13C NMR spectroscopic studies of the behaviors of carbonyl compounds in various solutions

Article abstract of DOI:10.1016/j.tetlet.2017.10.071

¹³C NMR spectroscopic studies were performed for carbonyl compounds having a hydroxyl group, a carboalkoxy group, an acetoxy group, or a carboxyl group in various solvents with different polarities for observation of their behaviors of ¹³C NMR chemical shifts of carbonyl carbons in solutions. It was found that the chemical shifts of the carbonyl carbons in ¹³C NMR have good correlation with the empirical parameter for solvent polarities, E_T^N, depending on the structures. Inter- or intramolecular hydrogen bonding and dipolar-dipolar interactions appear to play a key role in this observation.

Full text of DOI:10.1016/j.tetlet.2017.10.071

Accepted Manuscript
13C NMR spectroscopic studies of the behaviors of carbonyl compounds in var-
ious solutions
Yoshikazu Hiraga, Saori Chaki, Satomi Niwayama
PII:
S0040-4039(17)31376-X
https://doi.org/10.1016/j.tetlet.2017.10.071
TETL 49433
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
14 September 2017
24 October 2017
27 October 2017
Please cite this article as: Hiraga, Y., Chaki, S., Niwayama, S., 13C NMR spectroscopic studies of the behaviors of
carbonyl compounds in various solutions, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.10.071
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13C NMR spectroscopic studies of the
behaviors of carbonyl compounds in various
solutions
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Yoshikazu Hiraga, Saori Chaki, and Satomi Niwayama*

1
Tetrahedron Letters
journal homepage: www.els evier.com
13C NMR spectroscopic studies of the behaviors of carbonyl compounds in
various solutions
Yoshikazu Hiragaa, Saori Chakia, and Satomi Niwayama∗b
a1Department of Life Science, Hiroshima Institute of Technology, 2-1-1 Miyake, Saeki-ku, Hiroshima, Hiroshima, 731-519, Japan
b2Graduate School of Engineering, Muroran Institute of Technology, 27-1, Mizumoto-cho, Muroran, Hokkaido, 050-8585, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
13C NMR spectroscopic studies were performed for carbonyl compounds having a hydroxyl
group, a carboalkoxy group, an acetoxy group, or a carboxyl group in various solvents with
different polarities for observation of their behaviors of 13C NMR chemical shifts of carbonyl
carbons in solutions. It was found that the chemical shifts of the carbonyl carbons in 13C NMR
have good correlation with the empirical parameter for solvent polarities, ETN, depending on the
structures. Inter- or intramolecular hydrogen bonding and dipolar-dipolar interactions appear to
play a key role in this observation.
Received in revised form
Accepted
Available online
Keywords:
13C NMR spectroscopy
carbonyl compounds
solvent polarity
2009 Elsevier Ltd. All rights reserved.
hydrogen bonding
dipole interaction
Introduction
was caused by the increased polarity surrounding the camphor
molecule, leading to decease of the electron densities of the
NMR spectroscopy is a useful tool for studying not only
structures of molecules but also their internal and external
chemical environments. With the use of NMR spectroscopy, a
fair number of studies have been reported for investigation of
inter- or intramolecular interactions of organic molecules through
various forces such as hydrogen-bonding, dipole-dipole forces,
metal coordination, van der Waals interaction, and anisotropic
effects. For example, quantitative assessment of intramolecular
hydrogen bonding is reported for flavones having OH or NH
carbonyl carbon. This is a similar observation previously
reported for the 13C NMR chemical shifts for the carbonyl carbon
of acetone.3d Since 13C NMR chemical shifts can be a reasonable
indicator of electron density, here we extended this study to more
polar carbonyl compounds, including esters, carboxylic acids,
and carboxylates in order to observe how the polarities of the
solvents affect the carbonyl groups. We further studied more
polar carbonyl compounds having more than one polar functional
group in the same molecule by 13C NMR spectroscopy in order to
observe how the combination of these polar functional groups is
influenced by the polarities of the solvents.
1
groups based on the H NMR chemical shifts for the hydroxy
protons in chloroform-d and in DMSO-d6.1 A criterion for a non-
covalent intermolecular attractive interaction of halogenated
solvents was proposed by 31P NMR chemical shifts of
triethylphosphine oxide in correlation with calculated
parameters.2 Many other NMR spectroscopic studies have also
been reported that provide insights into solvent effects derived by
interaction between organic molecules and solvent molecules.3
Carbonyl compounds are known to form aggregates by
intermolecular forces, such as hydrogen bonding and dipole-
dipole interaction in a solution. Their behaviors have been under
close scrutiny with the use of NMR spectroscopy for several
decades. For example, during the investigation of Marangoni
flow around a camphor disk on water, a good linear correlation
was observed between an empirical parameter for solvent
polarity (ETN)2,4 and the 13C NMR chemical shifts of the carbonyl
(C=O) carbon in camphor in various NMR solvents,5 as the 13C
Results and Discussion
We first measured the 13C NMR chemical shifts of the
carbonyl groups in acetic acid, ethyl acetate, and sodium acetate
in various solvents, and plotted them against the solvent polarity
N
parameter, ET , as shown in Fig. 1. The carbonyl group in acetic
acid shows irregular changes with no particular correlation with
N
ET , while the carbonyl groups in ethyl acetate and in sodium
N
acetate shows downfield shifts with increase of ET . We
reasoned that intermolecular hydrogen bonding in acetic acid is
counteracting the polarity of the solvent, while such influence
does not exist in the others and hence show clearer correlation
N
with the ET .
Therefore, we continued this investigation for carbonyl
compounds, 1-14, having various polar functional groups such as
chemical shifts of the C=O were shifted downfield with the
N
increase of ET . It has been concluded that the downfield shift
———
∗ Corresponding author. Tel.: +81-143-46-5746; fax: +81-143-46-5701; e-mail: niwayama@mmm.muroran-it.ac.jp

