From single molecule to crystal: Mapping out the conformations of tartaric acids and their derivatives

Article abstract of DOI:10.1002/cphc.201200033

Stereoisomers of one of the most important organic compounds, tartaric acid, optically active and meso as well as the ester or amide derivatives, can show diverse structures related to the rotation around the three carbon-carbon bonds. This study determin

Full text of DOI:10.1002/cphc.201200033

DOI: 10.1002/cphc.201200033
From Single Molecule to Crystal: Mapping Out the
Conformations of Tartaric Acids and Their Derivatives
´
´
Agnieszka Janiak, Urszula Rychlewska, Marcin Kwit, Urszula Ste˛pien, Krystyna Gawronska,
[a]
´
and Jacek Gawronski*
Stereoisomers of one of the most important organic com-
pounds, tartaric acid, optically active and meso as well as the
ester or amide derivatives, can show diverse structures related
to the rotation around the three carbon–carbon bonds. This
study determines the controlling factors for conformational
changes of these molecules in vacuo, in solution, and in the
crystalline state using DFT calculations, spectroscopic measure-
ments, and X-ray diffraction. All structural variations can be
logically accounted for by the possibility of formation and
breaking of hydrogen bonds between the hydroxy or amide
donors and oxygen acceptors, among these the hydrogen
bonds that close five-membered rings being the most stable.
These findings are useful in designing molecular and crystal
structures of highly polar, polyfunctional, chiral compounds.
1. Introduction
The fascinating history of optically active tartaric acid, one of
the most important organic compounds existing in nature and
rightfully called a “lab animal” for its chemical history, reflects
numerous discoveries pertaining to the concepts of stereoiso-
merism and chirality by Pasteur and followers[1] and to practical
applications in stereoselective synthetic organic chemistry.[2] Its
optically inactive diastereoisomer, meso-tartaric acid, is not
available from renewable resources, but nevertheless it has
found uses in stereodifferentiating syntheses.[3]
derivatives in polar solutions, using NMR and ECD spectra,
where applicable. These studies are aimed at better under-
standing the structural changes the molecules undergo on
a pathway from the isolated to the highly ordered crystal
state.
The representative structures considered here include the
acids, their esters, and amides 1–10, shown in Scheme 1.
Whereas the structure of natural (R,R)-tartaric acid has been
the subject of several studies in the past, its conformation and
the conformations of its derivatives remained a less known
property. Even less is known about the structure of the meso
stereoisomer, (R,S)-tartaric acid. The past studies included abso-
lute configuration determination of natural tartaric acid by X-
ray diffraction (Bijvoet, 1951),[4]1 and conformational studies
using NMR spectroscopy, electronic circular dichroism (ECD),
and vibrational circular dichroism (VCD), supplemented by ab
initio calculations and X-ray diffraction analysis. Specifically, the
studies involved natural tartaric acid derivatives,[5] dialkyl tar-
trates,[6] tartaronitriles,[7] and a dianion of tartaric acid.[8]
Scheme 1.
In this study we show that the structure of polar molecules
such as tartaric acids and their derivatives is primarily con-
trolled by the possibility to form multiple hydrogen bonds
(HBs) under given conditions. The studies include DFT calcula-
tions for a single molecule, for a simulated continuous model
of water solution (polarizable continuum model (PCM)), and X-
ray determination of crystal structures of derivatives of meso-
tartaric acid. The structure calculations were confronted with
the results of conformational studies of tartaric acids and their
2. Results and Discussion
Tartaric acids and derivatives can (and in fact do) display nu-
merous structures, due to configurational isomerism and con-
´
[a] Dr. A. Janiak, Prof. Dr. U. Rychlewska, Dr. M. Kwit, U. Ste˛pien,
´
´
Dr. K. Gawronska, Prof. Dr. J. Gawronski
Department of Chemistry
A. Mickiewicz University
1
Grunwaldzka 6, 60 780 Poznan (Poland)
Fax: (+48)61-8291505
E-mail: gawronsk@amu.edu.pl
It is pertinent to note that the year 2011 was marked as the 110th anniversa-
ry of the Nobel Prize in Physics, awarded to Wilhelm Rçntgen, the discoverer
of X-rays, and as the 110th anniversary of the first Nobel Prize in Chemistry,
awarded to Jacobus H. van’t Hoff, the discoverer of the laws of chemical dy-
namics and a pioneer in the field of stereochemistry.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cphc.201200033.
