Interactions of hydroxy compounds and sugars with anions

Article abstract of DOI:10.1021/jo951435l

Complexations of aliphatic monohydroxy compounds, of trans-1,2 cyclohexanediol, and of several glucose and galactose derivatives with two to four free hydroxy groups are measured in chloroform with peralkylammonium salts containing different anions. It is shown that NMR titrations with up to four different OH signals as well as with some CH signals allow accurate and consistent calculation of equilibrium constants K and complexation induced shifts (CIS). The anions used generally show an increasing affinity in the order iodide < benzenesulfonate < bromide < diphenyl phosphate < chloride < benzenecarboxylate (benzoate). The K values increase from secondary to primary alcohols, and again substantially to vicinal diols, culminating at up to K = 10³ M^-1 for 1-dodecyl glucose or galactose compounds. The observed CIS and K values agree with the formation of 3 different 1:1 complexes of similar stability for the phosphate receptor, with binding one anion between the 2-, 3-, 4-, and 6-OH groups of the glucoside, or only one 1:1 complex in the interaction of halides with sugars. Vicinal ³J_HOCH coupling constants are analyzed before and after complexation and provide insight into the hydrogen bond network of the sugar derivatives.

Full text of DOI:10.1021/jo951435l

J . Org. Chem. 1996, 61, 1429-1435
1429
In ter a ction s of Hyd r oxy Com p ou n d s a n d Su ga r s w ith An ion s1
J ose Miguel Cotero´n, Frank Hacket, and Hans-J o¨rg Schneider*
FR Organische Chemie, Universita¨t des Saarlandes, D 66041 Saarbru¨cken, Germany
Received August 3, 1995X
Complexations of aliphatic monohydroxy compounds, of trans-1,2 cyclohexanediol, and of several
glucose and galactose derivatives with two to four free hydroxy groups are measured in chloroform
with peralkylammonium salts containing different anions. It is shown that NMR titrations with
up to four different OH signals as well as with some CH signals allow accurate and consistent
calculation of equilibrium constants K and complexation induced shifts (CIS). The anions used
generally show an increasing affinity in the order iodide < benzenesulfonate < bromide < diphenyl
phosphate < chloride < benzenecarboxylate (benzoate). The K values increase from secondary to
primary alcohols, and again substantially to vicinal diols, culminating at up to K ) 103 M-1 for
1-dodecyl glucose or galactose compounds. The observed CIS and K values agree with the formation
of 3 different 1:1 complexes of similar stability for the phosphate receptor, with binding one anion
between the 2-, 3-, 4-, and 6-OH groups of the glucoside, or only one 1:1 complex in the interaction
of halides with sugars. Vicinal 3J HOCH coupling constants are analyzed before and after complexation
and provide insight into the hydrogen bond network of the sugar derivatives.
In tr od u ction
structures strong acceptors and donors in the form of
acidic and basic amino acids, respectively.2a Synthetic
hosts containing phosphonates as anionic acceptors were
recently described by Hamilton et al.12 while our work
was still in progress. We wanted to explore systemati-
cally different anionic functions for the complexation of
aliphatic hydroxy compounds including carbohydrates.
The anions studied comprise carboxylates as the entities
used by nature, as well as phosphates, sulfonates, and
halides, the latter being of interest mostly as they can
interfere with other hydrogen bond acceptor sites also
in biological matrices. As will be shown, the binding
capacities of these anions differ substantially in spite of
their equal charges. Surprisingly, there are almost no
numbers characterizing the acceptor qualities of the
anions even in the vast tabulations of acceptor and donor
molecules published by Raevksy or by Abraham et al.3
Another aim of the present study was therefore to provide
such data, particularly in combination with hydroxy
groups as hydrogen bond donors.
The selective binding of carbohydrates by noncovalent
interactions is of enormous biological importance.2 At
the same time, it is a topic which only recently has begun
to be explored by synthetic supramolecular chemistry.
