The use of a single derivative in the configurational assignment of ketone cyanohydrins

Article abstract of DOI:10.1002/ejoc.201001107

The absolute stereochemistry of ketone cyanohydrins can be easily determined by preparing a single MPA derivative. The comparison of two NMR spectra at different temperatures allows the assignment by just paying attention to the evolution of the cyanohydr

Full text of DOI:10.1002/ejoc.201001107

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001107
The Use of a Single Derivative in the Configurational Assignment of Ketone
Cyanohydrins
Iria Louzao,[a] José M. Seco,[a] Emilio Quiñoá,[a] and Ricardo Riguera*[a]
Keywords: Chirality / Configuration determination / Cyanohydrins / Methoxyphenylacetic acid / NMR spectroscopy
The absolute stereochemistry of ketone cyanohydrins can be
easily determined by preparing a single MPA derivative. The
comparison of two NMR spectra at different temperatures al-
lows the assignment by just paying attention to the evolution
of the cyanohydrin chemical shifts. The special case of α-aryl-
substituted cyanohydrins is also described.
Introduction
Results and Discussion
Dialkyl-Substituted Cyanohydrins
The NMR methods[1] for assigning the absolute configu-
ration of organic compounds based on the preparation of
two derivatives of a chiral auxiliary reagent have proved to
be suitable procedures for this purpose. Moreover, the use
of a single derivative allows to save time, sample, reagents,
and to minimize purification steps.[1] Recently, methods for
the assignment of difunctional compounds (diols and
amino alcohols)[2] were developed, and the use of resin-
bound auxiliaries allows to save even more amount of sam-
ple and time.[3]
The relative energies calculated[7] for the conformers of
(R)- and (S)-MPA derivatives of (S)-2-hydroxy-2-methyl-
hexanenitrile (1, taken as model compound) are shown in
Figure 1.
In previous reports, the assignment of the absolute con-
figuration of optically active aldehyde[4] and ketone[5] cy-
anohydrins were described. In order to determine the abso-
lute configuration of cyanohydrins, the preparation of dia-
stereomeric esters by using both enantiomers of 2-methoxy-
2-phenylacetic acid (MPA) as chiral derivatizing agent
(CDA) is required.
Here we present a single derivatization procedure for the
determination of the absolute configuration of ketone cy-
anohydrins by using only one MPA [(R) or (S)] derivative
1
based on the differences of chemical shifts found in the H
NMR spectra performed at two different temperatures
(ΔδT1T2).[6]
When energy calculations were carried out on ketone cy-
anohydrins, different conformational compositions were
obtained for dialkyl and alkyl aryl cyanohydrins.[5] There-
fore, the results on those two classes of cyanohydrins are
presented separately in this communication.
Figure 1. Main conformations for (a) (R)-MPA ester and (b) (S)-
MPA ester of a typical ketone cyanohydrin. Relative energies, both
in the gas phase [B3LYP/6-31+G(d); kcal/mol] and in solution
[PCM, B3LYP/6-31+G(d); CHCl3; free energies; kcal/mol] are
shown for each conformation of the (R)- and (S)-MPA esters of
(S)-2-hydroxy-2-methylhexanenitrile (1). Expected populations,
based on Boltzmann distributions at 298 K (T1) and at 183 K (T2),
are also shown, as well as the shieldings of the main conformation
(curved arrows). (c) Sign distributions for L1 and L2 substituents.
[a] Departamento de Química Orgánica and Centro Singular de
Investigación en Química Biológica y Materiales Moleculares,
Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Fax: +34-981-591091
E-mail: ricardo.riguera@usc.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001107.
