Molecular structure and intramolecular hydrogen bond strength of 3-methyl-4-amino-3-penten-2-one and its N–Me and N-Ph substitutions by experimental and theoretical methods

Article abstract of DOI:10.1016/j.molstruc.2019.02.007

In the present work, molecular structures and intramolecular hydrogen bonding (IHB) of 3-methyl-4-amino-3-penten-2-one, 3-MeAPO, 3-methyl-4-methylamino-3-penten-2-one, 3-Me-MeAPO, and the 3-methyl-4-phenylamino-3-penten-2-one, 3-Me-PhAPO have been investi

Full text of DOI:10.1016/j.molstruc.2019.02.007

Accepted Manuscript
Molecular structure and intramolecular hydrogen bond strength of 3-methyl-4-
amino-3-penten-2-one and its N Me and N-Ph substitutions by experimental and
theoretical methods
Seyedabdollah Seyedkatouli, Mohammad Vakili, Sayyed Faramarz Tayyari, Poul Erik
Hansen, Fadhil S. Kamounah
PII:
S0022-2860(19)30131-0
DOI:
https://doi.org/10.1016/j.molstruc.2019.02.007
MOLSTR 26164
Reference:
To appear in: Journal of Molecular Structure
Received Date: 10 November 2018
Revised Date: 2 February 2019
Accepted Date: 4 February 2019
Please cite this article as: S. Seyedkatouli, M. Vakili, S.F. Tayyari, P.E. Hansen, F.S. Kamounah,
Molecular structure and intramolecular hydrogen bond strength of 3-methyl-4-amino-3-penten-2-one
and its N Me and N-Ph substitutions by experimental and theoretical methods, Journal of Molecular
Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.02.007.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Molecular structure and intramolecular hydrogen bond strength of 3-methyl-4-
amino-3-penten-2-one and its N-Me and N-Ph substitutions by experimental and
theoretical methods.
a
* a
a
b
Seyedabdollah Seyedkatouli , Mohammad Vakili , Sayyed Faramarz Tayyari
,
Poul Erik Hansen
,
c
Fadhil S. Kamounah
a
Department of Chemistry, Faculty of science, Ferdowsi University of Mashhad, Mashhad 91775-1436,
Iran.
b
Department of Science and Environment, Roskilde University, Universitetsvej 1, P.O. Box 260, DK-
000 Roskilde, Denmark.
4
c
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100, Copenhagen Ø,
Denmark.
Abstract
In the present work, molecular structures and intramolecular hydrogen bonding (IHB) of
-methyl-4-amino-3-penten-2-one, 3-MeAPO, 3-methyl-4-methylamino-3-penten-2-one, 3-Me-
3
MeAPO, and the 3-methyl-4-phenylamino-3-penten-2-one, 3-Me-PhAPO have been investigated
by means of density functional theory (DFT) calculations, at the B3LYP/6-311++G** level, and
experimental investigations including NMR, IR, Raman, UV spectroscopy, and X-ray
crystallographic methods. The mentioned results were compared to those of 4-amino-3-penten-2-
one, APO. DFT calculations suggest a relatively strong intramolecular hydrogen bond in 3-
MeAPO and its N-Me and N-Ph substituted derivatives with N···O distances of 2.597, 2.584,
and 2.581 Ǻ, and calculated hydrogen bond energies of about 10.9, 13.6, and 14.9 kcal/mol in 3-
MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO, respectively. While, the calculated N···O distances
and hydrogen bond energies, of APO, 2.669 Ǻ and 7.67 kcal/mol respectively, suggest a medium
IHB strength. According to the NBO results, the steric effect is the dominant factor for changes
of the IHBs. The calculated geometrical parameters of 3-MeAPO are in excellent agreement with
*
Corresponding author. Tel.: +98 9153215410;
E-mail address: vakili-m@um.ac.ir (M. Vakili).
1

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the X-ray results. UV-Vis spectra of 3-MeAPO, 3-Me-PhAPO, and 3-Me-MeAPO were recorded
in ethanol supporting the results mentioned above. According to the calculated results and
1
3
deuterium isotope effects on C chemical shifts, 3-MeAPO exists as a keto-amine. Comparison
of the observed and theoretical IR and Raman spectra and the spectral behavior upon deuteration
were used for assignment of the vibrational spectra of 3-MeAPO. The assigned normal modes
were compared to those of APO. The theoretical results were in good agreement with the
experimental data. The vibrational frequencies also confirmed that the IHB strength in 3-MeAPO
is stronger than that in APO.
Keywords: 3-methyl-4-amino-3-penten-2-one; Substitution effect; Intramolecular hydrogen
1
3
bond; Molecular spectroscopy; Isotope effects on C chemical shifts.
1
. Introduction
α,β-Unsaturated-β-ketoenamines, also known as β-ketoenamines, are important
organic chemicals for synthesis of an assortment of heterocyclic and medical compounds [1-4].
α,β-Unsaturated-β-ketoenamines have in many cases been shown to exist at the aminoketone
form [5-14], whereas o-hydroxy Schiff bases can be tautomeric [15, 16]. In the present case the
steric repulsion may reduce the N…O distance and lead to tautomerism. The compounds can in
principle exist as three different tautomers in equilibrium, i.e., iminoketone, aminoketone, and
iminoenols, see Fig. 1. The aminoketone forms are usually more stable than the iminoenol forms
,
which are the major form of β-enaminones [8-10, 12]. Hydrogen bonding is one of the most
important of all inter- and intramolecular interactions. The hydrogen bond plays an essential role
in phenomena such as crystal engineering, stabilization of the secondary structure of
biomolecules like proteins, and DNA [17-20]. The formation of an IHB leads to an increase of
the resonance conjugation of the π-electrons in the chelated ring. Any factor which effects this
resonance, can change the IHB strength. Synthesis, IR, and NMR spectra of some α,β-
unsaturated-β-ketoenamines have been already reported [5, 14, 21-25].
The study of IHB strength in 3-MeAPO, with a methyl group in the α-position could be
interesting. In addition, in 3-Me-MeAPO and 3-Me-PhAPO, with a methyl as bulky group or a
phenyl group as electron donating group on the nitrogen atom could influence the IHB strength.
2

