components of trifurcation
.mAol−1
ACCEPTED M NUSCRIPT
bond in 1a are elongated to 1.846, 1.910, and 1.968 Å with ρ(rc) 0.0351, 0.0309 and 0.0282 au and E
10.03, 8,60 and 7.58 Kcal.mol−1. In 1b and 2b, OH OH bonds between the hydroxyl groups (l
1.884−1.975 Å, ρ(rc) 0.023−0.028 au and E 5.9−7.6 Kcal.mol−1) are detected and one of these groups
in 1b acts as both proton donor and proton acceptor in hydrogen bonded chain O−H O−H O−H. The
N−O bonds are shortest (l 1.367−1.370 Å) with ρ(rc) 0.34−0.35 au and E 172−179 Kcal.mol−1 in
2b−3b, 1c and 4, which do not have intramolecular H-bonds or bear one longest OH OH bond. In 1b,
the N−O bond is elongated to 1.377 Å, when the molecule contains three hydroxyethyl groups with
HO HO intramolecular bonds (Fig. 1). In 1a−3a, due to formation of the OH ON bonds, the N−O
bond is elongated from 1.380 to 1.398 Å with ρ(rc) 0.32−0.34 au and E 156−168 Kcal.mol−1 with
increase of the number of hydroxyethyl groups.
H19
H22
O6
O8
1.965
O8
H25
O10
1.968
1.947
1.896
O26
H19
H22
1.910
1.851
C7
1.884
1.885
O10
1.846
1.820
C5
O6
1.398
1.404
C9
C3
C5
C9
C4
N1
C2
C7
C4
C2
N1
C3
1.377
1.378
O26
1a
1b
O5
O7
O5
H14
H17
H14
O18
1.823
1.897
1.975
1.390
C4
C6
C4
O7
N1
C19
C2
C19
C2
C3
C3
N1
1.369
C6
O18
2a
2b
H9
O4
O10
1.809
O4
1.380
N1
C3
C15
C11
C15
C2
C3
C2
N1
1.370
C11
O10
3a
3b

9
ACCEPTED MANUSCRIPT
O14
C3
1.366
N4
1.371
C1
C2
1c
4
Fig. 1. B3LYP/6-311+G(d,p) structures of amine-N-oxides 1a–3a, 1b–3b, 1c and 4. Interatomic distances are
shown in Å. Legend for values: Roman type, gas; boldface type, DMSO solution.
Geometry dependence of electron donating or accepting properties of the terminal amine group
has been confirmed by the scrutiny of crystallographic geometry and quantum chemical studies [47]. It
is shown that a planar amine group acts as an electron-donating group, while pyramidal amine group
behaves as electron-accepting group. It can be found in the interaction of nitrogen atom with the N-
oxide oxygen atom, and, therefore, in the change of its basicity. Pyramidality of the nitrogen atom (the
sum of CNC angles, (Table S3) in N-oxides 1a−3a, 1c and 4 having different geometric structures is
almost the same (~328°). It is smaller in 1b−3b (331−337°) and close to that of trimethylamine (335°).
Consequently, the electron interaction between hydroxyl groups and N-oxide oxygen atom has no
effect on pyramidality of nitrogen, while the steric factors are determining. The sum of CNC angles of
1с isomer is lowest (325°), NCC, CCO bond angles are the same and below even 1a, but COH ones
are closer to 1b. The stability of isomer 1a in a polar medium is higher by 4 Kcal.mol−1 than in gas
(Table. S1), which is due to the shortening of its intramolecular bonds NO HO by 0.03−0.07 Å (Fig.
1).
The proton affinities PA1 for 1a–3a, 1b–3b, 1c and 4 are given in Table 1. The O–H bonds
dissociation energies PA2 of proton donors 5 and 6 are 318.30 and 332.31 Kcal.mol−1 respectively. The
PA1 values of the molecules 1b–3b are higher by 3–5 Kcal.mol−1 than those of 1с, having the most
pyramidal nitrogen atom. Despite the different inductive effects of hydroxyethyl groups in 1c and
methyl groups in 4, these compounds are characterized by very similar values of PA1.
Table 1
B3LYP/6-311+G(d,p) proton affinities PA1 (Kcal.mol−1); the sum of the valence angles of the nitrogen atom
Σ CNC (degree), the energy gap ∆EMO = EHOMO − ELUMO (eV) of the bases 1a–3a, 1b–3b, 1c and 4
.
