Intramolecular hydrogen bonding in conformationally semi-rigid α-acylmethane derivatives: A theoretical NMR study

Article abstract of DOI:10.1039/c7ob01834g

Conformational mobility is a core property of organic compounds, and conformational analysis has become a pervasive tool for synthetic design. In this work, we present experimental and computational (employing Density Functional Theory) evidence for unusual intramolecular hydrogen bonding interactions in a series of α-acylmethane derivatives, as well as a discussion of the consequences thereof for their NMR spectroscopic properties.

Full text of DOI:10.1039/c7ob01834g

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Intramolecular hydrogen bonding in conformationally semi-rigid
α-acylmethane derivatives: a theoretical NMR study
Antonio J. Mota,*,a Jürgen Neuhold,b Martina Drescher,c Sébastien Lemouzy,c Leticia González*,b
and Nuno Maulide*,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Conformational mobility is a core property of organic compounds, and conformational analysis has become a pervasive
tool for synthetic design. In this work, we present experimental and computational (employing Density Functional Theory)
evidence for unusual intramolecular hydrogen bonding interactions in a series of α-acylmethane derivatives, as well as a
discussion of the consequences thereof to their NMR spectroscopic properties.
www.rsc.org/
Introduction
solution as governed (at a given temperature) by either
chelation or dipole attraction/repulsion effects.
Conformational flexibility is an intrinsic trait of most organic Herein, we present experimental and computational evidence
compounds.1 The remarkable ability of molecules to adopt for an unusual intramolecular hydrogen bonding interaction in
multiple possible conformations is usually accompanied by a a series of N-acyloxazolidinones and other α-acylmethane
defined preference for certain of those conformations, a derivatives, with striking consequences to their NMR
property that resides at the core of molecular interactions and spectroscopic properties. The study also includes theoretical
molecular recognition.2 Although the distribution of (density functional theory, DFT) 1H- and 13C-NMR
conformational states can be strongly influenced by solvent determinations. Theoretical NMR determinations are often
effects,3 intramolecular attractive or repulsive interactions are used in cases of problematic and dubious NMR assignments9
often decisive factors that lead molecules to “choose” a and should be more frequently used as a tool to prevent
specific spatial arrangement of atoms.4 Much, if not all, of the publication of (or correct published) erroneous NMR analyses.
chemical machinery that sustains life as we know it hinges on
subtle interactions of small thermodynamic value but
Results and Discussion
enormous structural importance. Such interactions are
deployed in multidirectional fashion and can on occasion result
During our recent studies on redox-neutral reactions of N-
alkynyloxazolidinones (ynamides),10 leading to the preparation
in robust, macroscopic 3D molecular scaffolds. Often,
unforeseen attractive interactions can become important
design elements with applications ranging from synthesis5 to
catalysis6 and, ultimately, biology.7
of various
α-arylated acyloxazolidinone products (1, Scheme
1
1), we noted the consistently and unusually low field H-NMR
shifts of the hydrogen marked in blue as Ha. For instance, in
product 1-nBu (R = nButyl) the signal for Ha appeared at δ =
5.67 ppm, at 5.68 ppm for 1-Cy (R = Cyclohexyl), and for 1-Ph
(R = Phenyl), the signal goes to 6.96 ppm, lying practically
within the aromatic region.
N-acyloxazolidinones, popularized through the seminal,
textbook work of Evans and others8 remain, even in the 21st
century, as cornerstone reagents for aldol- and related
transformations. This is largely due, as in most cases of
successful asymmetric induction (be it stoichiometric or
catalytic), to their adoption of predictable conformations in
O
O
O
Ha
N
O
cat. TfOH
δ(Ha), ppm
R
O
S
R = n-Bu
R = Cy
R = Ph
5.67
5.68
6.96
PhS
1-R
Scheme 1. Redox-neutral arylation of ynamides and unusual chemical shifts of
Ha.
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In order to eliminate any possible effect of the sulfur residue
on the aromatic ring, we compared the known compound 1-
Dec (R = Decyl) with its desulfurated analogue 2-Dec. A
decrease in chemical shift of 0.64 ppm (from 5.66 to 5.02 ppm,
respectively) was found, whereas an equally high chemical
shift value of δ = 5.11 ppm has been reported11 for the
desulfurated methyl derivative 2-Me (cf. Figure 1a).