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Therefore, comparison of IHB strength with APO may increase our insights into the effects of
these substitutions on the IHB strength.
The structure, vibrational assignment, and IHB strength of the title molecules,
theoretically and experimentally, were not reported previously. In addition, the aim of the present
study is to investigate tautomerism, conformations (3-MeAPO is special with its three
interlocking methyl rotamers), molecular structure, spectroscopic analysis, and the IHB strength
of title molecules, by different theoretical and experimental approaches. The theoretical (such as
the optimized configuration, the geometric parameters, simulating vibrational spectra, UV
1
13
spectra, and H and C NMR chemical shifts, NBO, and atoms in molecules (AIM) [26]
analysis) and experimental results (including IR, Raman, NMR, and UV-Vis spectra) for the title
molecules have been compared with the corresponding data for 4-amino-3-penten-2-one (APO),
as the simplest member of the β-enaminones compounds [27, 11]. In addition, we compared the
mentioned theoretical and experimental results of N-Me and N-Ph substitutions with 3-Me-APO.
3
These comparisons give a clear understanding of the substitution effects of “CH and phenyl
groups” in the α- and on the nitrogen positions on the IHB strength.
2
. Experimental
2
.1. Materials
-Methyl-2, 4-pentanedione (3-Meacac) was purchased from Alfa Aesar. Other
3
compounds and solvents were of analytical grades and used as received.
4
-Amino-3-penten-2-one (3-MeAPO):
This compound was prepared according to a procedure similar to that described for APO
28]. In a 25 ml round bottom flask, 3-Meacac (2.28 g, 20 mmol) was charged and cooled in the
[
ice bath with stirring and 25% of ammonia solution (3.5 ml) was added dropwise, immediate
white precipitation developed. After complete addition, the mixture was left stirred at room
temperature for 30 minutes and left stand in a stoppered flask for 48 h. The solid was treated
with diethyl ether (75 ml) and washed with distilled water (2x75 ml) and brine (75 ml). The
organic portion was separated and dried with anhydrous sodium sulfate. Evaporation of ether
under reduced pressure yields a white solid. Recrystallization from n-heptane/ethyl acetate gave
colorless needles (1.85 g, 82%), m.p. 111.5-112.0 °C, lit. 109-110 °C [29].
4
-(Methylamino)-3-penten-2-one (3-Me-MeAPO):
3

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This compound was synthesized by modification of a literature method [30, 31]. To a
solution of α-methyl acetylacetone (1.23 g, 11.0 mmol) in absolute ethyl alcohol (10 ml) was
added a 2M solution of methylamine in THF (10 ml, 20 mmol) and the clear solution was stirred
at room temperature in a stoppered flask for 15 hrs. The volatile solvents were evaporated under
reduced pressure and the light amber oil residue was purified by flash column chromatography
on silica gel using n-heptane/ethyl acetate (2:1) to obtain the desired pure product as a pale
amber oil which solidified on cooling 1.12 g (82% yield).
4
-(Phenylamino)-3-methyl-3-penten-2-one (3-Me-PhAPO):
To a solution of α-methyl acetylacetone (2.28 g, 20.0 mmol) in methanol (25 ml) was
added aniline (1.86 g, 20.0 mmol) at room temperature, followed by concentrated formic acid (3
drops). The mixture was stirred at room temperature for 15 minutes, then refluxed under a
nitrogen atmosphere for 15 hrs. Methanol was evaporated under reduced pressure and the yellow
oil residue was chromatographed on silica gel, using n- heptane/ethyl acetate (10:1) and (1:2) to
obtain the pure compound as an amber oil, which solidified on cooling 3.40 g (90% yield).
The deuterated analogues for the IR studies, include D -3-MeAPO, D-3-Me-PhAPO, and
2
D-3-Me-MeAPO, were prepared by the following procedure [32]. 0.5 g of the under-study
4
molecules was dissolved in CCl (3 ml) and a drop of triethylamine was added and stirred for an
hour. Then, D O (1 mL) was added and the mixture stirred for 24 h. The CCl solutions were
2
4
separated and dried over anhydrous Na
2
SO
4
. Solid D
2
-3-MeAPO was obtained by removing the
solvent in a vacuum desiccator. The IR and Raman spectra confirmed that the hydrogen atoms of
amino group were more than 90% replaced by deuterium atoms.
The partially deuterated compounds for the isotope effect on chemical shift studies were
obtained by dissolving the compounds in CH OD:CH OH and evaporating off the solvent under
3
3
reduced pressure.
2
.2. Instrumentation
The NMR spectra were recorded on an Avance Bruker-400 MHz spectrometer.
All chemical shifts are reported relative to TMS, using 2 mol% solutions in CDCl at 22ºC. For
3
1
3
-APO H NMR (CDCl ): δ 10.32 (br, NH ), 5.30 (br, NH ), 2.08 (s, H(CH -C=O)), 1.93(s,
3
in
out
3
1
3
H(CH
3
-C-N)), 1.78(s, H(CH
3
-Cα) and for CNMR: δ 197.35 (C2), 158.94 (C4), 99.01 (C3),
4

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1
2
5
2
8.56 (C1), 21.86 (C5), 14.40 (C8). For APO: H NMR (CDCl ): δ 9.71 (br NH ), 5.71 (NH ),
3
in
out
1
3
.03 (CH), 2.03 (CH3) and 1.91 (CH ). C NMR: δ 196.69 (C2); 160.98 (C4); 95.75 (C3);
3
9.29 (C1); 22.25 (C5).
1
For 3-Me-MeAPO: HNMR (CDCl ): δ 1.78 (s, 3H, CH -Cα), 1.91 (s, 3H, CH -C-N),
3
3
3
2
3 3
.06 (s, 3H, CH -C=O), 2.87 (d, 3H, CH -N, J=5.0), and 11.80 (b, 1H, NH bonded). The
1
3
mentioned results are close to those reported results by Mikysek et al. [31]. CNMR: δ 194.09
(C2), 162.89 (C4), 97.72 (C3), 29.59 (C1), 28.06 (C10), 14.68 (C8), and 14.58 (C5).
1
For 3-Me-PhAPO: H NMR (CDCl ): 1.91 (s, 3H, CH -Cα), 2.01 (s, 3H, CH -C-N), 2.21
3
3
3
1
3
(
s, 3H, CH
3
-C=O), 7.04 (d, 2H), 7.14 (t, 1H), 7.31 (t, 2H), δ 13.46 (br NH bonded). C NMR: δ
96.43 (C2), 158.23 (C4), 139.35 (C10), 128.90 (C11, C13, and C15), 124.99 (C12 and C14),
00.87 (C3), 28.54 (C1), 16.95 (C5), and 14.76 (C8), which is good agreement with those
1
1
reported by Xiang Chen et al. [23].
1
3
The C NMR spectra for isotope effect measurements of APO and 3-MeAPO were
recorded at 273K and data are given in Scheme1.
The ultraviolet absorption spectra were examined in the range of 200-400 nm at 298 K,
using a Perkin Elmer LAMBDA 25 spectrophotometer. The UV–Vis spectrum of 3-MeAPO, 3-
Me-MeAPO, and 3-Me-PhAPO were measured in ethanol solution.
-1
The IR spectra in the region 4000–500 cm were recorded on a Bomem MB-154 Fourier
transform spectrophotometer using KBr pellets and CCl solution. The spectra were collected
4
-1
with a resolution of 2 cm by signal averaging of 20 scans.
-1
The Far-IR spectra in the region 600–200 cm were obtained using a Thermo Nicolet
NEXUS 870 FT-IR spectrometer equipped with a DTGS/polyethylene detector and a solid
substrate beam splitter with use of polyethylene disks. The spectrum was collected using CsI
-1
pellets with a resolution of 2 cm by signal averaging the results of 32 scans.
-1
The FT-Raman spectra in the region 3200–200 cm were recorded employing a 180°
backscattering geometry and a Bomem MB-154 Fourier transform Raman spectrometer. The
instrument was equipped with a ZnSe beam splitter and a TE cooled In GaAs detector. The
excitation wavelength at 1064 nm was obtained from a Nd/YAG laser. Rayleigh filtration was
afforded by a set of two holographic technology filters. The spectra were accumulated for 8000
-1
scans with a resolution of 2 cm . The laser power at the sample was 500 mW.
5