Molecule
PA1
225.43
Molecule PA1
235.77
2b
Σ CNC
∆EMO
Σ CNC
∆EMO
5.36
328
6.59
331
1a

10
ACCEPT
5
E
.2
D
3
MANUSCRIPT
5.93
5.17
236.20
232.15
231.16
337
325
328
235.79
237.66
233.01
235.0a
328
331
328
1b
1c
2a
3a
5.54
6.32
3b
4
a Experimental values [48].
The PA1 values of endo isomers 1a–3a, having the intramolecular OH ON bonds are lower,
than at exo isomers 1b−3b. The basicity of 1a–3a decrease with increasing the number of the
hydroxyethyl groups unlike triethanolamines, the basicity of which augments due to inductive effect of
these groups [49]. The formation of intramolecular OH ON bonds in the amine-N-oxides lowers the
basicity of molecules to a greater extent than the inductive effect of substituent at the nitrogen atom
increases it. So, the PA1 value of 1a (225.43 Kcal.mol−1) is lower than that of 1c (232.15 Kcal.mol−1).
The principle frontier molecular orbitals of 1a–3a, 1b–3b and 1c are shown in Figure S2. The
calculated values for the molecular orbital energies EHOMO, ELUMO and energy gap ∆EMO = EHOMO
−
E
LUMO using B3LYP/6-311+G(d,p) are given in Tables 1 and S4. A decrease in the values of ∆EMO in
1a−3a series leads to the increase in their basicity. The highest values of PA1 of oxides 1b−3b
correspond to the lowest values of the energy gap of their MO. For molecules 1a−3a and 1c, HOMO is
mainly localized to N−O and OH groups. At the same time, LUMO of 1a−3a is localized to
α-CH2 and
CH3 groups, and in 1c their electron density is mainly distributed on -CH2 and OH groups. It should
β
promote the participation of hydroxyl groups of 1c in intermolecular interactions.
The NBO values of the second-order perturbation energies E(2) (Table S5) of the nO→σ*O-H
interaction between the Lone Pair (LP) of N-oxide oxygen atom and the hydroxyl groups in 1a–3a are
7.1–16.0 Kcal.mol−1. The total energies ΣE(2) of this interaction are 29, 25, and 16 Kcal.mol−1 for the
molecules 1a, 2a, and 3a, respectively. This interaction decreases the PA1 values in 1a–3a as
compared to the 1b–3b. The values of energies of nO→σ*O-H interaction between the hydroxyl groups
in isomers 1b and 2b are 5.5–9.2 Kcal.mol−1 and their total energies are by 17 and 6 Kcal.mol−1 lower.
The QTAIM energy values of H-bonding E both between N-oxide oxygen atom and hydroxyl groups
in 1a–3a and between hydroxyl groups in 1b–3b are in agreement with values E(2). According to NBO
and QTAIM classification, these H-bonds can be considered as of middle and high strength [50, 51]. In
addition, the N-oxide oxygen atom in all studied N-oxides acts as an electron donor towards three N–C
bonds providing so-called reverse donation O→N, which effects significantly on ability to the
intermolecular interaction [9]. The energies of interaction nO→σ*N-C between N-oxide oxygen atom
and N−Alk bonds in 1a–3a, 1b–3b and 1c change in the range 7–12 Kcal.mol−1. Their total values are
26–28 Kcal.mol−1 in 1a–3a and 1b and increase up to 32 Kcal.mol−1 in 1c and 4. This interaction can
explain the decrease in basicity of 1c and 4, as compared to 1b.

11
Consequently, the basicity of the N-oxide oxygen atom
ACCEPTED MANUSCRIPTin 1a–3a, 1b–3b and 1c depends on a
number of factors, namely, the intramolecular NO HO and HO HO bonds in the endo and exo
conformers, as well as their number, the energy of HOMO and LUMO, the orbital interactions of the
LP of N-oxide oxygen atom and the pyramidality of the nitrogen atom.