1500
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ChemPhysChem 2012, 13, 1500 – 1506

From Single Molecule to Crystal: Conformations of Tartaric Acids
Figure 2. Conformational profile of (R,R)-tartaric acid derivatives. All con-
formers are chiral and have their mirror image counterparts in (S,S)-tartaric
acid derivatives.
Figure 1. Conformational profile of (R,S)-tartaric acid derivatives. Conformers
Ta,a and Ts,s are centrosymmetric and therefore achiral. Ta,s and its mirror
image form a racemate. Conformers G+a,a/Gꢀa,a, G+a,s/Gꢀa,s, and G+s,s/
Gꢀs,s are enantiomers.
and percentage populations in vacuo are listed in Table 1). Ad-
ditionally single-point energy calculations were performed at
the B2PLYP(D)/Aug-cc-pVTZ level[14,15] (see Tables 1S and 2S in
formational flexibility of the carbon chain. These are shown in
Figure 1 and Figure 2.
Distinct conformers of 1–10
Table 1. Conformer types of 1–10, stabilizing interactions (Figure 4), relative energies [kcalmolꢀ1],[a] and per-
centage populations in vacuo calculated at the M06-2X/Aug-cc-pVTZ level and found in the solid state by X-
ray diffraction.
can be defined by torsion angles
a, b, and b’, defined in
Scheme 1. Figure 1 and Figure 2
represent generalized structures
of molecules with either trans (T)
or gauche (G) carbon chain and
either syn (s) or anti (a) arrange-
ment of vicinal C=O and CꢀO
bonds. In the R,S series conform-
ers Ta,a and Ts,s are of Ci symme-
try and therefore achiral whereas
G conformers are chiral (C1). Also
chiral are all conformers in the
R,R (or S,S) series and C2 symme-
try is ascribed to Ta,a, Ts,s, Ga,a,
and Gs,s structures.
Compound Conformer Stabilizing in- DEvac Pop.
DGvac Pop. Conformer
Intramolecular stabi-
lizing interactions
type
teractions[b]
in crystals
1
Ta,a
Ts,s
2(A+C)
2(B+E)
2B
2B
B+G
2(A+D)
2(B+F)
2(A+D)
2(B+F)
2A
0.00 77
0.72 23
0.00
0.92
0.92
0.00
0.42
0.00
1.62
0.00
0.94
1.23
1.23
0.00
1.27
0.00
–
61
13
26
68
32
94
6
83
17
5
Gs,s[c]
Gs,s[d]
Ga,s[d]
Gs,s[e]
K
not specified
not specified
B[f]
Gs,s
Gs,s
Ga,s
Ta,a
Ts,s
Ta,a
Ts,s
Ta,a
Ts,s
Ga,p[g]
G+a,a
Ts,s
G+s,s
G+a,s
Ta,s
–
–
2
3
4
5
0.00 70
0.50 30
0.00 90
1.33 10
0.00 96
Ga,a
Ga,a
Ts,s
2D, J
2D, J
1.88
4
0.00 64
0.57 25
2B,[f] 2J
2B
5
A+G
2(A+C)
2B
1.67
8
90
10
74
–
–
16
6
0.00 64
0.53 26
Ts,s[h]
G,[f] 2K
Calculations for single mole-
cules 1–10 were performed as
described in the Experimental
Section, first by generating
a number of low-energy con-
formers with the use of molecu-
lar mechanics (MM3 force field)
and CAChe WS Pro 5.0 soft-
ware.[11] All the conformers
found at the molecular mechan-
ics level were pre-optimized
with the use of the most popular
B3LYP/6-31G(d) method[12] and
then finally optimized at the
2(B+E)
A, A+C
B+G and/or
1.38
1.60
–
6
4
–
–
1.02
C,[g]
2B
J
7
8
Ts,s
Ta,s
0.00 93
1.53
0.00 88
0.00
1.57
0.00
1.01
1.23
93
7
77
14
9
88
7
5
Ta,s[i]
Ta,a[i]
G, J, K
B, H, J
2(A+D)
B+G+D, I
2(B+F)
2(A+D)
2(B+F)
2D, G, 2J
2B
7
G+a,a
Gꢀa,s
G+s,s
G+a,a
Gꢀa,s
G+s,s
G+s,s
G+a,a
2D, G, 2J
1.50
1.69
0.00
–
7
5
9
ꢁ100 0.00
Ta,a[i]
2D, 2J
–
1.51
1.76
0.00
0.38
–
–
10
0.00 87
1.10 13
66
34
Gꢀp,p[i,j]
not specified
2A
[a] Conformers with relative energies above 2 kcalmolꢀ1 are not shown. [b] Interactions due to H···O distances
longer than 2.55 ꢁ are not listed. [c] Data from ref. [9]. [d] Hydrated forms. [e] Data from ref. [16]. [f] Compo-
nent of a three-center HB. [g] Sum of conformers with C and/or G hydrogen-bond pattern. [h] Data from
ref. [10]. [i] Data from ref. [5]. [j] In this conformer the angle a (and a’) is close to 908.