This is due to the rather weak intermolecular forces,
characterized by small hydrogen bonding donor and
acceptor numbers for hydroxyl groups, which are placed
at the lower ends of corresponding acidity and basicity
scale.3 Aoyama et al.4a have shown, using phenolic
macrocycles, predominant interactions with hydroxy
groups in 1,4-position of pyranoses. Very recently, Bo-
nar-Law and Sanders5 have described a particularly
effective steroid-capped porphyrin receptor for sugars.
Aoyama et al.4b have presented evidence that lipophilic
interactions of sugar C-H bonds with aromatic receptor
moieties can provide weak additional stabilizations.
Other receptors for sugars have been reported by Davis,6
Gellman,7 Still,8 Anslyn9 et al. and, using reverse mi-
celles, Greenspoon et al.10 Recently, weak complexes of
some sugars with cyclodextrins have also been described11
even with water as competing solvent.
The major problem associated with the weak hydrogen
bonds is the need to maintain usually an aprotic environ-
ment, which is materialized inside globular proteins.2a
This is the reason why in the present work, as in other
studies,5,6,8,9,12 lipophilic solvents such as chloroform are
used. Aoyama et al.4c have recently shown that, even
using strongly anionic macrocyclic hosts, only weak
complexes with carbohydrates are formed in water. Our
strategy was based on the use of tetraalkylammonium
ions as counterions in order to allow solubility of the salts
in lipophilic solvents. The alkyl chains were planned to
be long and/or bulky so that the anionic charges could
be exposed to the OH-groups of the substrates or not. The
question to which degree the alkyl chains would shield
the anion from contact with the OH groups, and whether
formation of the extremely tight ion pairs in such media
would interfere too much, was investigated by using also
hexadecyltrimethylammonium (CTA) besides tetradecy-
lammonium (TDA) derivatives (Chart 1).
Nature has overcome the problem of inherently weak
hydrogen bonds mostly by providing in suitable protein
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Supramolecular Chemistry, Part 55; Part 54: Sartorius, J .;
Schneider, H.-J . FEBS Lett. 1995, 374, 387-392.
(2) (a) Lemieux, R. U. Chem. Soc. Rev. 1989, 18, 347-374. (b)
Kobata, A. Acc. Chem. Res. 1993, 26, 319-324.
(3) (a) Raevsky, O. A.; Grigor’ev, V. Y.; Kireev, D. B.; Zefirov, N. S.
Quant. Struct.-Act. Relat. 1992, 11, 49-63. (b) Abraham, M. H. Chem.
Soc. Rev. 1993, 22, 73-83.
(4) (a) Aoyama, Y.; Tanaka, Y.; Sugahara, S. J . Am. Chem. Soc.
1989, 111, 5397-5404. (b) Kobayashi, K.; Asakawa, Y.; Aoyama, Y.;
Supramol. Chem. 1993, 2, 133-135. (c) Yanagihara, R.; Aoyama, Y.
Tetrahedron Lett. 1994, 35, 9725-9728.
(5) Bonar-Law, R. P.; Sanders, J . K. M. J . Am. Chem. Soc. 1995,
117, 259-271.
(6) Bhattarai, K. M.; Bonar-Law, R. P.; Davis, A. P.; Murray, B. A.
J . Chem. Soc., Chem. Commun. 1992, 752-754.
(7) (a) Savage, P. B.; Gellman, S. H. J . Am. Chem. Soc. 1993, 115,
10448-10449. (b) Savage, P. B.; Holmgren, S. K.; Desper, J . M.;
Gellman, S. H. Pure Appl. Chem. 1993, 65, 461-466.
(8) Liu, R.; Still, W. C. Tetrahedron Lett. 1993, 34, 2573-2576.
(9) Huang, C. Y.; Cabell, L. A.; Lynch, V.; Anslyn, E. V. J . Am. Chem.
Soc. 1994, 116, 2778-2792.
(11) (a) Aoyama, Y.; Nagai, Y.; Otsuki, J .; Kobayashi, K.; Toi, H.