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2
.3. Single crystal X-ray measurements
Single crystals of C H NO were obtained by recrystallization from heptane/ethyl acetate
6
11
as solvent. A suitable crystal was selected, and the crystal structure analysis was performed on
a 'Bruker APEX-II CCD' diffractometer. The crystal was kept at 120 K during data collection.
Using Olex2 [33], the structure was solved with the olex2.solve [34] structure solution program
using Charge Flipping and refined with the ShelXL [35] refinement package using Least Squares
minimization.
The crystallographic data and the details of the X-ray analysis are represented in Table
S1. According to the X-ray results, the obtained unit cell dimensions are (7.916(4) × 9.438(4) ×
8
1
.951(4) Å). The other crystal data are: C H NO, M = 113.16, monoclinic, α = 90°, β =
6 11 r
3
04.308(17)°, γ = 90°, V = 648.0(5)Å , T = 120 K, Z = 4, 7239 reflections measured,
Independent reflections=1483[R =0.0264, Rsigma=0.0195], final R indexes [I>=2σ (I)] R1=
int
0
.0391, wR = 0.1046, final R indexes [all data] R = 0.0463, wR = 0.1097.
2 1 2
The selected calculated and observed bond lengths, bond angles, and dihedral angles for
this compound are given in Table 1, and the X-ray and calculated structures for 3-MeAPO are
shown in Fig. 2a-b. For comparison, the optimized structure of 3-Me-MeAPO and 3-Me-PhAPO
are shown in this figure, Fig. 2c-d and tabulated in Table 1. The fractional atomic coordinates
and anisotropic Displacement Parameters for heavy atoms are given in Tables S2 and S3,
respectively. The fractional atomic coordinates for hydrogen atoms are listed in Table S4.
3
. Method of analysis
Computations study have been carried out with the Gaussian 09 [36], AIM 2000 [37], and
NBO 5.0 [38] software packages. The calculated total electronic energies, relative stabilities of
all conformers of aminoketone, and iminoenol tautomers, and the calculated harmonic
frequencies of aminoketone form of 3-MeAPO, were determined at the B3LYP level [39, 40]
using the 6-311++G** basis set. In adittion, the molecular geometry and vibrational frequencies
of 3-Me-MeAPO and 3-Me-PhAPO were calculated at the same level of theory. The assignments
of observed wavenumbers were aided by the animation option of the Gauss View 4.1.2 graphical
interface [41], which gives a visual presentation of the shape of the vibrational modes.
The assignments of the experimental frequencies are based on the observed band
frequencies and intensities changes in the infrared and Raman spectra of the deuterated species
6

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and confirmed by establishing one to one correlation between observed and theoretically
calculated frequencies.
2
Second order interaction energies (E ) [42] and steric exchange energies [43] were
performed at the B3LYP/6-311++G**level, using NBO 5.0 software.
The nuclear shieldings for the three forms of 3-Me-APO and aminoketone form of other
molecules and tetramethylsilane (TMS) have been obtained using the gauge-including atomic
orbital (GIAO) method [44, 45] at the B3LYP/6-311++G** level. Data are given in section 4. 4.
1
13
1
and in the supplementary material, as Tables S5-6. The predicted H and C chemical shifts
are obtained in two ways. The first from equation δ = σ - σ, where δ is the chemical shift, σ is
the nuclear shielding, and σ is the nuclear shielding of TMS, and the second by using of the
0
0
1
13
equations between the experimental H and C chemical shifts (δ ) and nuclear shielding (σcalc)
exp
of 3-Me-APO. According to this method the predicted chemical shifts of 3-Me-MeAPO and 3-
Me-PhAPO are close to the experimental chemical shifts results, see Table S6.
The excitation transitions for the most stable conformer, the aminoketone form, of 3-
MeAPO, 3-Me-MeAPO, 3-Me-PhAPO, and APO were calculated at the time-dependent, TD-
DFT, B3LYP/6-311++G** level of theory in ethanol solution by the SCRF-PCM method [46].
2
AIM 2000 software was applied to obtain the electron density (ρ) and Laplacian (∇ ρ) of
electron density at the hydrogen bond critical points (BCP), according to Bader’s AIM theory
[26] at the above level of theory.
4
.
Results and discussion
4
.1. Molecular geometry
As mentioned in the introduction, α, β-unsaturated-β-ketoenamines can form a tautomeric
equilibrium between iminoketone, aminoketone, and iminoenol forms (see Fig. 1). We
considered all conformers of all possible tautomers for 3-MeAPO. According to our calculations,
the relative energies for the iminoenol and iminoketone forms are 6.86 and 10.38 kcal/mol higher
than that of the most stable tautomer, the aminoketone form.
From the theoretical point of view, by considering the rotation of methyl groups around
the C-C bonds, include C4-C5, C3-C8, and C2-C1 bonds, 8 cis-enol forms can be drawn for the
aminoketone form of 3-MeAPO. The structures of these conformers and their relative stabilities
7

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calculated at the B3LYP/6-311++G** level are shown in supplementary material, as Fig. S1.
Among these forms, only one of them (AK1) is stable, while all other forms under full
optimization turn to the AK1. The methyl groups in the C1 and C5 positions of 3-Me-APO (see
Figure 2) and 3-Me-PhAPO molecules are eclipsed in relation to each other, while in APO and
3
-Me-MeAPO molecules they are staggered.
The fully optimized geometrical parameters of 3-MeAPO, 3-Me-APO, 3-Me-PhAPO,
and 4-amino-3-penten-2-one, APO, at the B3LYP/6-311++G** are collected in Table 1 together
with the corresponding experimental data of 3-Me-APO. The calculated geometrical parameters
of 3-MeAPO are in excellent agreement with the X-ray results, nearly within the experimental
error. According to this table, the calculated N…O distance in 3-Me-PhAPO, 3-Me-MeAPO, 3-
MeAPO, and APO are 2.581, 2.584, 2.597, and 2.669Ǻ, respectively. These values confirm that
the trend of the IHB strength is:
3
-Me-PhAPO > 3-Me-MeAPO > 3-MeAPO > APO
(1)
This trend is confirmed by the changes in the theoretical structure parameters such as, the
shortening and lengthening of O···H distance, and N-H bond, respectively, and increasing of the
NHO bond angle. The reported N…O distances for N-H···O systems lie in the 2.48-2.76 Ǻ range
[13, 14]. According to Table 1 and comparison of 3-MeAPO with APO, substitution of the
methyl group in the α-position reduces the N…O and O…H distances and increases the OHN
bond angle and N-H bond length. These results could be attributed to the repulsion between
methyl groups in the α and β positions, which pushes the methyl groups in the β positions toward
oxygen and nitrogen atoms, while the C-N and C=O bond lengths in the chelated ring are almost
the same as those in APO. Comparison of N···O and the other component of the chelated ring in
3
-MeAPO with those in 3-Me-MeAPO and 3-Me-PhAPO shows that in addition to the steric
effect of the α-methyl group, the methyl and phenyl groups on the nitrogen atom are also
involved in steric interactions, see the NBO analysis section, which agrees with the previously
reported by Hill and Roodt [47]. The steric effect causes the N···O distance to diminish. The
N···O distance of 3-Me-PhAPO is shorter than that in 3-Me-MeAPO, so the IHB in the former is
stronger than the latter, which agrees with the other theoretical results and our experimental
results, see Intramolecular hydrogen bond Energy and Experimental studies sections. The
dihedral angle between the phenyl and the chelated rings in 3-Me-PhAPO is 142.3º, so
8