M06-2X/Aug-cc-pVTZ
level[13]
(relative energies (DE and DG)
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J. Gawronski et al.
the Supporting Information; specific values of torsion angles
for calculated individual conformers of 1–10 are given in Ta-
bles 3S and 4S, Supporting Information). The results turned out
qualitatively similar in terms of conformer populations (see dis-
cussion below). Representative calculated types of conformers
are shown in Figure 3 (see also the Supporting Information for
a color version of Figure 3), while all low-energy conformers
found by calculations are depicted in Figures 1S and 2S (Sup-
porting Information). In addition, Table 1 includes structural
characteristics of the conformers present in crystals, either de-
termined for the present work (3–5) or taken from the litera-
ture for comparison (1, 2, 6–10). Selected torsion angles de-
scribing the molecular conformations found in crystals are
listed in Table 2. We have also performed calculations of con-
former populations in a medium simulating water. Due to in-
trinsic limitations of the PCM for water solution, the results are
used only for confrontation with the experimental data (ECD,
NMR) in water solution and are listed in Tables 1S and 2S (Sup-
porting Information).
Our attempt to understand the logic of the conformational
changes of tartaric acid derivatives due to the change of con-
figuration and interaction with the medium starts with the
analysis of results of structure calculations for individual con-
formers of single molecules. The results show that all low-
energy conformers are stabilized by multiple HBs and 1,3-CH/
CO dipole–dipole interactions; the possible types of these are
shown in Figure 4.
In all structures 1–10 the hydroxy–carbonyl (A, B) and car-
boxy or amide–hydroxy (C–F) HBs are encountered (B type the
most), often in cooperative pairs (A+C, A+D, A+G; B+E,
B+F, B+G; D+G). In Ci - and C2-symmetrical structures these
pairs are doubled, which makes such structures particularly
stable in the isolated molecules. Calculated H donor–oxygen
acceptor distances vary within each type of HB (A 1.81–2.08, B
1.88–2.19, C 1.85–2.06, D 2.07–2.23 ꢁ). In the overwhelming
majority of the HB-forming six-membered rings A and E, the
donor–acceptor distances are the shortest, below 2.0 ꢁ. Short
HBs (below 1.9 ꢁ) are also observed in seven-membered-ring
type I in tartramides 8 and 9. Intramolecular hydroxy–hydroxy
(G) and hydroxy–alkoxy (H) bonds are apparently weaker. In
the case of G the donor–acceptor distance is within 2.3–2.5 ꢁ,
except in tartramides 8 and 9 (1.92–1.94 ꢁ) where it is a part
of a cooperative three-HB system. Except for G, all other types
of intramolecular HBs directly
Figure 3. Calculated (left column) and X-ray diffraction determined (right
column) structures of (R,S)-tartaric acid and its derivatives, with intramolecu-
lar HBs shown as broken lines and with arrows illustrating the antiparallel ar-
rangement of local dipoles situated in 1,3-positions. HBs due to H···O distan-
ces longer than 2.55 ꢁ are not shown. Labels mark the symmetry-independ-
ent part of molecules in crystals, the remaining part being generated by the
symmetry transformation 1ꢀx, 2ꢀy, 1ꢀz. Data for X-ray determined struc-
tures of 1[9] and 2[10] are taken from the literature.
affect the syn, anti conformation
Table 2. Selected torsion angles [8] describing the molecular conformation in crystals of meso-tartaric acid, its
ester and amides.[a]
of the molecules; anti is obvi-
ously associated with A, C, D,
and H, while B, E, F, and I are as-
sociated with the syn conforma-
tion of the vicinal C=O and CꢀO
bonds. The presence of a G-type
HB is associated with the prefer-
ence for a gauche conformer in
the R,S series and a trans confor-
mer in the R,R series.