Angew. Chem. 1992, 104, 785-786. (b) Eliseev, A. V.; Schneider, H.-
J . J . Am. Chem. Soc. 1994, 116, 6081-6088.
(12) Das, G.; Hamilton, A. D. J . Am. Chem. Soc. 1994, 116, 11139-
11140.
(10) Greenspoon, N.; Wachtel, E. J . Am. Chem. Soc. 1991, 113,
7233-7236.
0022-3263/96/1961-1429$12.00/0 © 1996 American Chemical Society

1430 J . Org. Chem., Vol. 61, No. 4, 1996
Cotero´n et al.
Ch a r t 1. Accep tor s a n d Alcoh ols Used in Th is
Wor k . TDA ) Tetr a d ecyl a m m on iu m . CTA )
Cetyltr im eth yla m m on iu m
substrates was considered to be negligible in view of
experimental dilution shifts of the OH signal; with >0.02
ppm these were much smaller than the CIS values with
the other acceptors (see below and Tables 1-5).
Assignment of the signals was achieved by COSY45
experiments at different concentrations where necessary
(see Experimental Section), allowing the unambiguous
assignment of all sugar OH signals in chloroform (Figure
2). The CIS values obtained from the least square fit
were found to be rather uniformly in the range of 2.5 to
3 ppm deshielding; their scatter may be partially due to
undetectable traces of acids. Thus, addition of 1%
p-toluenesulfonic acid with respect to tetraalkylammo-
nium diphenyl phosphate to a solution containing 60%
complexed 1,2-trans-cyclohexanediol (11) with 2 led to
an additional deshielding of 0.54 ppm. Addition of 3%
of the acid to the same solution produced 1.3 ppm
downfield shift of the OH signal; with 10% acid the OH
signal disappeared. There is no significant correlation
between the CIS and the K values, suggesting a fairly
constant charge depletion at the protons involved in
hydrogen bonding to the different anions.
The substrates (Chart 2) were so chosen that binding
contributions of single hydroxy and of vicinal dihydroxy
groups in different positions could be evaluated; the latter
may be expected to show higher basicities and acidities
as the result of known13 intramolecular hydrogen bonds,
which was studied by NMR spectroscopy. The use of
partially protected sugars and of configurational isomers
allowed evaluation of specificities, as well as the ac-
cumulative effects of the up to four OH groups present
in the n-dodecyl â-D-glycopyranosides used.
Meth od s. Th e Use of OH NMR Sign a ls for Com -
p lexa tion Stu d ies. One major obstacle in the study of
carbohydrate complexes is the lack of large NMR shield-
ing differences between free and complexed material,
which is the basis of most investigations with supramo-
lecular systems. Another problem which in fact blurs
many investigations is the extreme effect of water and
acid traces.14 Thus, in a 2.0 mM solution of n-dodecyl
â-D-galactopyranoside (18) in chloroform with 3 mM
water (see Experimental Section), the OH resonances of
the sugar were clearly observable; after addition of 1%
(only 2.0 × 10-5 M) p-toluenesulfonic acid they became
broad, and with 2% acid the OH signals disappeared
completely. It is likely for this reason that NMR was
until now barely used for the study of carbohydrate
associations, except where CH signals happened to show
enough differences.6,8,9,12 NH signals in amides, nucleo-
bases, etc., are less sensitive to random medium effects
and are therefore routinely used for studying correspond-
ing equilibria. We show for the first time that, under
suitable precautions, almost all OH signals in sugars can
be used routinely for the evaluation of equilibrium
constants K and complexation induced shifts (CIS values)
by NMR titrations.
Resu lts a n d Discu ssion
In spite of tight ion pairing in chloroform, steric
shielding of the anion by the peralkylammonium cation
does not prevent formation of hydrogen bond complexes
with stabilities reaching values beyond K ) 103 M (Table
5). The acceptor compounds 1a and 1b differ substan-
tially in the alkyl chains of the cation, yet interact with
the same energy with donor 11. The same is observed
in the case of 5a and 5b (Table 2).