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increasing of IHB strength through the resonance of the phenyl group with the chelated rings is
not effective.
As it is shown in Table 1, lengthening of C=C and C-C bonds in 3-MeAPO molecule in
comparison with APO, could be attributed to the steric effect of α-CH on C-C-C fragment of
3
chelated ring and increasing of π-electron delocalization in this fragment. This result is in
excellent agreement with the reported results for halogen-substituted acetylacetonates of boron
difluoride and α-alkyl derivates of copper (II) acetylacetonate [48, 49]. This Table also shows
that the C2-C1 and C4-C5 bond lengths in all molecules are longer than the corresponding bond
lengths in APO.
4
.2. Tautomerism
The fact that no hydrogens nor carbons have chemical shifts corresponding to C-3 of the
iminoketone form rules this out. Furthermore, the good agreement between the calculated
nuclear shieldings and the observed chemical shifts for the aminoketone form confirms this form
to be the major one. The fact that the fit could not be improved by mixing in calculated data for
the aminoenol form shows that no tautomerism is at play. In addition, this is confirmed by the
finding of a large positive two-bond isotope effect at C-4 and the negative deuterium isotope
effects at C-2 [5, 7]. This shows that the compound exist primarily at the aminoketone form as
the presence of the iminoenol form would lead to the opposite trend.
4
.3. Intramolecular hydrogen bond Energy
It has been debated whether steric compression can lead to a stronger hydrogen bond [50,
5
1]. Hydrogen bond energies have in several intramolecularly hydrogen bonded systems been
determined by the hydrogen bond and out method originally was suggested for salicylaldehyde
by Cuma, Scheiner, and Kar [52]. However, this method requires that no steric interactions occur
in the out position. This method can of course not be used for primary amines as investigated in
the present case. A more promising approach for primary amines is to calculate energies in the
cis hydrogen bonded system and subtract the energy of the relevant trans compound as suggested
by Jablonski et. al. [53]. However, this method is only well suited for aldehyde derivatives.
Jablonski et al. managed to estimate a hydrogen bond energy for 3-aminopropenal of 6.35 or
5
.28 kcal/mol using at the MP2 level with 6-31G** and 6-311++G** basis sets, respectively.
9

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According to our calculations, performed at the B3LYP/6-311++G** level, the electron density
at the bond critical point gave a value of 0.027. Using the Espinosa equation [54] a hydrogen
bond energy of 6.35 kcal/mol is estimated, near to Jablonski’s values [53]. The latter method was
developed based on intermolecular hydrogen bonds. Furthermore, this method was also used by
Afonin et. al. in the intramolecular hydrogen bond systems [55]. In addition, the AIM
calculations were also performed on the other studied molecules and APO, see Table 1. The EHB
values, in the gas phase, are 14.91, 13.63, 10.85, and 7.67 kcal/mol, in 3-Me-PhAPO, 3-Me-
MeAPO, 3-MeAPO, and APO, respectively using this method. Rozas et al. [56] reported that the
2
sign of the Laplacian of the electron density at the bond critical point (∇ ρBCP) could
characterize the strength of hydrogen bond strength. According to Table 1, in 3-Me-PhAPO, 3-
2
Me-MeAPO, and 3-MeAPO, the ∇ ρBCP´s are more negative than those in APO. Thus, these
AIM results also confirm the trend (1) for IHB strength.
1
3
The deuterium isotope effects on C chemical shifts have been used to estimate
hydrogen bond strength [57] and has in enaminones given clear indications of steric compression
[7]. The two-bond isotope effect on the C-4 chemicals shift for 3-APO is clearly larger than for
APO (see Scheme 1) showing as also indicated by the NH chemical shifts (10.32 vs. 9.71 ppm)
a stronger hydrogen bond in the former. Therefore, the IHB strength of 3-MeAPO increases
compared to that of APO and 3-aminopropenal. This is in excellent agreement with the
theoretical N…O distance. The mentioned value in 3-MeAPO, APO, and 3-aminopropenal, at
the B3LYP/6-311++G**, is 2.597, 2.669, and 2.718 Å, respectively. The increasing of the IHB
strength in 3-MeAPO and APO in comparison to that in 3-aminopropenal, seems to indicate that
the steric compression leads to a higher hydrogen bond energy.
4
4
.4. NBO analysis
.4.1. Electron delocalization
The NBO calculations can be used to estimate the energy of interactions between donor
and acceptor orbitals, for characterization of IHBs. In addition, the pairwise exchange energies
between filled NBO’s i and j, calculated by the NBO 5.0, show the steric effect of different
substitutions. Table S7, see supplementary materials, lists some of the important calculated
2
electron delocalization (E ) between donor and acceptor orbitals of APO, 3-MeAPO, 3-Me-
1
0

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2
MeAPO, and 3-Me-PhAPO molecules. According to our results for E , there is no significant
difference between the results for the studied molecules, which means that the IHB strength is
not affected by the conjugation of substituents with chelated ring. This result agrees with the
calculated dihedral angle between the phenyl ring and the chelated ring, 142.3º.
The lp(2) O6→σ* (N-H) parameter, as one of the most important hyperconjugative
interactions which is proportional to the IHB strength, gives values well correlated to the N…O
distance and this is in agreement with the trend (1) for IHB strength of the mentioned molecules.
The mentioned values for APO, 3-MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO are 8.19, 11.25,
1
6.09, and 19.00 kcal/mol. These values also confirm the trend (1) for the IHB strength.
.4.2. Steric effect
Since, the only difference between the studied molecules is the methyl group (in the α-
4
position), CH , and phenyl groups on the nitrogen, we only consider the steric effect of these
3
groups with the rest of the molecule. Table S8 shows the steric effects of the mentioned groups
in the α position and on the nitrogen atom. The α-methyl group in these molecules increase the
steric hinderance between methyl and the rest of molecule and confirms stronger IHB in α-
methyl molecules in comparison with APO. In addition, there is no significant difference for the
mentioned steric hinderance in 3-MeAPO, 3-Me-PhAPO, and 3-Me-MeAPO molecules. The
summation of pairwise exchange energies, which is made by N-Ph ring, is more than that in the
N-methyl group, so the IHBs in 3-Me-PhAPO is stronger than that in 3-Me-MeAPO. This result
also confirms the trend (1). The summation of the mentioned rows for 3-Me-PhAPO and 3-Me-
MeAPO are 33.1 and 29.5 kcal/mol, respectively. The value of repulsive interactions agrees with
the shorting of N…O distance and the trend (1). These values are 10.70, 14.83, 18.82, and 20.55
kcal/mol for APO, 3-MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO, respectively.
4
4
.5. Experimental studies
.5.1. NMR spectroscopy
1
3
1
The calculated C and H chemical shifts (δ) and isotropic nuclear shilding (σ ) for
iso
stable forms of the three tautomers of 3-Me-APO are also shown in Table S5. In addition, the
1
13
measured and calculated HNMR and C-NMR chemical shifts of 3-MeAPO, 3-Me-PhAPO,
1
13
and 3-Me-MeAPO, are also compared in Table S6. The HNMR and CNMR spectra of 3-Me-
1
1