2
Tetrahedron
a hydroxyl group, acetoxy group, carboalkoxy group, or
carboxyl group, including half-esters in various solvents for
observation of their behaviors of 13C NMR chemical shifts of
carbonyl carbons in solutions (Scheme 1), focusing on the
correlation between the solvent polarities and influence by the
combination of these polar groups.6
We next examined the correlation between 13C NMR chemical
shifts for the carbonyl carbons and the solvent polarity parameter
N
ET for 2-hydroxybenzoic acid (1), 4-hydroxybenzoic acid (2),
and trans- and cis-4-hydroxycyclohexane carboxylic acids (3 and
4). However, as shown in Fig. 2, no particular correlation was
observed between the chemical shifts of the carbonyl carbons in
N
the COOH groups of 1-4 and the solvent polarity parameter ET .
We reasoned that in 1, the intramolecular hydrogen bonding
keeps the chemical shift near-constant. In 2, 3, and 4,
intermolecular hydrogen bonding of the carboxyl groups and
hydroxyl groups as well as dipolar interaction with solvent
molecules are conceivable, and these forces may be
countervailing, making the chemical shifts irregular. It is notable
that the carboxyl carbons in 1 and 2 show noticeable upfield
shifts compared to those in 3 and 4 in all the solvents because of
somewhat increased electron densities through the resonance
effect from the benzene rings.
Fig. 1. 13C NMR chemical shifts of carbonyl carbons of (a) acetic
acid, (b) ethyl acetate, and (c) sodium acetate
Fig. 2. 13C NMR chemical shifts of carbonyl carbons
N
Figures 3 and 4 show the correlation between ET values of
various NMR solvents and the 13C NMR chemical shifts for the
carbonyls in 5 and 6 and the corresponding carboxylates 7 and 8.
As shown in Fig. 3 and 4, we observed some downfield shifts of
the 13C NMR chemical shifts for the carbonyl carbon for the
N
acetoxy group and carboxyl group in 5 and 6 with increase of ET
due to the lack of the above intramolecular hydrogen bonding in
1.
Next, the carboxyl group in 5 and 6 were converted to the
corresponding sodium carboxylate 7 and 8, respectively.
Although the solvent utilized here was limited to D2O, MeOH,
and DMSO due to the decreased solubility of 7, in all the cases,
Fig. 3. 13C NMR chemical shifts of C=O in 2-acetoxybenzoic acid
(5) and its carboxylate (7)
Scheme 1. Carbonyl compounds studied by 13C NMR
spectroscopy