Compound
Torsion angle
C1-C2-C3(C2)-C4(C1)
ꢀ75.0(8)
O2-C2-C3(C2)-O3(O2)
ꢀ71.1(8)
O1=C1-C2-O2
ꢀ8.8(8)
O4=C4-C3-O3
11.7(8)
1[b]
[b]
1ꢀH2O(triclinic)
1ꢀH2O(monoclinic)
2[c]
3
4
5
ꢀ73.4(5)
ꢀ71.3(5)
ꢀ5.7(5)
ꢀ4.2(5)
[b]
ꢀ75.4(5)
ꢀ73.4(5)
173.3(5)
0.2(5)
ꢀ175.2(1)
ꢀ173.4(1)
37.3(2)
ꢀ7.0(5)
ꢀ75.7(4)
ꢀ75.3(6)
4.5(5)
ꢀ81.6(1)
ꢀ82.6(1)
ꢀ173.2(1)
166.0(1)
37.3(2)
ꢀ73.6(1)
ꢀ71.9(1)
180
180
[a] Derivatives crystallizing in the gauche conformation are presented consistently as Gꢀ enantiomers, with liter-
ature data adapted accordingly. [b] Data from ref. [9]. [c] Data from ref. [10].
Intuitively one would expect
a planar carbon chain conforma-
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ChemPhysChem 2012, 13, 1500 – 1506

From Single Molecule to Crystal: Conformations of Tartaric Acids
lated (70%). The distribution of conformers is not much differ-
ent in water medium and the presence of gauche conformers
3
is confirmed by a low JH,H coupling constant (2.7 Hz) in D2O
solution. Furthermore, the Gs,s conformation is preserved in
the crystal structure[10] where only one of the two possible in-
tramolecular HBs of the B type is preserved but in a diminish-
ing form, that is, as a minor component of the three-center
bond with other components being intermolecular. The re-
markable stability of the conformation of diester 2 is apparent-
ly due to a lack of HBs that can be broken by intermolecular
interactions.
Figure 4. Possible stabilizing intramolecular interactions in tartaric acids and
their derivatives. Dashed lines indicate HBs while arrows in J and K mark an-
tiparallel local dipoles.
Diastereomer 7, as expected, is exclusively in a trans confor-
mation, with the Ts,s conformer stabilized by two B-type HBs
having the lowest energy as a single molecule (93%). This type
of conformational preference in solution is supported by mea-
tion for a molecule with two adjacent chiral centers of oppo-
site configuration, that is, in meso-tartaric acid. Indeed, calcula-
tions carried out for 1 show a strong preference for Ta,a and
Ts,s conformers of isolated molecules. These conformers are
highly populated (jointly up to 100%, Table 1) due to the stabi-
lizing action of cooperative intramolecular HBs involving the
carboxy and hydroxy groups (2(A+C) in Ta,a or 2(B+E) in Ts,s).
Gauche conformers of meso-tartaric acid may contribute more
significantly to the equilibrium in a medium of higher polarity
such as water. This is apparently due to limited possibilities to
form intramolecular HBs in a bent carbon atom skeleton of 1:
in gauche conformers the carboxylic groups are not involved
in intramolecular hydrogen bonding, according to calculations.
3
sured low values of the JH,H coupling constant of 7 in polar
solvents. Further support for the syn conformation in the most
abundant Ts,s conformer comes from ECD measurements in
water solution,[5] and recently this conformer was determined
as the lowest-energy component of the equilibrium in nonpo-
lar solvent by VCD measurements.[6] It was found that polar
solvent (DMSO) favors formation of intermolecular hydrogen-
bonded clusters between 7 and DMSO.[6] In the crystal the pre-
ferred structure of 7 is Ta,s.[5] The B-type intramolecular HBs no
longer stabilize the extended conformation but instead, the G-
type HB appears as a minor component of a three-center
bond, the other component being intermolecular.