ACCEPTED MANUSCRIPT
PhAPO, 3-Me-MeAPO, and 3-MeAPO are shown in Fig. S2a-f, respectively. Deuterium isotope
1
3
effects on C chemical shifts are measured for 3-MeAPO and APO (Scheme 1). These are
measured at 273 K as averaging was taken place at ambient temperature. The isotope effects due
to the hydrogen bonded deuterium are much larger than those from the non-hydrogen bonded
one [58]. As isotope effects are largest over two bonds, large effects are expected at C-4, in this
case 0.29 ppm for 3-MeAPO and 0.21 ppm for APO. This also confirms the assignment of C-4
and by default C-3. For C-5 the isotope effect is over three bonds and typically 0.05 ppm [7]. In
the present case slightly larger.
1
13
The relationship between the experimental H and C chemical shifts (δexp) and the
GIAO (Gauge-Including Atomic Orbitals) nuclear shielding (σcalc) are widely used to relate those
two parameters. This relationship is usually linear and described by the following equation: δexp
=
a (σcalc) + b. The equations for 3-Me-APO are -1.0278X+32.099 (-1.0265X+182.18), and their
2
13
R are 0.9925 (0.9999), respectively. The equation and value for CNMR are in parenthesis.
1
13
According to the mentioned equations, the estimated HNMR and CNMR chemical shifts of 3-
Me-MeAPO and 3-Me-PhAPO are near to the experimental value, see Table S6.
1
3
For C chemical shifts of aminoketone form in 3-MeAPO, the standard deviation, SD, is
2
0
.71 ppm. As regression coefficients (R ) indicate, the agreement between the experimental and
2
calculated data for this form is satisfactory for carbon-13 (R =0.9999) and for proton chemical
2
shifts (R =0.9925 and SD=0.38 ppm). Consequently, an agreement between B3LYP/6-
*
*
3
11++G calculated results and experimental NMR data is demonstrated. This could not be
2
1
improved by mixing in data for the iminoenol form. The SD and R values for HNMR of 3-Me-
MeAPO are 0.50(0.40) and 0.9998(0.9901), respectively. The values for 3-Me-PhAPO are in
1
3
parenthesis. The mentioned values for C-NMR are 1.01(3.30) and 0.9999(0.9972). The
calculated and experimental δOH (in CCl ) of all molecules confirm the trend (1) in IHB
4
strength.
1
Some discrepancies between the obtained HNMR results for 3-MeAPO with those
reported by Ostercamp [29] are attributed to the chemical shifts values of methyl groups and
hydrogen atoms of amine group (H9 and H10). We assigned the higher chemical shift to the
methyl group in the carbonyl side, while this was attributed by Ostercamp [29] to the methyl
group in the amine side. The other discrepancies between our results and Ostercamp work [29],
is related to the values of chemical shift of the H9 and H10, which the first one has not been
1
2

ACCEPTED MANUSCRIPT
reported, while the chemical shift of H10 is about 2.4 ppm less than the obtained result (See Fig.
S2a).
4
.5.2. UV-Vis spectra and electronic properties
The experimental UV–vis spectra of 3-MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO, in
ethanol, as the solvent, are shown in Fig. S3, see supplementary materials. This figure shows one
strong, broad band at 319, 327, and 342 nm for 3-MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO,
respectively. The mentioned result for 3-MeAPO is near to the previously reported result, which
had been reported as 316 nm by Ostercamp [59]. The corresponding experimentally UV band in
APO had been reported at 299 and 300 nm in ethanol and methanol, respectively, by Ostercamp
and Weinstein, respectively [59, 10]. The first 10 spin-allowed singlet–singlet excitations for the
mentioned molecules were calculated by TD-DFT method at B3LYP/6-311++G** level for the
same solvent, by using the PCM method. According to our theoretical results, the strongest
theoretical band in 3-MeAPO, 3-Me-MeAPO, 3-Me-PhAPO, and APO are observed at 276, 280,
3
18 and 263 nm, respectively, which are attributed to the HOMO → LUMO with 99% major
contributions of calculated transitions for APO and 3-MeAPO and about 80% for 3-Me-MeAPO
and 3-Me-PhAPO. The theoretical and observed red shift for these bands in 3-MeAPO, 3-Me-
MeAPO, and 3-Me-PhAPO, compared to the corresponding band in APO, is in excellent
agreement with the average lengthening of the chelated ring components. The increase of the
strength of IHB of 3-MeAPO, 3-Me-MeAPO, and 3-Me-PhAPO in comparison with the APO is
in accord with the trend seen in (1), (see section 4).
The HOMO and LUMO represent the ability to donate and obtain an electron. Also, the energy
gap between the HOMO and LUMO characterizes the chemical stability, reactivity and hardness
of the molecule [60]. According to Fig. 3a-b, the HOMO-LUMO energy gaps of the studied
molecules in 3-MeAPO, 3-Me-MeAPO, 3-Me-PhAPO, and APO are 3.71, 3.51, 3.17, and 3.98
eV, respectively. These energy gaps show that APO is more stable than the others.
4
.5.3. Vibrational analysis
The IR and Raman spectra of 3-MeAPO and its deuterated isotopomer, D -3-MeAPO, in
2
the CCl solution and solid phase, are compared in Figs. S4-5, respectively. The effect of methyl
4
substitution and dilution on the NH stretching of 3-MeAPO, is shown in Fig. 4. In this figure the
1
3