3
Fig. 6. 13C NMR chemical shifts of carbonyl carbons of half esters
11 and 12
Fig. 4. 13C NMR chemical shifts of C=O in 4-acetoxybenzoic acid
(6) and its carboxylate (8)
C=O in CO2R due to dipolar interaction by the solvent with the
C=O in CO2R. On the other hand, in the corresponding
carboxylate 12, similar downfield shifts were observed for both
the carbonyl carbons in the ester group and carboxylate group
because both the carbonyls were affected by the polarity of the
solvent due to lack of hydrogen bonding.
the carbonyl carbons in both the acetyl group and carboxylate
group show clearer downfield shifts in 13C NMR as the polarity
of the solvent increases as shown in Fig. 3 and 4.
Based on these observations, we conclude that the carboxyl
group has both intermolecular hydrogen bonding and polar
interaction with NMR solvents and that these interactions are
counteracting with each other, resulting in complex, irregular
We next examined 13C NMR spectroscopic behavior of 3-
carbomethoxybicycle[2.2.1]hept-2-ene-2-carboxylic acid (13),
which is known to form intramolecular hydrogen bonding by the
carbomethoxy group and the carboxyl group.7 Figure 7 shows
N
changes with respect to ET while the acetyl group alone
experiences polar interaction with the solvent.
N
the correlation between ET and the 13C NMR chemical shifts of
We next examined half-esters having both a carboalkoxy
group and a carboxyl group in order to observe the 13C NMR
spectroscopic behavior of the carbonyl carbons in the
carboalkoxy group and the carboxyl group in various solvents.
Figure 5 shows the 13C NMR chemical shifts for the carbonyl
the carbonyl carbons in 13. As can be seen in Fig. 7, the 13C
NMR chemical shifts for the ester carbonyl group remained
almost constant regardless of the polarity of the solvent except
for one case (DMSO-d6) presumably because of somewhat
reduced solubility of 13 in DMSO. The carbonyl carbon in the
carboxyl group showed a weak degree of downfield shift with
increase of the polarity of the solvent, perhaps due to its fixed
structure through the intramolecular hydrogen bonding and hence
absence of intermolecular hydrogen bonding. Therefore, we
examined the 13C NMR spectroscopic behaviors of the
corresponding sodium carboxylate (14), which lacks the
intramolecular hydrogen bonding. Although the solvents are
limited to D2O, MeOH-d4, and DMSO-d6 due to the reduced
solubility of 14, the downfield shifts were again more clearly
observed for both the carbonyl carbons in the carboxyl group and
N
carbons in relation to ET for monomethyl succinate (9) and
monoethyl phenyl malonate (10). The chemical shifts of
carboxyl carbonyls again show irregular changes with respect to
the solvent polarity indicated by ET due to the intermolecular
N
hydrogen bonding as well as to dipolar interaction by the
solvents. On the other hand, carbonyls in the ester groups of 9
N
and 10 moved slightly downfield as the solvent polarity, ET ,
increased. Here again, the chemical shifts of both the carbonyl
carbons in 10 appear somewhat more upfield than those of 9,
perhaps due to the slightly increased electron density through the
resonance effects by the benzene ring as noted for 1 and 2 above.
N
the carboxylate group with increase of the solvent polarity, ET .
Fig. 5. 13C NMR chemical shifts of carbonyl carbons of half esters
9 and 10
Fig. 7. 13C NMR chemical shifts of carbonyl carbons of half ester
13 and its carboxylate 14
Figure 6 shows monomethyl adipate (11) and its sodium salt
12. Monomethyl adipate (11) showed a tendency similar to
monomethyl succinate (9). However, for the corresponding
sodium carboxylate, 12, the 13C NMR chemical shifts of both the
C=O carbons of 12 were again more clearly shifted downfield as
We reasoned that when a carboxyl group and an ester group
have an intramolecular hydrogen bonding, the downfield shifts
with increase of ETN are observed only on the carbonyl group in
the carboxyl group because polar solvents interact primarily with
the C=O in CO2H due to the intramolecular hydrogen bonding.
The ester carbonyl group primarily interacts with the proton from
the carboxyl group through the intramolecular hydrogen bonding
N
the solvent polarity, ET , increased.
Therefore, in half esters 9-11, the downfield shifts with
N
increase of ET were observed for the 13C chemical shifts of the