Figure 2. Possibility of six-membered intramolecular hydrogen bonding in 2-Me
.
This far exceeds, for instance, the predicted value for this
structure obtained by simple NMR-predicting software (the
ChemOffice 13.0 suite,12 for example, predicts a chemical shift,
δ, of just 3.52 ppm). The value is all the more striking if one
compares the acyloxazolidinone 2-Me with other carbonyl
analogues (cf. Figure 1b). Indeed, the aldehyde 3-Me (which
could be expected to exert a comparable electron-withdrawing
To validate this assumption, we required a tool to accurately
model the two extreme conformational situations where this
hydrogen bond is present and absent, compare their relative
stability and simulate the NMR spectrum of both forms. We
resorted to high-level DFT calculations since it is well-known
that general purpose, theoretical 1H-NMR spectra could be
reliably covered by this level of theory.13 This required
accuracy aims not only at reliably reproducing the already
known experimental data but mostly predict new values for
unknown derivatives or non-detectable conformers. The latter
is a crucial requirement as we need to compare experimentally
assessed H-bonded situations with non-measurable
conformers for which no H-bonding is operative and
experimental quantification by NMR is not accessible.
effect on the C-H bonds in
α
acyloxazolidinone moiety), the ethylester 4-Me
-position with respect to an
the
,
methylthioester 5-Me or the N-methylcarboxamide 6-Me are
all known compounds reported to have chemical shifts for Ha
inside a narrow window not exceeding a δ value of 3.80 ppm
(vide infra Table 1).
O
O
O
O
O
Ha
Me
N
O
We will initially focus on desulfurated α-acylmethane
derivatives, i.e., the known compounds 2-Me−6-Me (cf. Figure
1c). We further added an unknown compound, the N-
Ha
C10H21
N
(a)
(
Ha), ppm
1-Dec
2-Dec XR = H
XR = SPh
5.66
5.02
(
Ha), ppm
RX
methylimidazolidinone (Imid) 7-Me
,
to enlarge the
2-Me
5.11 [ref. 11]
predictability test of our model, and resynthesized 5-Me to
1
ascertain the H-NMR chemical shift for Ha, since calculations
O
(
Ha), ppm
Ha
Me
YR
found a discordant value with that reported in literature (see
below in ref. 24).
3-Me
4-Me
5-Me
YR = H
YR = OEt
YR = SMe 3.92 (this work)
3.64 [ref. 22]
3.72 [ref. 23]
(b)
6-Me YR = NHMe 3.55 [ref. 25]
Computational details.
Calculations were performed using the GAUSSIAN09 suite of
programs.14 Initial lowest-energy conformations were
optimized by density functional theory (DFT) using the well-
known hybrid B3LYP functional15 with the Pople’s diffuse,
polarized, split-valence, double-zeta 6-31+G* basis set.16 From
these geometries, the corresponding 1H-NMR isotropic
magnetic shielding values were calculated reoptimizing them
with the larger triple-zeta 6-311+G(d,p) basis set17 (necessary
O
O
2-Me
XR= Oxaz
3-Me XR= H
O
(c)
N
Ha
Me
XR
Oxaz =
Imid =
4-Me
5-Me
6-Me
7-Me
XR= OEt
XR= SMe
XR= NHMe
XR= Imid
O
N
N
(acylmethyl)phenylmethane
derivatives
Figure 1. (a) Evaluation of the influence of an arylsulfur residue on the chemical
shift of Ha, and on its desulfurated version, for oxazolidinone compounds. (b) to get a high accuracy in the determination of chemical
Comparative analysis of analogous desulfurated carbonyl derivatives. (c) The
different experimentally known α-acylmethane derivatives studied in this work, shifts,13 see the Electronic Supplementary Information, ESI, for
with the exception of 7-Me that has been prepared by us for the first time.
geometries) combined with different functionals. These
include the hybrids B3LYP, which gives reliable 1H-NMR
chemical shifts for the most common compounds, their
Detailed analysis of the structure of acyloxazolidinones 1-R/2-
empirical dispersion, B3LYP-D3,18 and long-range corrected,
R
revealed the possible intervention of an intramolecular
CAM-B3LYP,19 versions, and the Minnesota M06-2X
functional,20 which accounts for non-covalent interactions. We
have also included for comparison the non-hybrid GGA-
functional LC-ωPBE,21a the long range corrected version of
PBE21b (another widely used functional for general purposes).