ACCEPTED MANUSCRIPT
IR spectra of 3-MeAPO, D
2
4
-3-MeAPO, and APO are compared in CCl solution. For comparison
also, the IR spectrum of 3-MeAPO in solid phase is shown in this figure. For confirmation of the
assignment, when this is appropriate, the IR spectra of the title molecule are also compared with
2
those of APO. The recorded Far IR spectra of 3-MeAPO and D -3-MeAPO in solid phase are
shown in Fig. S6. The IR spectra of 3-MeAPO, D -3-MeAPO, and APO in the CCl solution, in
2
4
-1
the 1700–900 cm region, are compared in Fig. S7. The IR spectra of 3-MeAPO in the solid
state and CCl solution in the mentioned range are compared in Fig. S8. In addition, the IR
4
spectra of 3-Me-MeAPO and 3-Me-PhAPO and their deuterated isotopomer, D-3-Me-MeAPO
4
and D-3-Me-PhAPO, in the CCl solution are shown in the Figs. S9-S10, supplementary
materials. The computed frequencies of harmonic vibrational band and their approximate
assignments, along with the experimental results of infrared and Raman frequencies for the
stable aminoketone form of 3-MeAPO and its corresponding deuterated forms are presented in
Tables 2 and 3, respectively. According to these tables, there are some differences between the
calculated and experimental wavenumbers. These discrepancies are caused by several factors,
such as anharmonicity, Fermi resonance, and solvent effects, which were not considered in our
theoretical calculations.
4
.5.3.1. Band assignment
The NH and CH stretching of amine, methyl, and methylene groups region
In this region, the NH/ND and C-H stretching vibrations are expected to be observed. In
the amino compounds, the asymmetry and symmetrical NH stretching vibrations are expected to
-1
be observed in the 3520–3420 and 3420–3325 cm regions, respectively [61, 62]. However, the
existence of both intermolecular and intramolecular hydrogen bond systems perturbs this pattern
[63]. For example, in CCl
4 a
solution, the ν NH band of APO and methyl 3-amino-2-butenoate
-1
(
MAB) [11, 27] appear at 3375 and 3509 cm , respectively. The ν NH band of the mentioned
s
-1
molecules appear at 3184 and 3335 cm , respectively. While the theoretical and the other
experimental results confirm that the strength of the intramolecular hydrogen bond (IHB) in
APO is stronger than that in MAB [11, 27].
1
4

ACCEPTED MANUSCRIPT
In the solid phase IR spectrum of 3-MeAPO, two strong bands were observed at 3280 and
-1
-1
3
120 cm , which upon deuteration shifts to 2476 and 2320 cm (in the solid phase),
respectively. The corresponding Raman bands of 3-MeAPO in the solid state appear at 3250 and
-1
3
095 cm . According to our calculations, these bands are assigned to the NH asymmetrical and
symmetrical stretching, respectively. However, in solutions the frequency of the former shifts
-1
considerably towards higher wavenumbers, appears at 3367 cm , and its intensity decreases,
-1
while the position and intensity of the latter is almost constant, appears at about 3135 cm , see
Fig. 4 and Table 2. The positions of the corresponding bands in the solid phase of APO have
-1
been reported at about 3353 (3354) and 3179 (3179) cm , the Raman values are in parenthesis
11], indicating that both intermolecular and intramolecular hydrogen bonds in 3-MeAPO are
[
stronger than those in APO, which is in excellent agreement with the results of the DFT
1
calculations and experimental HNMR and UV spectra, see sections 4.4.1 and 4.4.2. The
corresponding IR bands in the CCl solution of D -3-MeAPO appear at 2595, 2562, 2520, and
4
2
-1
2
373 cm . The first two bands are attributes to asymmetric ND
bonded molecules. The last two bands are attributed to the overtones and symmetric ND2
stretching modes, respectively. The corresponding IR bands in the solid phase of D -3-MeAPO
2
stretching in free and hydrogen
2
-1
are appeared at 2473, 2401, 2363, and 2320 cm . The asymmetry and symmetry ND stretching
bands of ND in the Raman spectrum of D -3-MeAPO in the solid phase appear at 2476 and
2
2
-
1
2
3
320 cm , respectively.
The infrared spectrum of 3-MeAPO, in the CCl solution, shows a weak band at about
4
-
1
200 cm , which upon dilution slightly shifts toward higher frequencies. We believe that this
-1
-1
band is an overtone of IR band at 1624 cm , which is in Fermi resonance with the 3135 cm
band.
3
The CH bond stretching of the CH groups are expected to be appeared in the 2900–3000
-1
cm region [62, 64]. The IR spectrum of 3-MeAPO in the solid phase indicates 4 bands with
-1
relatively medium-intensity at 2985, 2965, 2923, and 2870 cm , which are assigned to the CH
stretching modes of the CH groups. The corresponding Raman bands in 3-MeAPO observed at
3
-1
3
005, 2960, 2915, and 2880 cm .
By considering the reported IR spectrum of 3-Me-PhAPO by Xiang Chen et al. [23], it
-1
seems that the NH stretching wavenumber, 3280 cm , is not in agreement with our prediction.
As explained in section 4.1, with increase of the IHBs, the N…O distance and NH str.
1
5

ACCEPTED MANUSCRIPT
wavenumber decrease. Furthermore, the NH stretching wavenumbers should obey the trend (1).
Moisture was removed by adding anhydrous Na SO to the CCl solution of the compounds. The
2
4
4
-1
IR spectrum of dried CCl solution of 3-Me-PhAPO shows no band at about 3280 cm , see Fig.
4
S10 in supplementary material. As Figs. S9-10 show, the NH str. band cannot easily be
identified. According to the N… O distance, we expect to observe the NH str. band frequencies
-1
at about 3000 cm , which is overlapped with the CH str. bands. To estimate the NH str.
wavenumber, we used the deuterated compounds (NH exchanged with deuterium). Since, the
-1
ND str. of 3-Me-MeAPO and 3-Me-PhAPO are 2270 and 2220 cm , respectively, see Figs S9-
1
0, so, the NH str. of the 3-Me-PhAPO is lower than that in 3-Me-MeAPO.
-
1
1
700–1000 cm region
In this region, as the most significant region of vibrational spectra, beside the CH and
3
NH
2
deformation and rocking modes, the C-CH
3
, C-CN, C=O, C=C, and C-N stretching modes
of the chelated ring are expected to be observed.
The IR spectrum of 3-MeAPO in the CCl
4
solution shows three strong bands at 1624,
-1
1
578, and 1491cm . The corresponding IR bands in the solid phase appear at 1636 (as a
-1
shoulder), 1603, and 1498 cm (see Fig. S8). In the Raman spectrum of 3-MeAPO in solid
-1
phase, the corresponding bands appear at 1571 and 1487 cm . According to the theoretical
-1
results the band at 1624 cm is assigned to ν OCCC coupled to δ CH (β). The corresponding
a
a
3
-1
band in the IR spectrum of APO in the CCl solution occurs at 1630 cm . We assign the other
4
-1
two IR strong bands at 1578 and 1491 cm to the other normal modes, see Table 2. For APO, the
-1
corresponding bands appear at 1599 and 1536 cm , respectively, see Fig. S7. The lower
frequencies of these bands for 3-MeAPO, in the IR and Raman, in comparison with the
corresponding values for APO confirm stronger hydrogen bond in 3-MeAPO compared with that
-1
in APO. The 1578 cm band in the IR spectrum of 3-MeAPO, in the CCl solution, is assigned
4
2 s s
to the NH bending coupled with ν OCCC, ν CCCN, which upon deuteration, this band
-1
disappears, and new bands appear at about 1280 (1289) and 1206 (1193) cm . The values of the
Raman bands of D2-3-MeAPO are given in parenthesis.
By considering the theoretical calculations and comparing with the spectrum of APO
-1
[
11], the medium to weak intensity IR bands at 1460-1350 cm region, in the CCl solution of 3-
4
1
6