3
Experimentally this is supported by the fact that the JH,H cou-
Primary and secondary diamides 3 and 4 behave similarly in
computational structural studies. The planar amide structure
combined with strong acceptor properties of the amide C=O
group (due to polarization of the amide group) and HB donor
properties of the amine hydrogen atom(s) make the number
of available structures for these molecules very limited. In fact,
the preferred conformers of diamides are similar to those of
diacid 1, that is, Ta,a and Ts,s, where there are cooperative in-
tramolecular HBs involving the C=O, OH, and NH groups
2(A+D) in Ta,a (over 84% in equilibrium) or 2(B+E) in Ts,s. On
the other hand, the preferred gauche conformation of di-
amides 3 and 4 in polar solutions (DMSO and D2O) receives
strong experimental support from the low measured values of
3JH,H coupling constants (3.2 and 2.6 Hz for 3, 3.3 Hz for 4). It
should be noted that the calculations of conformer population
in simulated (PCM) water solution for highly polar diamide
molecules do not accurately represent the actual conformer
population in water solutions, as these calculations neglect in-
termolecular interactions with explicit water molecules. Low-
energy gauche conformers of NH diamides in water solutions
do not possess the two cooperative HBs present in trans con-
formers. For example, the Ga,s conformer is stabilized by one
cooperative D+G+B HB system and one unusual, I-type,
seven-membered HB ring, joining the NH donor of one amide
group with the C=O acceptor of the other amide group. Other
gauche conformers would leave NH donors and/or C=O ac-
ceptors available for intermolecular hydrogen bonding, for ex-
ample with the solvent molecules. The structure of diamides 3
and 4 in the crystal is therefore Ga,a since in this conformer
the only intramolecular HBs utilized are two of D type
1
pling constant in the H NMR spectrum of 1 measured in D2O
solution is low, typical for the gauche conformer. In the crystal
structure of 1[9] the Gs,s conformer is indeed present, in which
the carboxylic groups are solely involved in intermolecular
HBs, either with themselves or with water molecules as media-
tors.
In the case of diastereomeric natural tartaric acid (6) the pre-
ferred conformation of the isolated molecule is G+a,a (in DE),
just opposite to that of 1. This conformer is stabilized by coop-
erative HBs 2(A+C) and similarly other bent conformers G+s,s,
2(B+E), and G+a,s (A, A+C) are stabilized. Trans conformers
are less populated: the Ts,s population is one third that of
gauche conformers, since trans conformers are not stabilized
by cooperative HBs. However, in polar environments the pro-
portion of trans conformers increases and the presence of
3
trans conformers is again supported by a low JH,H coupling
1
constant (2.4 Hz) of 6 in the H NMR spectrum in D2O solution.
In the crystal structure of 6 the Ts,s conformer is present.[16] In
this structure the intramolecular HB of the G type (Figure 4)
appears as a minor component of a three-center bond (the
other component being intermolecular) and the intramolecular
bond of the B type is replaced by the so-called mediated
HB.[17]
The number of HB donors is significantly reduced in the di-
ester derivative 2, and therefore cooperative HBs stabilizing
trans conformers are not available. According to calculations,
gauche conformers constituting the minority in the case of
diacid 1 are dominant in the case of diester 2. Among these,
conformer Gs,s stabilized by two B-type HBs is the most popu-
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J. Gawronski et al.
(Figure 3), which allows the various types of intermolecular
HBs to be formed (intermolecular interactions will be discussed
in a separate paper).
3JH,H coupling constant of 2.9 Hz measured for 10 in CDCl3 solu-
tion is in agreement with the dominant presence of the
(+)-gauche conformers. However, in polar solvents (water,
3
The tartramides of natural configuration 8 and 9 do not
differ in their conformational profile; however, their calculated
low-energy conformers are different from those of diastereo-
meric diamides 3 and 4. The lowest-energy conformers of 8
and 9 are (+)-gauche, G+a,a dominating (over 88%). This con-
former was found to be the most stable by previous calcula-
tions at the HF/6-31G level.[5] In gauche conformers the stabiliz-
ing factors are the same as in the case of low-energy conform-
ers of 3 and 4, that is, two A+D-type HBs in G+a,a conformers
and two B+E-type HBs in G+s,s conformers. A small contribu-
tion of another conformer, Gꢀa,s, stabilized by one cooperative
D+G+B and one I-type HB system, is calculated for isolated
molecule 8. Whereas calculations for simulated water solution
yield a conformer distribution similar to that for the isolated
molecule, the experimental evidence gathered earlier (1H NMR,
ECD)[5] strongly supports a Ta,a conformer of 8 or 9 as a domi-
nant one in water solutions. In this conformer available intra-
molecular HBs are of D type, thus leaving other oxygen donors
and acceptors accessible for intermolecular hydrogen bonding.