All the calculations have been carried out including implicit
solvent (in which the corresponding experimental spectra have
been recorded, see below) through a Polarizable Continuum
Model (PCM).22 Results obtained from these calculations for
hydrogen bonding interaction through a 6-membered ring
ranging from the electron-rich oxazolidinone (Oxaz) carbonyl
oxygen to the methinic hydrogen Ha, giving rise to the
conformer shown in Figure 2. We recognised that this
structure-specific interaction might lie at the heart of the
unusually high chemical shift observed for this particular
compound (which is absent in the other derivatives, cf. Figure
1b).
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the chemical shift (in ppm) of the Ha hydrogen of the selected, that include the energetically accessible conformers as the
lowest-energy conformers for compounds 2-Me−7-Me calculated chemical shift on the most stable conformer is
(Scheme 4) are summarized in Table 1.
directly compared to the experimental one, which includes all
1
It should be noted that the precision in the H-NMR chemical those conformations.
shift determination is fairly high along the different methods At this juncture, we wished to dive into simulated spectra, with
employed. Yet, for this set of molecules, the LC-ωPBE the aim to modulate the strength of the intramolecular H-bond
functional performs extremely well, achieving δ values in very by the calculated value for Ha. Accordingly, we elected several
close agreement to the experimental ones (see the SI for ad hoc unreported derivatives: the permethylated 8-Me and
details), therefore we elected to keep the LC-ωPBE functional the perfluorinated 9-Me oxazolidinone analogues, and the
for further analyses related to these compounds.
acylcarbamate 10-Me, which constitutes the ring-strainless
open-chain version of the oxazolidinone derivative 2-Me
(Figure 3). Calculations made on these compounds were
performed for the conformations for which the 6-membered,
intramolecular hydrogen bond is expected to be operative and
gave rise to the set of δ values for Ha collected in Table 3 along
with the calculated O···Ha distances.
Table 1: Experimental and calculated 1H-NMR chemical shifts (in ppm) of Ha for
derivatives 2-Me−7-Me in chloroform.
2-Me
(R1
3-Me
4-Me
(R1
5-Me
(R1
6-Me
(R1
7-Me
(R1
1H-NMR
=
(R1
H)
=
=
=
=
=
chemical shifts
Oxaz)
5.23
5.02
5.16
5.12
5.10
5.1111
OEt)
3.68
3.68
3.63
3.82
3.64
3.7224
SMe)
NHMe)
Imid)
5.43
5.17
5.36
5.20
5.29
5.28a
Table 2: Calculated 1H-NMR chemical shift (in ppm) of Ha in conformers including and
excluding hydrogen bonding for derivatives 2-Me and 7-Me, in chloroform, at the LC-
ωPBE/6-311+G(d,p) level of theory.
B3LYP
B3LYP-D3
CAM-B3LYP
M06-2X
3.69
3.70
3.62
3.79
3.64
3.6423
3.88
3.26
3.91
3.33
1H-NMR
2-Me
2b-Me
7-Me
7b-Me
3.85
3.21
chemical shifts
hydrogen
bonding
non-hydrogen
bonding
hydrogen
bonding
non-hydrogen
bonding
4.22
3.48
LC-ωPBE
5.10
3.64
5.29
3.53
LC-ωPBE
3.92
3.30
a
a
−
Experimental
5.1111
−
5.28b
Experimental
3.9225,a
3.5526
a Non applicable. b This work (see ESI).
a This work (see ESI).
Interestingly, the calculated lowest-energy conformations for
2-Me and 7-Me correspond to that depicted in Figure 2, in
which a 6-membered hydrogen bond27 is established between
Ha and the carbonyl group of the heterocyclic moiety. We had
originally postulated that this was at the origin of the unusual
chemical shift values for Ha. With the help of DFT calculations,
we are able to consider conformations in which the hydrogen
bonding event is absent and recalculate the chemical shift
associated to Ha in the same solvent (chloroform). Results for
the two limiting conformations in each case (hydrogen
bonded, 2-Me and 7-Me, and non-hydrogen bonded, 2b-Me
and 7b-Me) are presented in Table 2. An important drop
(about 1.5 ppm to high field) is observed affecting the δ value
of Ha of the conformer in which the hydrogen bonding is not
operating with respect to the one in which the hydrogen bond
is established (lowest-energy conformer).