ACCEPTED MANUSCRIPT
MeAPO, which are not affected by deuteration (See Fig. S5), are assigned to δCH which are
3
coupled to some other motions. The corresponding Raman bands for CH
3
bending occur at 1463
-1
-1
and 1373 cm in solid phase and at 1467 and 1377 cm in the CCl solution. The mentioned IR
4
-1
bands of APO, in the CCl solution, appear at 1358-1425 cm region (See Fig. S8).
4
-1
The strong IR band in the CCl solution of APO at 1282 cm is assigned to the ν CCCN,
4
s
-1
which is coupled to ρNH , ρCH (β). The mentioned IR band in 3-MeAPO, appears at 1259 cm .
2
3
-1
The corresponding Raman bands in APO and 3-MeAPO appears at 1287 and 1278 cm ,
respectively. A comparison between these bands, shows that this vibrational mode is shifted
3
toward lower frequencies upon substitution of the CH group in the α-position of APO and
increases the IHB strength. This frequency shift is in excellent agreement with our calculated
results and confirm our assignment. The calculated corresponding band in 3-MeAPO and APO
-1
are 1296 and 1317 cm , respectively.
-1
The weak and medium IR bands in the CCl solution of 3-MeAPO at 1100-990 cm and
4
-1
9
70 cm are assign to ρNH and ρCH vibrations coupled with the νC-CH stretching mode,
2 3 3
respectively. Upon deuteration, the intensity of these bands increases (See Fig. S4), which
according the theoretical results, these bands are assigned to the ρCH , δND , and νC-CH
vibrational modes. The corresponding Raman bands appear at 1095, 1046, and 972 cm (See
Fig. S5). According to the theoretical results, the vibrational mode of ρND in the IR spectra of
3
2
3
-1
2
-1
D -3-MeAPO is observed at 843 cm , as a medium-weak intensity band.
2
-
1
Below 1000 cm region
3
In this region, we expect to observe the C-CH stretching, N-H out of plane bending
mode, and C-CH in plane and out of plane bending modes and in plane and out of plane
3
chelated ring deformations.
-1
Theoretical calculation attributes the IR band at 875 cm in the solid phase, to the νC-
CH , which coupled with ρCH (α) and in-plane chelated ring deformation, ꢀ. The mentioned
3
3
-1
normal mode in the IR spectrum of D
2
-3-MeAPO appears at 877 cm . The above Raman bands
-1
are at 875 and 878 cm . In the solid state a relatively IR broad band, which upon deuteration
-1
2
disappears, is observed at 798 cm , we assigned this band to the torsion of NH . The mentioned
-1
IR band in MAB has been observed at 692 cm [27].
1
7

ACCEPTED MANUSCRIPT
According to our calculations, in the solid-state IR spectrum of 3-MeAPO, the weak
-1
intensity band at 798 cm is assigned to the out-of-plane NH bending which disappears upon
deuteration. The corresponding vibration in APO and MAB is strongly coupled with the out-of-
α
plane CH bending. In the solid-state IR spectrum of APO, the coupled vibrations appear at 818
-1
-1
and 755 cm , its averaged is 786 cm , while in solid MAB it is reported to be occurred at 772
-1
cm [11, 27]. These values confirm that the intramolecular hydrogen bond in 3-MeAPO is
stronger than that in APO and MAB.
The out of plane bending of chelated ring, Γ, appears in the solid phase IR spectrum of 3-
-1
MeAPO at 645 cm , as strong intensity band. The corresponding band in APO appeared at 630
-1
cm [11]. This result is also in agreement with the stronger of hydrogen bond in 3-MeAPO
compared to that in APO.
The infrared spectrum of 3-MeAPO in the CCl
4
solution shows a shoulder band at 430
-1
cm , which in the solid phase this band splits to two medium bands and observed at 450 and 432
-1
cm . According to the theoretical calculating, this band is assigned to the in-plane deformation
of the chelated ring (ꢀ). The corresponding bands in the Raman spectra of 3-MeAPO in the solid
-1
and solution phase are observed at 451 and 445 cm , respectively. The corresponding band in
-1
the IR and Raman spectra of MAB reported at lower frequency, 399 and 408 cm , respectively
[27]. This shift also shows that the IHB strength in 3-MeAPO is more than that in MAB.
By considering the theoretical calculation and comparing with the vibrational spectra of
-1
APO and MAB, the IR band at 380 cm in the CCl solution of 3-MeAPO is assigned to the
4
N…O stretching, coupled with δC-CH . The corresponding band in APO and MAB appeared at
3
-1
3
60 and 344 cm , respectively, [27], which also supports the stronger IHB in 3-MeAPO than
that in APO and MAB. These frequency shifts are in excellent agreement with the UV, NMR,
DFT, and the other IR bands related to IHB strength. The Raman band of this normal mode in
-1
the solid phase of APO and 3-MeAPO appears at 360 and 404 cm , respectively. Upon
deuteration, the mentioned IR and Raman bands are appeared slightly lower than the observed
values for 3-MeAPO, which are consistent with the theoretical results.
-1
According to the theoretical results, the IR band at 289 cm in the solid phase of 3-
MeAPO is assigned to the out-of-plane of chelated ring deformation coupled with γC-CH (β),
for which the corresponding Raman band appears at 292 cm . The IR and Raman bands of this
3
-1
-1
normal mode in D -3-MeAPO are observed at 289 and 284 cm , respectively.
2
1
8

ACCEPTED MANUSCRIPT
5
. Conclusion
According to our theoretical and experimental results, among 3 possible tautomers of 3-
MeAPO, the aminoketone tautomer is the most stable form. In addition, from the theoretical
point of view, by considering the conformations of the CH groups in 3-MeAPO, with respect to
3
the plane of the molecule, 8 aminoketone conformers can be drawn for that. Among them, only
one conformer of aminoketone tautomer is stable at the B3LYP/6-311++G** level calculations.
The structures of the other conformers turn under full optimization to the stable form, AK1.
The crystal structure of 3-MeAPO was determined by single crystal X-ray diffraction.
There is an excellent agreement between the X-ray result and the calculated molecular structure.
In addition, the molecular structure, vibrational, UV, and NMR spectra, of 3-MeAPO and its
deuterated analogue, D -3-MeAPO, were predicted using DFT calculations at the mentioned
2
level. A complete vibrational assignment of the 3-MeAPO compound is presented. The infrared
spectra also show that in the solid state, 3-MeAPO is not only engaged in an intramolecular
hydrogen bond, but also forms an intermolecular hydrogen bond. In addition, the intermolecular
4
hydrogen bond will disappear in dilute CCl solutions. All theoretical and experimental results
include vibrational, NMR, and UV spectra show that the following trend in IHB strength is
obtained:
3
-Me-PhAPO > 3-Me-MeAPO > 3-MeAPO > APO
This result could be attributed to the steric effect of CH group in the α-position with the
3
hydrogen atoms of methyl groups in the β position, which pushes the methyl groups toward
oxygen and nitrogen atoms. In addition, the NBO results show, the steric effect of methyl and
phenyl substitutions on the nitrogen atom also causes to decrease the N…O distance and increase
the IHB strength.
Acknowledgement
This work was supported by the Ferdowsi University of Mashhad, Grant No. 42561.
The authors wish to thank Kristina Eriksen (Ph.D, Copenhagen University) for her valuable help
in the analysis of the X-ray data and Eva Marie Karlsen (Roskilde University) for scanning of
IR and UV spectra of 3-Me-MeAPO and 3-Me-PhAPO molecules.
1
9