Consequently, in the crystal the conformation of diamides 8
and 9 is Ta,a.[5]
methanol) a much larger value (7.6 Hz) of the JH,H coupling
constant indicates that the preferred conformation is the one
with vicinal hydrogen atoms anti, that is, Gꢀ.[5] This has been
confirmed by calculations with the use of the AMSOL
method.[18] Interestingly, in the crystal diamide 10 assumes
a rather unusual Gꢀp,p conformation in which the two vicinal
O=C/CꢀO bonds are perpendicular and no intramolecular HB is
present.[19] Therefore it is justified to say that N,N’-tetraalkylat-
ed tartramides prefer a (+)-gauche conformation in nonpolar
medium, stabilized by two intramolecular HBs, whereas in
polar medium and in the crystal their conformation changes to
(ꢀ)-gauche, which cannot be stabilized by strong intramolecu-
lar HBs but favors formation of very strong intermolecular
HBs.[19]
Moreover, in all types of conformers present in crystals,
there appears at least one pair of antiparallel CH and CO di-
poles situated in the 1,3-positions.[20] The presence of such di-
poles brings about an additional stabilizing effect, J and K, al-
though apparently less significant than hydrogen bonding. In
molecules possessing the trans conformation the effect is dou-
bled (Figure 3).
Tetraalkylated diamide 5 represents a special case. N,N-Di-
alkylation not only removes a strong NH donor but also it may
introduce steric crowding, absent in other tartaric acid deriva-
tives. As in the case of tartrate 2, no cooperative intramolecu-
lar HBs are possible in 5. Low-energy conformers of 5 are trans
(over 80%) and are stabilized by two HBs, either type A (Ta,a)
or B (Ts,s), the former prevailing for the isolated molecule. De-
spite its tertiary nature, the amide bond remains nearly planar
in these two conformers and no steric crowding is apparent.
1H NMR data indicate that in solution the trans conformation
In general, the available data and the discussion above indi-
cate reshuffling of the conformer population on going from
molecules in vacuo to polar solution and to crystal, but only in
the case of polar diacids 1 (T!G) and 6 (G+!T) and NH-di-
amides 3, 4 (T!G), 8, and 9 (G+!T). The conformations of
less polar derivatives, diesters and tetraalkyldiamides are less
dramatically affected by the molecular environment and
remain G for 2, T for 5, and 7 and G+/Gꢀ for 10. Note that in
all cases the diastereoisomeric tartaric acid derivatives assume
the opposite preferred conformation, G or T.
3
of 5 is preferred, which results in a higher value of the JH,H
coupling constant (7.3 Hz in CDCl3, 8.2 Hz in D2O). Significantly,
the Ts,s conformer is just the one found in the crystal. It is sta-
bilized by a pair of intramolecular HBs of the B type and again
this intramolecular linkage is a part of the three-center HB with
the other component intermolecular. Unlike in the previous
cases, in this instance the intramolecular HB is quite strong
and weakens the intermolecular component which conse-
quently displays the longest donor–acceptor distances in the
studied series.
3. Conclusions
Despite a large number of variables that should be considered,
the conformation of tartaric acids and their derivatives under
various external conditions (molecules in vacuo, in water, and
in the crystal) could be readily determined with the use of mo-
lecular modeling, NMR and ECD spectra, and X-ray diffraction
analysis. The results obtained are complementary and consis-
tent for both the R,S and the natural R,R series; the data for
the latter series[5] were used for comparison. Therefore, for the
first time we are in a position to correlate conformational
changes caused by a change of relative configuration R,S/R,R,
molecule substitution, and molecule environment (in vacuo/in
the crystal). The results are summarized in Figure 5.