3.2. Structure and stability of the complexes of the tris-(2-hydroxyethyl)amine-N-oxides with acids
The molecular structure and the energetic parameters of the tris-(2-hydroxyethyl)amine-N-oxides
1a,b,c complexes with the acids 5 and 6 are given in Figure 2 and Table 2 and their QTAIM
topological electron density properties at the bond critical points are presented in Table S6 and S7. The
minimum on the PES corresponds to HB complexes of 1a with trifluoroacetic 5 and 2-
methylphenoxyacetic 6 acids (1a 5-HB and 1a 6-HB) in gas, formed via intermolecular bond OH ON
between the hydrogen atom of the acid and the oxide oxygen atom of the base. On the contrary,
triethanolamine, having the similar orientation of the hydroxyethyl groups, can form with the organic
acids the complexes of two types: hydrogen bonded complexes and proton transfer PT complexes via
bond NH+ O− [24]. The proton transfer complex 1a 5-PT forms in the polar medium (DMSO, ε =
46.7), where it is more stable.
F
O
H
C
O
H
O
O
F
O
O
H
H
N
O
O
H
N
F
O
O
H
C
H
H
O
O
H
H
O
1a 5-HB
1a 6-HB
H
F
O
O
O
F
H
O
H
F
O
O
N
N
H
O
H
H
O
O
H
O
O
O
O
H
1b 5-HB
1b 6-HB

12
ACCEPTED MANUSCRIPT
O
H
O
O
N
F
N
O
H
O
F
O
H
O
F
1c 5-HB
1c 6-HB
F
F
O
O
H
O
O
H
O
H
O
F
N
O
1.546
H
H
1.029
O
N
1.986
O
F
O
F
H
F
H
O
1.954
O
1a 5-PT
1b 5-PT
O
H
O
1.815
F
O
F
H
O
N
F
1.004 1.669
N
O
H
O
O
H
O
1c 5-PT
1c 6-PT
Fig. 2. B3LYP/6-311+G(d,p) structures of HB and PT complexes of 1a,b,c molecules with acids 5 and 6.
Interatomic distances are shown in Å. Legend for values: Roman type, gas; boldface type, DMSO solution.
Table 2

13
Relative electron energies ∆E(ZP
E) and free energies ꢀ cal.m
GU29S8 C(K ol−1), entropies ꢀS298 (eu) of complexes,
ACCEPTED MAN RIPT
QTAIM H-bond energies E, NBO Е(2) energies of the N-oxide oxygen atom interaction nO→σ*O−H, formation
energies of HB Е1(В НА) and PT E2(BH+ A−) complexes (Kcal.mol−1) and H-bond lengths lNO···H and lNOH ···A
+
−
(Å).
−∆G298
Complex
∆E(ZPE)a
∆S298
E
E(2)
lNO···H
B HA
−E1(В НА)
12.05
16.26
10.04
16.86
22.11
25.89
18.18
24.16
20.84
25.13
19.02
24.57
23.55
18.56
0
0
0
19.78
15.26
41.25
28.14
37.65
26.64
43.10
30.83
98.59
87.33
87.37
1.588
1.667
1.371
1.480
1.396
1.495
1a 5-HB
0
0
0
0
1a 6-HB
1b 5-HB
1b 6-HB
1c 5-HB
1c 6-HB
0
2.42
3.48
4.35
5.82
6.54
8.17
6.36
9.33
2.01
4.74
3.97
3.45
−1.42
1.45
−12.41
−12.79
46.11
28.64
110.70
81.86
1.342
1.475
4 5-HB
4 6-HB
BH+ A−
1a 5-PT
1b 5-PT
−E2(BH+ A−)
102.44
103.75
114.41
106.47
109.79
116.08
116.30
102.08
108.56
lNOH ···A
+
−
0
0
0
26.98
1.491
50.43
114.05b
98.41b
1.320
−2.61
−4.04
−2.18
−5.23
1.86
22.59
1.546
40.69
1.378
1c 5-PT
−6.00
14.12
36.55
46.10
1.669
1.404
1.341
1c 6-PT
110.70b
4 5-PT
a
b
−
Values with zero-point energy correction. Е(2) energies of the acid О− atom interaction nO →σ*O−H+. Legend
for values: Roman type, B3LYP/6-311+G(d,p), gas; italic type, MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p), gas;
boldface type, SCRF/B3LYP/6-311+G(d,p) calculations with DMSO as a solvent (ε 46.7).