ACCEPTED MANUSCRIPT
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/??.????/ Journal of molecular structure,??.??.??.
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Caption for Figures
Fig 1: Tautomery in β-ketoenamines.
2
5

ACCEPTED MANUSCRIPT
Fig 2: a) ORTEP structure of 3-MeAPO. b, c, d) the optimized structures at B3LYP/6-
3
11++G** level, of 3-MeAPO, 3-Me-PhAPO, and 3-Me-MeAPO, respectively.
Fig 3: The calculated HOMO-LUMO energy gaps: a) for the 3-MeAPO and APO. b) for the 3-
Me-MeAPO and 3-Me-PhAPO.
Fig. 4: The recorded infrared spectra of APO (…), 3-MeAPO (———), and D
2
-3-MeAPO (—
…
—…) in CCl , 3-MeAPO (– – – –) in solid phase (in the 3500–2700 cm-1 range).
4
Supplementary material
Fig. S1: The atom numbering and conformations for aminoketone form of 3-MeAPO, only AK1
is stable by calculations at B3LYP/6-311++G** level.
Fig. S2: The recorded NMR spectra of 3-MeAPO, 3-Me-PhAPO, and 3-Me-MeAPO in CDCl3:
1
13
a, c, e) HNMR and b, d, f) CNMR.
Fig. S3: The recorded experimental UV-Vis spectra of 3-MeAPO, 3-Me-MeAPO, and 3-Me-
PhAPO in ethanol as solvent.
Fig. S4: The recorded infrared spectra of 3-MeAPO (———) and its deuterated analogue
-1
(………) in CCl
4
(in the 1700–900 cm range).
Fig. S5: The recorded Raman spectra of 3-MeAPO (———) and D
solid phase (in the 3300–200 cm range).
2
-3-MeAPO (………) in
-1
2
Fig. S6: The recorded Far IR spectra of 3-MeAPO (———) and D -3-MeAPO (………) in solid
-1
phase (in the 620–250 cm range).
Fig. S7: The recorded infrared spectra of 3-MeAPO (———), APO (………), and D -3-MeAPO
2
-1
(– – – –) in CCl
4
(in the 1700–900 cm range).
Fig. S8: The recorded infrared spectra of the 3-MeAPO in the solid phase and CCl
4
solution (in
-1
the 1800–800 cm range).
Fig. S9: The recorded infrared spectra of 3-Me-MeAPO (———) and D-3-Me-MeAPO
-1
(
4
………) in CCl (in the 3200–800 cm range).
2
6

ACCEPTED MANUSCRIPT
Fig. S10: The recorded infrared spectra of 3-Me-PhAPO (———) and D-3-Me-PhAPO
-1
(
………) in CCl (in the 3200–900 cm range).
4
1
3
Scheme 1. Deuterium isotope effects on C chemical shifts of 3-MeAPO and APO. For 3-
MeAPO the order is deuterium at the hydrogen bonded position, deuterium at the non-hydrogen
bonded position. For APO the last number is for deuteration at C-3.
*
The central line is broad, so isotope effects cannot be measured accurately.
*
* Assignment tentative.
2
7

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Table 1
Some selected theoretical parameters of 3-MeAPO, 3-Me-MeAPO, 3-Me-PhAPO, and APO
calculated at B3LYP/6-311++G** level of theory (bond lengths and bond angles are in Å and °,
respectively) and the mentioned experimental parameters of 3-MeAPO.
3
-MeAPO
3-Me-MeAPO
Theoretical
3-Me-PhAPO
Theoretical
APO
a
Theoretical
X-ray
Theoretical [27]
Bond length
C2-C3
1.453
1.387
1.350
1.244
1.521
1.511
1.020
1.005
1.802
2.597
1.4248(15)
1.3915(15)
1.3371(16)
1.2625(14)
1.5123(15)
1.5046(15)
0.9231
1.448
1.396
1.349
1.249
1.524
1.508
1.025
…..
1.451
1.393
1.359
1.248
1.521
1.509
1.032
…..
1.443
1.377
1.348
1.242
1.518
1.505
1.019
1.006
1.890
2.669
1.442
C4-C3
1.378
1.347
1.242
….
C4-N
C2-O
C2-C1
C4-C5
1.505
1.019
1.006
1.885
2.666
N-H9
N-H10
0.8865
O...H9
1.8738
1.732
2.584
1.702
2.581
N...O6
2.6187(16)
Bond angles
C2C3C4
C3C4C5
C3C2C1
OC2C3
C4NH9
C4NH10
C5C4N
C1C2O
OH9N
120.0
122.6
118.4
123.7
117.1
120.7
115.0
118.0
131.9
120.27(10)
121.80(10)
118.13(10)
124.26(9)
115.44
120.0
121.9
119.8
123.3
113.2
…..
120.7
120.6
119.4
123.3
111.8
…..
123.1
121.6
117.0
123.1
117.3
121.4
116.3
119.5
130.8
123.0
121.6
…..
123.1
…..
120.00
…..
115.16(9)
117.61(9)
135.76
116.2
116.9
137.6
118.5
117.3
140.3
116.3
…..
130.9
b
DA (°)
C5C4NH9
C3C4NH9
C3C4NH10
OC2C3C4
NC4C3C2
AIM results c
180.0
0.0
178.0
2.2
-179.1
1.2
172.3
-4.4
…..
-1.2
2.5
-179.9
0.1
179.8
-0.2
180.0
0.0
173.5
…..
2.8
179.8
-0.5
-179.6
0.2
3.9(17)
-2.9(16)
0.0
-3.0
0.3
0.0
ρ
0.039
-0.0345
10.85
….
….
….
0.046
-0.0376
13.63
0.049
-0.0383
14.91
0.031
-0.0277
7.67
….
….
….
BCP
2
∇
BCP
EHB
a
Data from [27].
b
c
DA is dihedral angle.
-3
2
-5
Charge density (ρ) in e.au , Laplacian of charge density (∇ ρ) in (e.au ) at the bond critical point (BCP) of the
O…H bond. EHB is the IHB energy in kcal/mol, according to Espinosa et al. suggestion [54].