A contribution from a higher-energy conformer of 5, Ga,p,
has been found by calculation. This conformer is of nontypical
structure since one of the carbonyl groups and the vicinal CꢀO
bond form a torsion angle close to 908 (p). Such a structural
feature becomes dominant in the case of diastereomeric mole-
cule 10 in the solid state. Here a trans conformation introduces
significant crowding of the substituents, whereas steric crowd-
ing due to dialkylamino substituents is absent in the case of
conformers (+)-gauche, according to calculations. As in the
case of 5, only two B-type (conformer G+s,s) or A-type (confor-
mer G+a,a) intramolecular HBs stabilize the low-energy con-
formers of 10. Conformers (+)-gauche are the lowest-energy
structures calculated for molecules in vacuo. The experimental
The results of Figure 5 and Table 1 can be interpreted in
terms of available number and relative stability of intramolecu-
lar HBs. Molecules of lower polarity (diesters 2, 7 or tetraalkyl-
diamides 5, 10) do not change the preferred conformation
(trans or gauche) on going from a single molecule to the crys-
tal. The opposite holds for polar diacids 1 and 6 and diamides
3, 4, 8, and 9. This is because intermolecular interactions (polar
environment, crystal formation) weaken HBs of type A, C, and
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ChemPhysChem 2012, 13, 1500 – 1506

From Single Molecule to Crystal: Conformations of Tartaric Acids
tector at 290.0(1) K. Data reduction and analysis for these struc-
tures were carried out with CrysAlisPro program v.171.33.34d.[21]
Multiscan correction for absorption was also applied.[22] All struc-
tures were solved by direct methods using SHELXS97,[23] and re-
fined by the full-matrix least-squares technique with SHELXL97.[23]
All heavy atoms were refined anisotropically. H atoms attached to
N and O atoms were located reliably on difference Fourier maps
and their positions and isotropic displacement parameters were re-
fined. The methyl H atoms were first found in difference Fourier
maps and then were allowed to rotate freely during refinement
using the AFIX 137 command with CꢀH=0.96 ꢁ and Uiso
=
1.5 Ueq(C). The methine H atoms were placed in their idealized po-
sitions and were refined as riding on their parent atoms, with CꢀH
distances of 0.98 ꢁ and their Uiso values of 1.2 Ueq(C). In 3 all
H atoms were located in a difference Fourier map and their posi-
tions and displacement parameters were refined freely. The rota-
tional disorder in methyl groups of 4 and 5 was modeled as two
equivalent 0.50 occupancies of H atoms.
Figure 5. Summary of the hydrogen-bonding effect on conformational pref-
erences of tartaric acid derivatives in media of increasing ability to form in-
termolecular HBs. [a] In the crystal.
Crystallographic data for 3–5 are presented in Table 7S (Supporting
Information). Newman projections illustrating molecular conforma-
tions present in crystals of 1–5 are shown in Figure 3S (Supporting
Information). CCDC-862696 (3), 862697 (4), and 862698 (5) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
E–H whereas the stronger HBs of type B and D are retained.
Also retained is the antiparallel arrangement of at least one
pair of local CH and CO dipoles (J or K), which imposes addi-
tional constraints on the spatial orientation of the two interact-
ing bonds and therefore has an effect on the molecular confor-
mation. In this way the molecular conformation is accordingly
changed, although in crystals additional factors such as steric
crowding may affect the conformation and make the less typi-
cal one (e.g. Gꢀp,p in the crystal structure of 10[19]) better
suited for the crystal packing.
Computational Methods:
A preliminary conformer distribution
search was performed by CONFLEX software (a part of the CAChe
WS Pro package[11]) using the MM3 molecular mechanics force
field. The systematic search of all possible conformers was per-
formed using a molecular mechanics method taking into account
all degrees of freedom of the molecule. The real minimum-energy
conformers found by molecular mechanics were further fully opti-
mized at the DFT/B3LYP/6-31G(d) level as implemented in the
Gaussian 09 package.[24] This reduced significantly the number of
conformers. Then all stable conformers, regardless of their relative
energies, were reoptimized at the M06-2X/Aug-cc-pVTZ level[13] in
vacuo and with the use of the PCM solvent model simulating
water solution.[25] Conformers obtained at this stage were the real
minima (no imaginary frequencies were found). To verify the results
obtained with the use of the M06-2X functional, we performed
single-point energy calculations with a new functional recently
proposed by Grimme,[14] dubbed B2PLYP, which belongs to a gener-
al class of double-hybrid density functionals (DHDFs). Several stud-
ies have shown that DHDFs give very accurate results for large
molecules, with energetic and thermodynamic data and molecular
structures comparable to those obtained with the use of
CCSD(T).[15] The calculations with the use of the B2PLYP(D) func-
tional and Aug-cc-pVTZ basis set were performed for all structures
optimized in the gas phase and with the use of the PCM solvent
model.