A. Mon oh yd r oxy Der iva tives. These provided data
for the weak donor capacities of single OH groups
compared to the vicinal diols or polyols, as well as for
the difference between primary and secondary OH groups
(Table 1). The number of anions tested with the simple
alcohols was restricted to a few cases in view of the small
constants K, and the therefore smaller degrees of com-
plexation which could be obtained in the titrations, with
the consequence of larger errors involved here. Never-
theless, the results show, as the diols discussed below, a
stronger binding to chloride than to bromide and a 10
times higher equilibrium constant with primary com-
pared to secondary alcohols.
As documented, for instance, with Figure 1, not only
the different OH signals in a sugar where observable, but
also CH signals in typical titration experiment show
satisfactory agreement with computer simulated least
square fit curves15 and usually yield constants K within
a rather narrow range (Tables 2-5). The model used for
all associations was based on a 1:1 complex formation.
As the fitting showed no systematic deviation, and the
K values for one system generally showed no significant
disagreement between evaluation of different NMR sig-
nals, there was no justification to use other models, such
as different 1:1 complexes which certainly are present
with the sugars (see below). Self-association of the
B. tr a n s-1,2-Cycloh exa n ed iol. Diol 11, containing
gauche vicinal OH groups as the most frequent structural
motif in carbohydrates, was used to compare the ability
of many different anions to act as acceptors (Table 2).
Noticeably, halides were found to be as efficient as
oxygen-containing anions, in the usual activity sequence
Cl > Br > I, which is in line with the pK differences of
the corresponding hydrogen halides in aqueous systems.
A similar order has been observed in studies of anion
complexation with different hydrogen bonding host struc-
tures.16 Fluoride in the form of tetraalkylammonium
salts, unfortunately, was too hygroscopic for these mea-
(13) Nagy, P. I.; Dunn, W. J ., III; Alagona, G. J . Am. Chem. Soc.
1992, 114, 4752-4758.
(16) (a) Beer, P. D.; Gale, P. A.; Hesek, D. Tetrahedron Lett. 1995,
36, 767-770. (b) Scherder, J .; Fochi, M.; Engbersen, J . F. J .; Rein-
houdt, D. N. J . Org. Chem. 1994, 59, 7815-7820. (c) Smith, P. J .;
Reddington, M. V.; Wilcox, C. S. Tetrahedron Lett. 1992, 33, 6085-
6088 and references cited therein.
(14) Pearce, C. M.; Sanders, K. M. J . Chem. Soc., Perkin Trans. 1
1994, 1119-1124.
(15) Schneider, H.-J .; Kramer, S.; Simova, S.; Schneider, U. J . Am.
Chem. Soc. 1988, 110, 6442-6448.

Interactions of Hydroxy Compounds and Sugars with Anions
J . Org. Chem., Vol. 61, No. 4, 1996 1431
Ch a r t 2
8
F igu r e 2. COSY45 for a 13 mM solution of 17 in CDCl3.
Ta ble 1. Associa tion w ith Mon oh yd r oxy Com p ou n d sa
alcohol acceptor proton K (M-1
)
∆G (kcal mol-1
)
CIS (ppm)
7
7
4
5a
2
OH
OH
OH
R-CH
â-CH2
â-CH2′
R-CH
â-CH3
17
3.6
1.68
0.76
1.41
0.08
0.08
0.08
0.10
0.14
4.60
4.40
2.43
-0.34
-0.19
-0.18
-0.24
-0.18
8
10.7
0.9c
0.9c
0.9c
1.2
9b
2
10b
2
1.3
a
In CDCl3 at 298 ( 1 K. Association constants K (error,
standard deviation, <10% unless noted otherwise); free energies
of complexation, ∆G; complexation induced shifts, CIS, positive
values ) deshielding, negative values ) shielding. b The OH signal
dissapeared after the first addition and could not be used.
c Estimated error in K ( 25%.