4
Tetrahedron
and thereby remains near constant in its electron density. On
have dipolar-dipolar interaction with the solvents. In the
corresponding sodium carboxylate, which lacks the
intramolecular hydrogen bonding, the carbonyl carbons in both
the ester group and carboxylate group showed the downfield
shift, indicating solider dipolar interaction with the solvents (Fig.
9b).
N
the other hand, the downfield shifts with increase of ET were
more clearly observed for both the carbonyl carbons in the
carboxylate 14. These results indicate that both the C=O carbons
were affected by polarity of the solvent due to lack of the
intramolecular hydrogen bonding in the sodium carboxylate, 14.
Conclusions
The 13C NMR spectroscopic studies were performed in
various solvents for carbonyl compounds, including
hydroxybenzoic acids (1 and 2), which have a hydroxyl group
and a carboxyl group, acetoxybenzoic acids (5 and 6), which
have an acetoxy group and a carboxyl group, and half esters (9,
10, 11, and 13), which have a carboalkoxy group and a carboxyl
group for observation of their behaviors of carbonyl carbons in
solutions. It was found that in hydroxybenzoic acids (1 and 2),
polar solvents interact with the carbonyl group of the carboxyl
group. When the hydroxyl group and the carboxyl group form
intramolecular hydrogen bonding, or when the carboxyl group
forms intermolecular hydrogen bonding, the NMR solvents show
dipolar interaction with the carbonyl group in the carboxyl
groups because of the change of the electron density of the
carbonyls as depicted in Fig.8. In the acetoxy benzoic acid (5
and 6), the carboxyl group forms intermolecular hydrogen
bonding and interact with the solvent by dipolar-dipolar
interaction. The acetoxy group also exhibits dipolar interaction
with the solvents, leading to decrease of the electron densities of
the carbonyls and causing the downfield shifts in the 13C NMR
chemical shifts.
Fig. 9. Interaction of half esters with solvents (a) linear half esters
and their carboxylates, (b) half ester 13 having intramolecular
hydrogen bonding and its carboxylate 14
In summary, our 13C NMR spectroscopic analysis revealed
interactions of the carbonyl groups with a variety of solvents with
different polarity. Among the conceivable forces, it appears that
intramolecular hydrogen bonding has especially notable effects
on electron densities of carbonyl carbons compared to
intermolecular hydrogen bonding or dipole interaction from
solvent molecules, leading to near-constant 13C NMR chemical
shift regardless of polarity of the solvents. Intermolecular
hydrogen bonding and dipolar-dipolar interaction with the
surrounding solvent molecules appear to be competing with each
other, leading to irregular chemical shift changes when these two
N
forces countervail or to downfield shifts with the increase of ET
when the latter surpasses.
Acknowledgments
The authors are grateful for the financial support from the
Strategic Research Foundation Grant-aided Project for Private
Universities (MEXT), Grants-in-Aid for Scientific Research
(JSPS) (YH), Tokyo Ohka Foundation for the Promotion of
Science and Technology (SN), OHARA Pharmaceutical Co. Ltd.
(SN), and KAJIMA Foundation (SN).
Fig. 8. Interaction of hydroxybenzoic acids (1 and 2) and
acetoxybenzoic acids (5 and 6) with solvents