Amine-N-oxides 1b and 1c in the gas form HB and PT complexes with acid 5 and only HB
complexes with acid 6. The difference in the total energies of 1b 5-HB and 1b 5-PT complexes does

14
not exceed 0.5 Kcal.mol−1,
ACCEPTEcaD MANUSCRIPT
and they n be easily transformed into each other due to the
spontaneous proton transfer. This difference for 1c is 2.9 Kcal.mol−1 and a single minimum proton
potential is shifted from the acid to the N-oxide as shown in the FTIR study of O···H···O hydrogen
bonds with larger proton polarizability in sulfonic acid-N-oxide systems [52]. The PT complex of
isomer 1c with acid 6 is formed in the polar medium (DMSO). The complexes 1a 5-HB and 1a 6-HB
are more stable by 2−6 Kcal.mol−1 ∆E(ZPE) and ∆G298) than similar complex 1b at DFT and MP2
(
methods. However, this difference for free energies decreases to 3 Kcal.mol−1. As in the case of 1c 5-
HB and 1c 6-HB complexes, these differences increase approximately twofold at B3LYP and M06-2X
methods (Tables 2 and S8). While the ∆S298 values for these complexes increase to 9−13 Kcal.mol−1.
The intramolecular bonds OH ON in HB complexes of 1a with acids 5 and 6 remain, but they
lengthen to 1.95−2.14 Å as compared to those in 1a (l 1.85−1.97 Å). It is accompanied by a decrease
in the electron densities ρ(rc) by 0.01 au and the energies E by 1−3 Kcal.mol−1. In the case of the
complex 1a 5-PT, only two intramolecular bonds OH ON (l 2.13 and 2.17 Å, ρ(rc) 0.0201 and 0.0185
au, E 5.21 and 4.64 Kcal.mol−1) are observed. The hydrogen atom of the third hydroxyl group of N-
oxide 1a participates in formation of the bifurcation bond NO−H+···O−···H−O with carboxyl oxygen.
More basic N-oxide 1b gives more stable HB complexes with acids 5 and 6 than 1a (Table 2),
however, the intramolecular bonds between hydroxyl groups in its complexes change insignificantly. It
should be noted that the intramolecular and intermolecular bonds CH···OH and CH···O=C (l 2.3−2.6
Å) contribute to the stabilization of these complexes. BCP for them are found, and the topological
properties are evaluated (Table S6). The energies of these H-bonds are 2−3 Kcal.mol−1, and the
electron density ρ(rc) does not exceed 0.014 au. The similar bonds CH···O=C are also formed in the
complexes of 1a with acids 5 and 6. The linear dependences between lengths of the intermolecular
NO···H bonds in HB complexes of 1a,b,c and 4 with acids 5 and 6 and their energetic parameters E(2)
(NBO) and E (QTAIM) are observed (Fig. 3).
120
y= -239,22x + 429,75
4-5
R2 = 0,9432
100
1b-5
1b-6
4-6
1c-5
80
60
40
20
0
4-5
1a-5
1b-5
1c-5
1a-6
1a-6
1c-6
4-6
1b-6
1a-5
y= -94,18x+ 169,51
R2 = 0,9623
1,3
1,35
1,4
1,45
1,5
1,55
1,6
1,65
1,7
Bond length

15
Fig. 3. The dependence of the nO→σ* N-oxide oxygen atom
ACCEO-HPTED MANUSCRIPinT
teraction energies (E(2), Kcal.mol−1) (top
line) and of the QTAIM intermolecular H-bond energies (Е, Kcal.mol−1) (bottom line) on the NO···H bond
lengths (lNO···H, Å) in HB complexes of 1a,b,c and 4 with acids 5 and 6.
The intermolecular hydrogen bond energies of 1b HB and 1с HB with acids 5 and 6 E1(В НА)
are almost twice as high as in analogous 1a complexes, as well as the energy of their intermolecular H-
bonds E (QTAIM) and E(2) (NBO). A higher by 2−6 Kcal.mol−1 stability of complex 1a as compared
to complexes 1b and 1c is explained by contribution of the intramolecular bonds OH ON formation
energy. In a polar medium, complexes 1b 5-PT and 1c 5-PT are more stable than 1a 5-PT by 2.61 and
4.04 Kcal.mol−1 at B3LYP method. Thus, the least stable 1c isomer in the polar solvent forms with
acid 5 the most energetically stable the PT complex. At M06-2X method in a polar medium, stability
of 1c 5-PT complex decreases due to less stability of 1c isomer.