Tartaric acid and its derivatives are widely used not only for
synthetic purposes but also for pharmaceutical formulations.
The results presented here can be useful in designing molecu-
lar and crystal structures not only of tartaric acid derivatives
but also of other similar polyfunctional compounds.
Experimental Section
Synthesis: (R,S)-Tartaric acid diamides 3–5 were obtained from di-
ester 2 by aminolysis with ammonia, methylamine, or dimethyl-
amine in methanol solution at 58C for 1 week, according to a pro-
cedure described for aminolysis of diester 7.[5] Crude products
were purified by crystallization.
meso-Tartramide (3): M.p. 181–1848C (methanol/water); 1H NMR
([D6]DMSO): d=4.05 (d, J=5.5 Hz, 2H), 5.59 (d, J=5.5 Hz, 2H), 6.97
(s, 2H), 7.10 ppm (s, 2H); 13C NMR ([D6]DMSO): d=72.7, 173.0 ppm;
ESI(ꢀ) MS: m/z 147 (MꢀH); ESI(+) MS: m/z 171 (M+Na).
meso-N,N’-Dimethyltartramide (4): M.p. 181–1848C (ethanol);
1H NMR ([D6]DMSO): d=2.57 (d, J=4.8 Hz, 6H), 4.10 (s, 2H), 5.75 (s,
2H), 7.53 ppm (q, J=4.8 Hz, 2H); 13C NMR ([D6]DMSO): d=25.3,
73.9, 171.3 ppm; ESI(ꢀ) MS: m/z 175 (MꢀH), ESI(+) MS m/z 199
(M+Na).
The total energy values calculated at both M06-2X/Aug-cc-pVTZ
and B2PLYP(D)/Aug-cc-pVTZ levels were used to obtain the Boltz-
mann population of conformers at 298.15 K. Only the results for
conformers that differ from the most stable one by less than 2 kcal
molꢀ1 were taken into account for further calculations, following
a generally accepted protocol.[26] Since the values of relative DE en-
ergies and populations of the respective conformers obtained with
the use of the B2PLYP(D)/Aug-cc-pVTZ method were not much dif-
ferent from those obtained with the use of the M06-2X/Aug-cc-
pVTZ method, only the latter DE-based data were taken into con-
sideration and discussed here.
meso-N,N,N’,N’-Tetramethyltartramide (5): M.p. 189–1908C (chloro-
form/hexane); 1H NMR (CDCl3): d=3.04 (s, 6H), 3.14 (s, 6H),
4.50 ppm (s, 2H); 13C NMR (CDCl3): d=36.7, 70.4, 172.3 ppm; ESI(+)
MS: m/z 227 (M+Na).
X-ray Crystallography: Reflection intensities for crystals of 3, 4, and
5 were measured on a SuperNova diffractometer equipped with
a Cu microfocus source (l=1.54178 ꢁ) and 135 mm Atlas CCD de-
ChemPhysChem 2012, 13, 1500 – 1506
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www.chemphyschem.org
1505

´
J. Gawronski et al.
[18] a) A. Szarecka, J. Rychlewski, U. Rychlewska in Quantum Systems in
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McWeeny, S. Wilson), Kluwer Academic Publishers, Dordrecht, 2000,
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tional Methods in Science and Technology, Vol. 2 (Eds.: J. Rychlewski, J.
Acknowledgements
A.J. thanks the Foundation for Polish Science for a FOCUS fellow-
´
ship. All calculations were performed at the Poznan Supercom-
´
We˛glarz, K. W. Wojciechowski), Scientific Publishers OWN, Poznan, 1996,
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Keywords: density functional calculations · hydrogen bonds ·
structure elucidation · tartaric acid · X-ray crystallography
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Published online on March 13, 2012
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ChemPhysChem 2012, 13, 1500 – 1506