Me
N
F
Me
Me
F
O
O
O
N
O
Me
Ha
Me
Ha
Me
Ha
N
O
O
F
O
Ca
Ca
Ca
F
O
O
Me
8-Me
9-Me
10-Me
Figure 3. Ad hoc structures created for the study of the 6-membered,
intramolecular hydrogen bond in this series of compounds.
Table 3. Calculated 1H-NMR chemical shifts of Ha for known structures 2-Me and 7-Me
and unknown 8-Me−10-Me and O ··· Ha distances.
Parameters
2-Me
(R1
7-Me
(R1
8-Me
(R1
9-Me
(R1
10-Me
=
=
=
=
(R1 = open
Oxaz)
Oxaz)
Imid)
Oxaz(Me4))
Oxaz(F4))
Since the free-energy difference (ΔG) between the two limiting
conformations (B3LYP/6-31+G(d)) is 4.46 Kcal·mol−1 for 2-Me
and 5.44 Kcal·mol−1 for 7-Me, a conformational equilibrium of
conformers 2b-Me and 7b-Me (without hydrogen bonding)
can be excluded. This means that, besides other possible,
energetically accessible conformations, the apparent chemical
shifts of Ha for 2-Me and 7-Me should be very close to the
theoretical calculated values, as it is evidenced in Table 2,
making the considered functionals as ‘effective functionals’
δ (in ppm)
5.10
5.29
5.21
4.75
5.31
distance (in Å)a
2.243
2.198
2.201
2.295
2.173
a
O
···Ha distances were extracted from the corresponding 1H-NMR calculations
(LC-ωPBE/6-311+G(d,p) in chloroform (PCM)).
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From Table 3, it could be pointed out that, concerning the remaining carbonyl group establishes three different close
deshielding of Ha, the ureido derivative 7-Me and the open interactions: at 2.589 (C=O···CH2), 2.644 (C=O···Me) and 2.792
acylcarbamate 10-Me appear to be the more effective Å (C=O···H-Ph) (Figure 5), all them around the expected Van
compounds establishing the intramolecular hydrogen bond, der Waals distance.
given the enhanced Lewis basicity (and hence stronger aIn order to characterize this special interaction and evaluate
hydrogen bond-donor ability) of the carbonyl oxygen its strength, we applied the quantum theory of atoms in
interacting with Ha. Contrarily to this, the fluorinated 9-Me molecules (QTAIM)31 over derivatives 2-Me and 7-Me
−10-Me
derivative lead to a less electron-rich carbonyl, weakening the (from the corresponding LC-ωPBE/6-311+G(d,p) calculations)
hydrogen bond and observing the corresponding δ value of Ha using the Multiwfn suite.32 This theory is a topological analysis
at higher field (by about 0.6 ppm, see Table 3). Interestingly, able to identify bonding interactions within a molecule by
the incorporation of four methyl groups in 8-Me did not means of the gradient vector field of the charge density, ρ(
r).
substantially affect the chemical shift of Ha with respect to the Typical ρ(r) values in shared interactions are 0.722, 0.551, and
pure oxazolidinone moiety (2-Me). On the other hand, the 0.252 a.u. for N2, O2, and C−C bond in ethane molecules,
hydrogen bonds (if available) expected to be stronger when respectively, whereas in closed-shell interactions they are
presenting a higher δ value for Ha, also present, in general, 0.046 and 0.036 a.u. for LiCl molecules and NaCl molecules,
shorter distances (Table 3).
respectively.31a,33 These bonding interactions can be classified
in terms of the properties of the Laplacian of the electron
2ρ(
density,
∇
r
), into two broad general classes: shared (
2ρ(
) > 0, i.e.