Ta ble 2. Associa tion w ith 1,2-tr a n s-Cycloh exa n ed iol
(11)a
anion
proton
Kass. (M-1
)
∆G (kcal mol-1
)
CIS (ppm)
F igu r e 1. Experimental points and calculated curves for the
binding of 18 and 5a . All OH signals and that of 4-CH for
compound 18 are shown.
1a
OH
â-CH
OH
5.4
6.8
5.3
1.00
1.12
0.99
1.05
1.76
1.53
1.63
2.05
2.08
2.27
2.10
1.43
1.33
0.76
2.93
-0.11
6.48
-0.17
5.62
-0.13
-0.17
2.87
-0.10
-0.09
2.44
1b
2b
â-CH
OH
â-CH
â-CH′
OH
â-CH
â-CH′
OH
5.8
surements, but is expected to compete very effectively
with organic anions such as carboxylates. For the
organic anions, aryl derivatives were chosen with the
hope to observe NMR shielding effects by ring current
anisotropies. The donor strength of the organic anions
decreases substantially in spite of the same total charge,
with the following order: carboxylate > phosphate .
sulfonate, which is interesting in view of the role of acidic
amino acids in carbohydrates binding proteins. Again,
the ∆Gcplx differences qualitatively follow the order of pK
values in aqueous solution, reflecting the decreasing
stabilities of the corresponding anions. This order quali-
tatively agrees with the one found by Wilcox et al.16c in
the interaction of these anions with an urea.
The reason for the almost 20 times larger association
found for the diol in comparison to the monohydroxy
derivatives, which also is substantiated with the pro-
tected sugars (see below), may be seen in the acidity of a
proton which is already involved in the well known
intramolecular hydrogen bond. Recent data accumulated
19.4
13.0
15.6
31.3
32.9
47.0
34
11
9.3
3.6
3b
4
5a
5b
6
OH
OH
OH
2.45
2.67
1.83
a
b
See footnote a to Table 1. Error, standard deviation, in K <
30%.
by Abraham17 suggest acidities of vicinal diols to be much
higher (with ΣR ) 0.58) than those of mono- (ΣR ) 0.37),
or other dihydroxy derivatives (ΣRav ) 0.37 if only one
hydrogen bond complex per OH group is taken into
account). That one proton can participate in several
hydrogen bonds, in this case one being intra- and the
(17) Abraham, M. H. Personal communication.

1432 J . Org. Chem., Vol. 61, No. 4, 1996
Cotero´n et al.
Ta ble 4. Associa tion w ith n -Dod ecyl
â-D-Glu cop yr a n osid e (17)a
1a
2
4
5
6
OH2
OH3
OH4
OH6
CH1
Kass
∆G
CIS
Kass
∆G
CIS
Kass
∆G
CIS
Kass
∆G
CIS
Kass
∆G
CIS
∆Gav
b
b
b
b
b
b
b
b
b
b
b
b
470
3.66
1.48
902
4.04
3.15
889
4.04
3.43
615
3.82
0.55
686
3.88
2.38
695
3.89
2.96
153
2.99
0.42
166
3.04
1.75
165
3.04
2.28
26
1.94
0.24
d
d
d
d
d
d
589
603
151
25
3.79
1.92
c
c
c
3.81
1.39
c
c
c
2.98
1.14
c
c
c
1.91
0.85
c
c
c
F igu r e 3. Diol type binding sites in compound 17.