In half-esters, the polar interaction with the solvents was
observed primarily with the ester carbonyl carbons, leading to
decrease of the electron densities hence the downfield shifts of
the 13C NMR chemical shifts. These downfield shifts by the
polar solvents were observed more clearly for both the carbonyls
in the corresponding sodium carboxylates (Fig. 9a). On the other
hand, in the half-esters having intramolecular hydrogen bonding
such as the half ester 13, the electron density of the ester
carbonyl carbon did not change noticeably by the solvent
polarities. However, as the carboxyl carbonyl carbon showed
some downfield shifts in the 13C NMR chemical shifts with the
increase of the solvent polarity, the carboxyl group appeared to
References and notes
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5
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N
Reichardt, C. Chem. Rev. 1994, 94, 2319-2358. The ET values
N
utilized in this work are as follows: benzene-d6, ET 0.111;
N
tetrahydrofuran-d8, ET 0.207; chloroform-d, ET 0.259; acetone-
N
N
N
d6, ET 0.355; dimethyl sulfoxide-d6, ET 0.444; acetonitrile-d3,
ETN 0.460; methanol-d4, ETN 0.762; D2O, ETN 1.000.
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6. The experimental procedures are as follows: The compounds, 2-
hydroxybenzoic acid (1), 4-hydroxybenzoic acid (2), cis- and
trans-4-hydroxycyclohexanecarboxylic acids (3 and 4),
monomethyl succinate (9), monomethyl adipate (11), and NMR
solvents were purchased from Wako Pure Chemicals Co., Ltd.
(Japan) and Tokyo Chemical Industry Co., Ltd. (Japan). 2-
Acetoxybenzoic acid (5) and 4-acetoxybenzoic acid (6) were
prepared by acetylation of corresponding acids
1 and 2,
respectively. The half esters, monoethyl phenylmalonate (10) and
monomethyl norbornadiene carboxylic acid (13) were prepared by
a
selective monohydrolysis of the corresponding symmetric
dimethyl esters.8 2-Acetoxybenzoic acid sodium salt (7), 4-
acetoxybenzoic acid sodium salt (8), monomethyl adipate sodium
salt (12), and monomethyl norbornadiene carboxylic acid sodium
salt (14) were prepared from the corresponding acids by
neutralization reaction with Na2CO3.9 All other reagents and
solvents were of analytical grade.
13C NMR spectra were collected on a JEOL JNM-ECZ400S
(JEOL Ltd) 400 MHz spectrometer operating at 100.53ꢀMHz at
298.0
1.0 K with 5 mm (o.d.) Pyrex glass tubes. The
concentration of the sample solutions was 25.0 5.0 mmol L-1. In
the case of aqueous solutions, the chemical shifts were recorded
with reference to TSP-d4 as an external standard. In the case of
organic solutions, the chemical shifts were recorded with
reference to the carbons in used solvent as an internal standard
(acetone-d6, δ 29.8; acetonitile-d3, δ 1.3; benzene-d6, δ 128.0;
chloroform-d, δ 77.0; dimethyl sulfoxide-d6, δ 53.8; methanol-d4, δ
49.0; tetrahydrofuran-d8, δ 67.4).
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9. Cure, J.; Poteau, R.; Gerber, I. C.; Gornitzka, H.; Hemmert, C.
Organometallics 2012, 31, 619-626.

6
Tetrahedron
•
•
•
13C NMR studies of various carbonyl
compounds in relation to solvent polarity
Inter- or intramolecular interaction with
surrounding molecules by 13C NMR studies
Linear relationship between chemical shift
and solvent polarity for many structures