∇ r) <
2ρ(
0, i.e. covalent bonds) and closed-shell (
∇
r
LC-ωPBE/6-311+G(d,p)
hydrogen bonds) interactions.34 Concerning our study, the
well-known criteria of the hydrogen bonding on the basis of
AIM theory at the bond critical point (BCP), where the gradient
5.7
5.5
5.3
5.1
4.9
4.7
4.5
R² = 0.9468
7-Me
10-Me
vector field,
0.034 a.u., and (ii)
Mata et al.36 correlated the hydrogen-bonding energy, EHB
with the Lagrangian kinetic energy, G( ), at the BCP as EHB
0.429 × G( ).
∇
ρ(
r
), vanishes, are: (i) ρ(
r) between 0.002 and
2-Me
∇
2ρ( ) between +0.024 and +0.139 a.u.35
r
8-Me
,
9-Me
r
=
r
2.1
2.15
2.2
distance in Å
Figure 4. Calculated 1H-NMR chemical shifts vs. O···Ha distance for derivatives 2-
2.25
2.3
2.35
Me and 7-Me 10-Me.
−
Additionally, the LC-ωPBE chemical shifts correlate fairly well
with the O···Ha equilibrium distances in compounds 2-Me and
7-Me−10-Me (see Figure 4), with some small variations for
shorter distances.28
Figure 6. Interatomic bond critical points (orange circles) identified by QTAIM
and the corresponding paths between the concerned atoms. Circles in yellow
correspond to ring critical points.
Therefore, we calculated the BCPs and searched for those with
a positive value of
the C=O···Ha path (2-Me, as an example, in Figure 1c).
Laplacians of the electron density, ), charge densities,
2ρ(
ρ( ), and Lagrangian kinetic energies, G( ), at each C=O···Ha
∇ r), finding a BCP in all cases in between
2ρ(
Figure 5. Close interactions in the two carbonyl groups present in 2-Me.
∇
r
r
r
A comparison of these distances with the sum of the
corresponding Van der Waals radii for hydrogen and oxygen
atoms, that is, 2.70 Å,29 constitutes another observation
pointing to the presence of intramolecular hydrogen bonding
because its short distance,30 as the oxazolidinone carbonyl
group establishes another weak C=O···H-Ph interaction in 2-
Me at 2.777 Å, a distance slightly higher than the sum of the
corresponding Van der Waals radii. Interestingly, the
BCP, Ha chemical shifts, C=O···Ha equilibrium distances, and
calculated EHB energies are summarized in Table 4.
As shown, the data in Table 4 corroborates the presence of
hydrogen bonds in the C=O···Ha paths for oxazolidinone- (2-
Me and 8-Me−9-Me), imidazolidinone-based (7-Me) and the
open-chain 10-Me compounds. The strongest hydrogen bond
can be found in the latter structure 10-Me, with a rather short
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O
···
H
distance, whereas the weakest one, as expected, 3.53 ppm, we must conclude that, even with polar solvents,
the conformational equilibrium at room temperature keeps
appeared in the fluorinated derivative 9-Me
.
Based on both the energy (EHB) and the O···Ha distances, these this specially stabilized conformation the most part of the
hydrogen bonds are positioned in the limit in between time, avoiding the expected shielding of the chemical shift of
medium and weak and, hence, they present
a bond Ha.
contribution mostly electrostatic.27b,37 As a reference, the
calculated CCSD(T) interaction energy for a water dimer, a HF
dimer, or a HCl dimer is 4.92, 4.52 and 1.90 Kcal/mol,
respectively.38 Although the hydrogen-bond energy (EHB) could
be well correlated with the O···Ha distance (Figure 7a), the
best correlating descriptor with EHB is the corresponding
charge density (ρ(r
)) at the BCP,39 as it is showed in Figure 7b.
Table 4: Laplacians of the electron density, ∇2ρ(r), charge densities, ρ(r), and
Lagrangian kinetic energies, G(r), at each C=O···Ha BCP, Ha chemical shifts, O···Ha
equilibrium distances, and calculated EHB energies for derivatives 2-Me and 7-Me−10-
Me.
(a)
Parameters
2-Me
(R1
7-Me
(R1
8-Me
(R1
9-Me
(R1
10-Me
(R1
=
=
=
=
=
Oxaz)
Imid)
Oxaz(Me4))
Oxaz(F4))
open
Oxaz)
∇2ρ(r) (in a.u.)