33.5
2.09
-0.03
2.09
Ta ble 3. Associa tion w ith P a r tia lly P r otected Su ga r s
12-16a
alcohol
proton
Kass. (M-1
)
∆G (kcal mol-1
)
CIS (ppm)
3.88
3.85
3.01
1.92
11
12
OH
11
1.43
1.14
1.14
1.34
1.34
0.73
0.76
0.35
0.38
1.18
1.19
1.20
2.45
2.54
2.67
2.90
2.45
1.81
2.58
2.82
2.39
1.42
2.64
0.48
a
b
See footnote a to Table 1. Proton not observable in the
OH2
OH3
OH4
OH6
OH2
OH3
OH3
OH4
OH4
OH6
CH4
6.8
6.8
9.6
9.5
3.4
3.6
1.8
1.9
7.3
7.4
7.5
titration. c Proton not shifted with the interaction. Proton not
distinguishable at some points of the titration due to signal
overlapping.
d
13
intramolecular hydrogen bond strength between cis- and
trans-1,2-cyclohexanediol. The glucose derivative with
free 3-OH and 4-OH was not prepared because its
synthesis is not trivial, and its binding capacity is
expected to be close to compound 11.
15
16
D. Bin d in g t o n -Dod ecyl â-D-Glu cop yr a n osid e
(17). Compound 17, in which only one alkyl chain was
introduced for the sake of chloroform solubility, showed
free enegies of complexation with the anions much higher
than the ones observed with the diols (Table 4). These
sugar derivatives offer four OH groups for binding. The
increase of the effective concentration of binding sites
within one donor molecule is reflected in the high
constants K which nevertheless could be derived without
systematical deviations from fitting to a 1:1 model. In
the anion concentration range used, the formation of 1:2
or 1:3 complexes, containing more than one anion, is
disfavored. In contrast, formation of three different 1:1
complexes A, B, and C (Figure 3) is suggested by the fact
that the sugar derivatives 12 and 13 with vicinal diols
as well as the diol 11 show similar complex stabilities.
The formation of three different 1:1 complexes A, B, C
(Figure 3) is reflected to a different degree also in the
observed CIS and K values for the interaction between
compound 17 and the phosphate 2. In this case, all 4
OH signals show a good fitting to a 1:1 complexation
mode; however, the 3-OH and 4-OH signals yield CIS and
K values roughly twice as large as obtained with the
2-OH and 6-OH signals. This indicates that the central
OH groups 3 and 4 are involved twice in different
complexes, namely either A and B, or B and C, respec-
tively, whereas the 2-OH and 6-OH groups are involved
only once (in A or C). A J ob plot20 for the binding of 17
and 2 (Figure 4) showed a maximum between x ) 0.5
and x ) 0.6, indicating only a preference for 1:1 complexes
over 2:1 complexes, which obviously coexist in solution
to a minor degree.
a
See footnote a to Table 1.
other intermolecular, is in line with structural findings
in the solid state,18 as well as with current views and
calculational processing of hydrogen bonds based es-
sentially on electrostatic interactions. Alternative ex-
planations can be based on the formation of two instead
of one hydrogen bonds to an anion with the diols.
Intramolecular hydrogen bonding in similar partially
protected sugar derivatives have been shown to be not
very strong in chloroform.19 Changes in coupling con-
stants observed with galactose derivative 14 actually do
speak for breaking of intramolecular hydrogen bond by
complexation.
C. Bin d in g to P a r tia lly P r otected Su ga r s. The
sugars 17 and 18 have three different binding sites
(Figure 3). Compound 17 has two of the 1,2-trans-
cyclohexanediol type and one of a 1,3-diol type binding
sites, while 18 has one 1,2-trans-cyclohexanediol, one 1,2-
cis-cyclohexanediol, and one 1,3-diol type binding sites.
In order to check the binding capacities of the different
binding sites, we decided to prepare the partially pro-
tected sugars 12-16 and to study their interactions with
the ammonium bromide 5a . The results are listed in
Table 3.
Binding of bromide to partially protected sugars 12 to
16 largely reflects the affinities and CIS values observed
with the simple model compounds. Thus, 12 and 13 show
similar values as the diol 11, indicating the same binding
mode and donor acidity. The situation is different in the
case of galactose derivatives: 16 shows the same affinity
as 11-13, but compounds 14 and 15 show an energetic
The situation is different in the complexation of 17 by
halides. In this case, the K values are similar for the 4
OHs and a J ob plot showed a maximum at x ) 0.5; the
CIS values follow the order 4-OH > 3-OH > 6-OH >
2-OH. This can be due to the formation of only one 1:1
complex between the halide and the 3- and 4-OH groups
disadvantage compared to the other derivatives.