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Configurational Assignment of Ketone Cyanohydrins
The most populated conformations for (R)- and (S)-
In accordance with this reasoning, the NMR spectra at
MPA derivatives are sp-g+ and sp-g–, respectively (Figure 1). variable temperatures of the (R)-MPA ester derivative of
Main conformations were generated around the Cα-C(O) (1R,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexanecar-
(MPA moiety) and O-CαЈ (cyanohydrin moiety) bonds. Ro- bonitrile (2; Figure 2a) show that the signals corresponding
tation around the Cα–C(O) bond provided two main con- to Me (8Ј,9Ј), H(2Ј) and H(7Ј) (L1 in the model) are more
formers, sp and ap, whereas rotation around O–CαЈ gave shielded at lower temperatures, whereas those of Me(10Ј),
rise to another two conformers, g+ and g–, in which the H(6Ј) and H(5Ј), located at the other side of the stereogenic
dihedral angle formed by atoms C(O)–O–CαЈ–CN is ca. carbon atom (L2 in the model) are deshielded (Figure 2a).
+60° and –60° respectively. In the (R)-MPA derivative, the
For its part, the (S)-MPA ester derivative of 2 shows that
L1 substituent is under the shielding cone of the phenyl H(6Ј) and Me(10Ј) become shielded at lower temperatures,
group, whereas in the (S)-MPA derivative the substituent whereas Me(8Ј,9Ј) and H(7Ј) are deshielded (Figure 2b).
shielded by the phenyl ring is L2.[8]
This correlation between the chemical shifts and the ab-
Lowering of the temperature of the NMR probe modifies solute configuration holds for the series of dialkyl cyanohy-
the relative populations, increasing those of the most stable drins of known absolute configuration shown in Figure 3
conformers [sp-g– and sp-g+ for the (R)- and (S)-MPA de- and can therefore be used as a tool for their configurational
rivatives, respectively; Figure 1]. Consequently, in the (R)- assignment.
MPA derivative, the number of molecules with L1 shielded
increases at lower temperatures. The populations of the next
conformers in energy terms for the (R)-MPA ester – sp-g+
and ap-g–, where none of the substituents L1 or L2 are shi-
elded – decrease after lowering of the temperature. There-
fore, L2 signals should show either no significant differences
or just a slight deshielding due to the loss of population of
higher energy conformations. For its part, the sp-g+ confor-
mation of the (S)-MPA derivative increases its population
at lower temperatures. Thus, as the L2 substituent is shi-
elded in this conformation, its NMR signals move to higher
field. The next conformers in energy terms for the (S)-MPA
ester are sp-g– and ap-g+, in which none of the substituents
is shielded. For this reason, a weak deshielding of L1 is
expected due to the loss of contribution of the remaining
conformations.
Therefore, for a cyanohydrin derivatized with (R)-MPA,
the chemical shift differences (ΔδT1T2 [9] are positive for L1
)
and negative for L2 (Figure 1).[10] Similar reasoning for the
(S)-MPA derivative leads to positive ΔδT1T2 values for L2
and negative for L1.
1
Figure 2. Partial H NMR spectra at different temperatures of (a)
Figure 3. (a) ΔδT1T2 signs and values for (R)-MPA cyanohydrin de-
rivatives, and (b) sign distributions for L1 and L2 substituents (T1
= 298 K, T2 = 183 K). ΔδT1T2 values for (S)-MPA derivatives are
included in the Supporting Information (Figure S1).
(R)-MPA and (b) (S)-MPA esters of (1R,2S,5R)-1-hydroxy-2-
isopropyl-5-methylcyclohexanecarbonitrile (2) (500 MHz; CS2/
CD2Cl2, 4:1).
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I. Louzao, J. M. Seco, E. Quiñoá, R. Riguera
SHORT COMMUNICATION
It should be noted that in the case of acyclic cyano- (sp-g–) and third (ap-g+) conformer decrease, therefore a de-
hydrins, one or both of the protons of the methylene group shielding is expected for the Me and Ar groups. This is in
1
adjacent to the asymmetric carbon atom can show anoma- fact observed in the H NMR spectra of the (R)-MPA (S)-
lous ΔδT1T2 signs. This is originated by the anisotropic ef- 2-hydroxy-2-phenylacetonitrile derivative (12; Figure 5a),
fect of the carbonyl group that affects those diastereotopic where all the Ar and L protons show small values and nega-
protons.[11] As shown in Figures 3 and S1, in some cases tive ΔδT1T2 signs (Figure 6).
one proton lies on the shielding zone, while the other is
located at the deshielding one [i.e. CH2(3Ј) in 7, Figure 3;
CH2(3Ј) in 1, Figure S1]. In other cases, both protons are
affected [i.e. CH2(3Ј) in 1, Figure 3; CH2(3Ј) in 4, Fig-
ure S1].