ρ(r) (in a.u.)
G(r) (in a.u.)
δ (in ppm)
0.06209
0.01745
0.01359
5.10
0.06791
0.01899
0.01493
5.29
0.06790
0.01878
0.01484
5.21
0.05658
0.01586
0.01234
4.75
0.07821
0.02069
0.01712
5.31
(b)
distance (in Å)
2.243
2.198
2.201
2.295
2.173
Figure 7. Correlation between the calculated energy of the hydrogen bond (EHB
and either the O···Ha distance (a) or the charge density (b).
)
EHB
(in
3.66
(4.46)a
4.02
(5.44)a
3.99
3.32
4.61
(5.14)a
Kcal/mol)
a
In parenthesis, the B3LYP/6-31+G(d) calculated energy difference between the
limiting conformations (those following an intramolecular C=O ··· Ha hydrogen
bonding scheme and those that does not). Note that most part of this energy
difference corresponds to the hydrogen bonding event.
Table 5: Theoretical and experimental solvent effects on the 1H-NMR chemical shift
of Ha for compound 7-Me.
1H-NMR chemical shifts
Theoreticala
CDCl3
5.29
5.28
MeOD
5.31
DMSO-d6
5.30
Solvent is usually an important parameter in NMR theoretical
calculations and must be considered in order to accurately
reproduce experimental NMR spectra.3,40 In hydrogen
bonding, the election of the solvent for spectroscopic
properties is not innocent, since high-polar solvents can
theoretically disrupt or even break these types of
interactions.41 Thus, expecting that we could achieve different
chemical shifts for Ha in polar solvents and have access to
other molecular conformations than those stabilized by
hydrogen bonding, we experimentally and theoretically (LC-
ωPBE/6-311+G(d,p)) studied the corresponding 1H-NMR
spectra for 7-Me (R1 = Imid) in deuterated methanol and
dimethylsulfoxide (Table 5).
Experimentalb
5.26
5.24
a LC-ωPBE/6-311+G(d,p). b This work (see ESI).
1
Traditionally, organic chemists rely mostly on H-NMR spectra,
with relatively little attention being paid to 13C-NMR analysis.
However, 13C-NMR constitutes a crucial axis to determining
and ascertaining structures mainly due to the fact that it
presents a much larger window allowing the appreciation of
even small variations and rendering the collapsing of two
different signals unlikely. In addition, H-H coupling often
leading to broad/multiplet bands and often complicating
assignment is absent in 13C-NMR. Therefore, 13C-NMR
provides, from a theoretical point of view,13d,42 an ideal ground
where many organic products could be unambiguously
Nevertheless, the conclusion that is drawn from Table 5 is that
no solvent effect is observed in the chemical shift of Ha, even
in the presence of methanol, a polar protic solvent. Therefore,
since in Table 2 was clearly shown that the non-hydrogen
bonded form of 7-Me (7b-Me) presented a chemical shift of
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characterized by a unique fingerprint. We thus set out to quite sensitive to steric factors (about an order of magnitude
1
complete our findings and reinterpret the problem at hand more than H-NMR)44 the reported δ values calculated for Ca
based on 13C-NMR data for the Ca carbon (the methinic carbon do not correlate with any property treated in this text. This is
to which Ha is bonded), see Figures 1 and 3.
Table compiles the chemical shift values for Ca for determinations are better oriented to the unambiguous
compounds 2-Me and 2b-Me 3-Me 6Me, and 7-Me and 7b- assignment of spectroscopic data and, hence, the accurate
in the line presented just above, for which 13C-NMR
6
,
−
Me, using the four functionals initially considered (Tables 1 prediction of spectra for unknown products.
and 2). Nevertheless, the basis set used was Pople’s polarized
split-valence double-zeta 6-31G(d,p),16 since it is known that
Table 7: Calculated 13C-NMR chemical shifts (in ppm) of Ca for known structures 2-Me
and 7-Me and unknown 8-Me−10-Me.a
Pople’s double-zeta basis sets perform better than the triple-
zeta ones for 13C-NMR calculations, probably due to some
cancellation errors.43
13C-NMR
2-Me
7-Me
8-Me
9-Me
10-Me
chemical shifts
Table 6 also reflects a traditional problem associated with the
theoretical determination of 13C-NMR chemical shifts, namely
that the obtained values are very sensitive to the functional
used. This variability is perhaps the main reason why
theoretical calculations on 13C-NMR spectra are less common.