3.3. FTIR Spectra
The structure of complexes of (2-hydroxyethyl)amine-N-oxides 1–3 with acids 5 and 6 in solid, waxy
state and solutions of methylene chloride was studied using FTIR spectroscopy (Table 3). The
corresponding spectra of the parent compounds and their complexes are presented in Supplementary
Information (Fig. S3–S19). In the spectrum of solid 1 a narrow band ν(OH) at 3202 cm-1 is present
belonging to the hydroxyl groups, which form (like in a crystal [29]) three similar intermolecular H-
bonds with N-oxide oxygen atom of epi isomer 1c. The shape of this band is due to high symmetry of
the crystalline molecules. Resembling bands are observed in the spectra of highly symmetric
triethanolamine salts with inorganic acids, where oxygen atoms of three hydroxyl groups of a cation
form intramolecular H-bonds with the endocyclic hydrogen atom of the N+H moiety, while their
hydrogen atoms form the bonds with anion [53]. In the spectrum of compound 1 in solution of CH2Cl2,
two ν(OH) bands are observed: the weak band at 3610 cm-1 of free OH groups and the broad band at
3304 cm-1 of the OH groups participating in formation of the intermolecular H-bonds OH ON.
According to long-wavelength shift of low-frequency band ν(OH) and change of its shape, the
ordering of structure 1 is violated in a solution. However, bands of intermolecular OH ON bonds
remain strong enough, since at low concentration in a polar medium, only partial dissociation of these
bonds occurs. Hence it appears that in a solution of compound 1, its epi isomer 1c is predominant (like
in a crystal), which contains no intramolecular H-bonds and forms supramolecular structure 1 via
intermolecular bonds OH ON.
Table 3
The frequencies of modes ν(OH), ν(C=O) and νas(COO)– (cm–1) in the IR spectra of solid compounds
and their solutions in CH2Cl2
.

16
ACCEPTED MANUSCRIPT
Compound
ν(OH)
ν(C=O)
νas(COO)–
CH2Cl2
Solid
CH2Cl2
Solid
CH2Cl2
Solid
3202 m
3610 w
1
5
3304 m br
3577 w
3131a m br
3366 s br
1785a s
1782 sh
1803 s
3443 w br
1788 sh
3601 w
1786 m
1682 s
1603 s
1675 m
1603 m
1 5
6
3382 w br
3000–2600 w 3599 w
3471 w
1742 s
1777 s
1738 s
1775 sh
1737 w
1706 sh
1730a sh
3333a s br
3605 w
1 6
2
3346 w br
3583b w
3232 m br
3305 m br
3480b m
3607 w
3330 m
1703 sh
1727 w
1727 w
1732 m
1599 m
1596 m
1605 m
1606 m
2 6
3c
3291 m br
3317 w br
3598 w
3 6
3428 s br
a
b
c
Compound in film. Solution in MeCN. Compound does not dissolve.
The interaction of acid 5 with 1 leads to the formation of proton transfer complex 1 5-PT. In its
spectrum, the bands of asymmetric and symmetric vibrations of carboxylate ion ν(COO)– are at 1682
–
and 1432 cm-1, while an intense broad bands ν(OH) are observed at 3366 and 3000 2400 cm-1.
Notably, a band νas(COO)– is shifted by 103 cm-1 to low-frequency region of the spectrum as compared
to a band ν(C=O) at 1785 cm-1 in the spectrum of acid 5. In CH2Cl2 solution, complex 1 5-PT
undergoes partial dissociation and its spectrum contains, along with a band νas(COO)– at 1675 cm-1, a
band ν(C=O) at 1786 cm-1. The ν(OH) bands at 3601 and 3382 cm-1 are assigned to hydroxyl groups of
amine-N-oxide, free and those participating in the formation of intermolecular bonds OH OH. Proton
transfer complex 1 6-PT is formed via the interaction of amine-N-oxide 1 with acid 6. In the spectrum
of this complex, an intense band νas(COO)– is observed at 1603 cm-1. Vibration ν(C=O) of acid 6 is
characterized by intense doublet with maxima at 1742 and 1706 cm-1 in its spectrum and a weak
shoulder at 1730 cm-1 in the spectrum of the complex. Intensity of the last band increases in the
spectrum of the complex in solution owing to its partial dissociation. An intense broad bands ν(OH) of
the associated hydroxyl groups are observed at 3333 and 3000–
2400 cm-1. In the spectrum of its

17
solution, ν(OH) band is shifted to 3346 cm , and a weak baIPnd of free OH group vibrations appears
ACCEPT D MANUSCR T
E-1
at 3605 cm-1. The similar characteristics are in spectra 2 and 3 and in their PT complexes with acid 6.