Alkyl-Aryl-Substituted Cyanohydrins
It is known that alkyl-aryl-substituted cyanohydrins pos-
sess a different conformational composition than dialkyl-
substituted ones.[5] In order to obtain more information on
this phenomenon and to take into account the role of the
solvent, we performed DFT calculations (PCM, B3LYP) on
(R)- and (S)-MPA esters of (S)-2-hydroxy-2-phenylacetoni-
trile (12). The results show that for these compounds, and
when the solvent is considered, the most stable conformer
1
Figure 5. Partial H NMR spectra at different temperatures of (a)
(R)-MPA and (b) (S)-MPA esters of (S)-2-hydroxy-2-phenylaceto-
nitrile (12). The structures of the most stable conformers and their
shieldings are also shown (500 MHz; CS2/CD2Cl2, 4:1).
for both the (R)- and the (S)-MPA derivatives is sp-g+ (Fig-
ure 4). Anisotropic effects from the MPA phenyl group are
different in both derivatives. In the case of the (R)-MPA
derivative, neither the Ar nor the L group are shielded by
the auxiliary. The second and third more stable conformers
are sp-g– (Me group shielded) and ap-g+ (Ar group
shielded) respectively (Figure 4a). Consequently, when the
temperature drops, the relative populations of the second
Figure 6. ΔδT1T2 signs and values for (R)-MPA alkyl aryl cyanohyd-
rin derivatives (T1 = 298 K, T2 = 183 K).
For its part, the most stable conformer for the (S)-MPA
derivative causes the shielding of the cyanohydrin Ar sub-
stituent by the MPA moiety (Figure 5b). This disposition
enables the cyanohydrin aryl ring to shield protons belong-
ing to the other substituent (Me, βЈ protons).[5] Since this
conformation increases its population after lowering the
temperature, both cyanohydrin aryl and methyl substituents
are more shielded at low temperatures (positive ΔδT1T2).
Figure 4. Main conformations for (a) (R)-MPA ester and (b) (S)-
MPA ester of a typical alkyl aryl cyanohydrin. Relative free energies
in solution [PCM, B3LYP/6-31+G(d); CHCl3; kcal/mol] are shown
for each conformation of the (R)- and (S)-MPA esters of (S)-2-
hydroxy-2-phenylacetonitrile (12). Expected populations, based on
Boltzmann distributions at 298 K (T1) and at 183 K (T2), are also
shown, as well as the shieldings of the main conformation by
curved arrows. (c) Sign distributions for Ar and L substituents.
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Configurational Assignment of Ketone Cyanohydrins
This additional effect does not occur on protons at further configuration by examination of the signs of ΔδT1T2 ob-
distance, such as the γЈ protons (16; Figure 6), that exhibit tained for the substituents L1/L2.
negative ΔδT1T2 values.
The methodology here presented is based on both theo-
Figure 6 shows the experimental ΔδT1T2 values obtained retical and experimental data. Summaries of the steps to
for aryl alkyl cyanohydrins of known absolute configura- follow and how to assign the absolute configuration of di-
tion. These results allow to establish a correlation between alkyl and alkyl aryl cyanohydrins can be found in
configuration and ΔδT1T2 signs. In this way, a cyanohydrin Schemes 1 and 2, respectively. We have recently demon-
derivatized with (R)-MPA presents small and negative strated that these approaches based on 1H NMR spec-
ΔδT1T2 signs for Ar and βЈ protons, and positive ΔδT1T2 troscopy can be complemented with 13C NMR spectro-
signs for γЈ protons (Figure 4b). If the cyanohydrin pos- scopic data.[12]
sesses the opposite configuration, Ar and βЈ protons show
longer and positive ΔδT1T2 values, whereas the γЈ protons
show negative values (Figure 4b). A cyanohydrin derivat-
ized with (S)-MPA gives rise to opposite signs with regard
to the (R)-MPA derivative.