In this case, although CAM-B3LYP and LC-ωPBE are again the
more reliable functionals, LC-ωPBE clearly outperforms,
delivering chemical shifts very close to the experimental
values.
δ (in ppm)
43.08
42.61
44.63
45.57
45.44
a
Structures referred here were calculated at the LC-ωPBE/6-31G(d,p) level of
theory and using chloroform as solvent (PCM).
Finally, and as expected given the results achieved for 1H-NMR,
solvent effects on compound 7-Me were almost negligible, as
it could be drawn from Table 8, indicating that the hydrogen-
bonded conformer should be largely favoured within the
timescale of the experiment.
Table 6: Experimental and calculated values of the 13C-NMR chemical shifts (in ppm) of Ca for
derivatives 2-Me−7-Me (along with 2b-Me and 7b-Me) in chloroform.
13C-NMR
B3LYP
B3LYP-D3
CAM-B3LYP
M06-2X
LC-ωPBE
Experimental
Table 8: Theoretical and experimental solvent effects on the 13C-NMR chemical shift
chemical shifts
(in ppm) of Ca for compound 7-Me.
2-Me
45.86
46.16
44.33
48.59
43.08
42.611a
42.811bi
13C-NMR chemical shifts
Theoreticala
CDCl3
42.61
42.69
MeOD
43.58
43.78
DMSO-d6
43.60
ii
2b-Me
3-Me
51.18
57.22
51.17
56.91
49.38
55.23
53.20
58.89
47.55
52.94
−
Experimentalb
42.13
53.223a
53.1123b,23c
45.5924a
45.524b
a LC-ωPBE/6-31G(d,p). b This work (see ESI).
4-Me
49.15
48.82
47.39
50.03
45.46
Conclusions
In summary, we have presented experimental and
computational evidence for an unusual intramolecular
5-Me
6-Me
7-Me
7b-Me
58.00
51.61
45.45
50.63
57.75
50.73
45.67
50.71
55.75
49.72
43.91
48.91
60.32
51.68
47.83
52.47
53.46
47.23
42.61
47.14
54.23iii
hydrogen bonding interaction in
a
series of N-
47.226a
acyloxazolidinones and other α-acylmethane derivatives, with
striking consequences to their NMR spectroscopic properties.
In the course of this study, theoretical (density functional
theory, DFT) 1H- and 13C-NMR determinations, along with
QTAIM analysis, were employed to clearly identify the nature
of such special interaction, among others found in these
structures. Of special interest is the finding of the reliability
and accuracy of the LC-ωPBE functional, which works fairly
well in this domain, at least for this kind of derivatives. Crucial
has been the possibility to calculate conformers not accessible
by synthesis and that emphasize the stronger interaction
involved in this series of compounds. Therefore, results
presented here hint at possible general applications to the
prediction of highly accurate NMR spectral properties for
organic compounds.
42.69iii
ii
−
i
ii
Carbon non-assigned in the experimental spectrum. Non-applicable. This
work (see ESI).
iii
Furthermore, it is important to highlight the difference of ca.
11 ppm between the chemical shifts calculated for Ca in the
imidazolidinone (7-Me) and the methylthio (5-Me) derivatives.
This showcases the large spectral window made possible by
13C-NMR.
Calculations for the ad hoc structures 8-Me−10-Me led to the
results collected in Table 7. Owing to the fact that 13C-NMR is
6 | Org. Biomol. Chem., 2017, 00, 1-3
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Raton, 2011; (b) Ch.F. Chen and Y.-X. Ma, Yptycenes
Chemistry: From Synthesis to Applications, Springer-Verlag,
Berlin-Heidelberg, 2013.
Acknowledgements
This research was supported by the ERC (FLATOUT 278872),
and the University of Vienna. Calculations were partially
performed at the Vienna Scientific Cluster (VSC). We also
would like to thank the Centro de Supercomputación de la
Universidad de Granada (Alhambra, CSIRC) for computation
resources.
6
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