The bands ν(OH) at 3366 and 3333 cm-1 in the spectra of complexes 1 5-PT and 1 6-PT are
observed at significantly higher frequencies than in the spectra of PT complexes of triethanolamine
with organic acids (3130–
3190 cm-1) [53]. According to the calculations and X-ray diffraction data, in
PT complexes of triethanolamine, H-bonds between cation and anion close six-, seven- and eleven-
membered cycles [35]. As seen from the ν(OH) values, these bonds are more stable. In the calculated
structures of complexes 1c 5-PT and 1c 6-PT, only one H-bond of the hydroxyl group of a cation with
anion oxygen atom closes ten-membered cycle. Two other OH groups are free and form the
intermolecular bonds HO HO, which are responsible for the bands ν(OH) in the IR spectra. The bands
ν(OH), which could be assigned to the hydroxyl groups participating in the formation of
intramolecular H-bonds of 1a or 1b, are not observed in the spectra of complexes 1 5-PT and 1 6-PT.
This evidences that epi isomer 1c takes part in their formation.
Conclusion
The quantum chemical calculations by DFT and MP2 methods of tris- 1, bis- 2, and mono-3 (2-
hydroxyethyl)amine-N-oxides have shown that stability of the endo isomers 1a−3a in a gas phase is
higher by 6−12 Kcal.mol−1 than that of the exo isomers 1b−3b due to the intramolecular OH ON
bonds in 1a (trifurcational), 2a (bifurcational), and 3a (two-centered), which are absent in 1b−3b. The
epi isomer 1c, bearing free hydroxyl groups, is least stable. The proton affinity of 1a−3a increases with
decrease of the number of hydroxyethyl groups as opposed to previously studied ethanolamines. A
decrease of energy gap ∆EMO = EHOMO − ELUMO in the 1a−3a series leads to an increase of the basicity.
The NBO interaction between the N-oxide oxygen atom and the hydroxyl groups in 1a–3a decreases
their PA1 values as compared to the 1b–3b. The PA1 values of the molecules 1b–3b are higher than
those of 1с, having the most pyramidal nitrogen atom. Comparison of experimental and calculation
results shows, that the structure of 1 is defined by equilibrium state of its isomers during phase
transitions and interaction with acids. Molecules 1a in a gas phase form the hydrogen bonded (HB)
complexes with trifluoroacetic 5 and 2-methylphenoxyacetic 6 acids. The proton transfer (PT)
complex 1a 5-PT is stable only in the polar medium. Isomers 1b and 1c are more basic as compared to
1a. In a gas phase, they form with 5 two types of complexes, HB and PT. In a polar medium, complex
1c 5-PT is most stable. In crystal state, (X-ray [29] and FTIR) high symmetry structure of compound 1
with intermolecular OH ON bonds is formed by epi isomer 1c. According to FTIR spectroscopy
transition of 1 to CH2Cl2 solution is accompanied by disordering of this orderly structure due to
loosening the intermolecular bonds and their partial dissociation. In a solution of 1, its epi isomer 1c

18
ACCEPTED MANUSCRIPT
forms supramolecular structure with intermolecular OH ON and OH OH bonds. This isomer
participates in the formation of PT complexes of 1 with acids 5 and 6 in the solid state and solutions.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version, at
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ACCEPTED MANUSCRIPT
Highlights
Structure of (2-hydroxyethyl)amine-N-oxide isomers was calculated by DFT and
MP2 methods.
Proton affinities of isomers depend on their intramolecular NO HO and HO HO
bonds.
Isomers of N-oxides form hydrogen bonded and proton transfer complexes with
organic acids.
Type of complexes was determined by FTIR spectroscopy in the solid state and
solution.