Especially rigid alkyl aryl cyanohydrins (such as 10 and
11) present a behavior similar to that of dialkyl cyano-
hydrins. Their particular geometry, essentially planar, im-
poses that in those cases some protons belonging to the
cyanohydrin aryl group are hidden from the MPA shielding
effect and may remain unaffected as it is observed in the
(S)-MPA derivatives of 10 and 11 (see Figures S1 and S2),
providing non diagnostic ΔδT1T2 values.
Conclusions
Comparison of the NMR spectra of just one MPA ester
[either (R) or (S)] of a ketone cyanohydrin, taken at dif-
ferent temperatures, allows the assignment of its absolute
Scheme 2. Diagram to deduce the absolute configuration of a chiral
alkyl aryl cyanohydrin from ΔδT1T2 experimental signs of either its
(R)- or its (S)-MPA ester.
Experimental Section
General Esterification Procedure: The MPA esters were prepared by
treatment of the compound (1.00 equiv.) with the corresponding
(R)- or (S)-MPA (1.25 equiv.) in the presence of 1-[3-(dimeth-
ylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC·HCl,
1.25 equiv.) and cat. DMAP (20 mol-%) in dry CH2Cl2 and under
nitrogen. The reaction mixtures were stirred overnight. Next, the
organic layer was sequentially washed with water, HCl (1 m), water,
NaHCO3 (satd.) and water. Then, the organic layer was dried
(anhydr. Na2SO4) and concentrated under reduced pressure to pro-
vide the corresponding esters. If needed, further purification was
achieved by means of flash column chromatography (silica gel 230–
400; elution with hexanes/ethyl acetate, 9:1 to 4:1; ca. 80% yields
after purification). MPA racemization was never observed at any
extent.
NMR Spectroscopy: Low-temperature 1H NMR spectra were re-
Scheme 1. Diagram to deduce the absolute configuration of a chiral
dialkyl cyanohydrin from ΔδT1T2 experimental signs of either its
(R)- or its (S)-MPA ester.
corded with a 500 MHz (500.13 MHz) spectrometer. The solvent
used was a mixture of CD2Cl2/CS2 in a 1:4 ratio. 1H chemical shifts
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I. Louzao, J. M. Seco, E. Quiñoá, R. Riguera
SHORT COMMUNICATION
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Supporting Information (see footnote on the first page of this arti-
cle): ΔδT1T2 values for dialkyl (Figure S1) and alkyl aryl (Figure S3)
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Acknowledgments
We thank the Ministerio de Ciencia e Innovación (CTQ2008-01110/
BQU and CTQ2009-08632/BQU) and the Xunta de Galicia (PGI-
DIT09CSA029209PR) for financial support. I. L. thanks Minis-
terio de Ciencia e Innovación for a predoctoral Formación del Pro-
fesorado Universitario fellowship. We are also grateful to the
Centro de Supercomputación de Galicia for their assistance with
the computational work, to Yamakawa Chemical Industry Co. Ltd.
(Japan) for their gift of (R)- and (S)-MPA and to Bruker Española
S. A. for its contribution as Observant Development Entity (EPO).
[8] L1 and L2 correspond to the substituents placed spatially as
shown in Figure 1 independently of their size. The steric bulk
of these substituents does not determine the main conforma-
tional preferences, that are mainly controlled by the position
of the CN group as shown by the calculations and the NMR
experimental data.
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[10] For the (R)-MPA ester, the magnitudes of the ΔδT1T2 values for
L2 are smaller than for L1. In the case of the (S)-MPA ester,
the values for L1 are smaller than for L2.
[11] In secondary alcohols, the carbonyl group bisects the methyl-
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Received: August 6, 2010
Published Online: October 27, 2010
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