A
similar difference has been observed before by Anslyn et
al.9 and is believed to be due to the difference of
(18) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures, 2nd ed.; Springer-Verlag: Berlin Heidelberg, 1994; pp 181-
184.
(19) Muddasani, P. R.; Bozo´, E.; Bernet, B.; Vasella, A. Helv. Chim.
Acta 1994, 77, 257-290.
(20) J ob, A. Ann. Chim. (10th Series) 1928, 9, 113-204.

Interactions of Hydroxy Compounds and Sugars with Anions
J . Org. Chem., Vol. 61, No. 4, 1996 1433
F igu r e 4. J ob plot for the binding of 17 and 2. Concentration
of 17 + 2 was held constant at 2 × 10-3 M.
F igu r e 5. Structure with three hydrogen bonds obtained for
the complex [18 + 2] using CHARMm 4.0.21
Ta ble 5. Associa tion w ith n -Dod ecyl
â-D-Ga la ctop yr a n osid e (18)a
1a
2
3
4
5
OH2 Kass
∆G
b
b
b
b
b
b
b
b
b
b
b
b
210
3.18
1.85
471
3.66
2.94
396
3.56
2.72
331
3.45
2.86
b
b
b
b
b
b
b
b
b
b
b
b
597
3.80
0.42
530
3.73
1.10
567
3.77
2.15
551
3.75
136
2.92
0.33
134
2.91
0.89
121
2.85
1.78
120
2.85
CIS
OH3 Kass
∆G
CIS
OH4 Kass
∆G
CIS
OH6 Kass
∆G
CIS
2.51
1.86
CH1 Kass
∆G
38.7
2.17
-0.05
52.0
2.35
-0.06
360
3.50
-0.07
c
c
c
c
c
c
c
c
c
-
-
-
c
c
c
CIS
CH4 Kass
∆G
1067
126
4.15
0.182
4.15
2.88
0.171
2.88
CIS
∆Gav 2.26
3.47
3.76
a
b
See footnote a to Table 1. Proton not observable. c Proton not
shifted with complexation.
which show the highest CIS values; 2-OH and 6-OH
would still be involved in intramolecular hydrogen bonds.
Upon complex formation the oxygens 3 and 4 become
more basic, in other words, better acceptors and the
intramolecular hydrogen bonds OH(2)-O(3) and OH(6)-
O(4) would be stronger than before complex formation.
The larger CIS value for 6-OH compared to 2-OH might
be due to the higher flexibility of the CH2OH group to
form intramolecular hydrogen bonds.
E. Bin d in g to n -Dod ecyl â-D-Ga la ctop yr a n osid e
(18) (Table 5). The CIS values observed for the interac-
tion of compound 18 with phosphate 2 suggest that the
interaction takes place with 3-OH, 4-OH, and 6-OH, all
of them showing comparable, but higher values than the
one observed for 2-OH. In this case, a 1:1 complex
including three hydrogen bonds is possible between
acceptor 2 and 18, as galactose provides an axial OH
directed toward the acceptor. This is suggested by
molecular modeling21 (Figure 5), indicating the OH
groups in position 3, 4, and 6 as donors. A J ob plot
F igu r e 6. J ob plot for the binding of 18 and 2. Concentration
of 18 + 2 was held constant at 2 × 10-3 M.
(Figure 6) for 18 and 2 gave a maximum at x ) 0.5
indicating a 1:1 complexation mode. A three-fold hydro-
gen bond is not possible for acceptor 5a which can
interact only with two OH groups at the same time. The
results in Table 3 clearly indicate that, for the complex
18 + 5a , interaction with binding site A (2-OH and 3-OH,
as in compound 14) or B (3-OH and 4-OH, as in
compound 15) is less favorable than interaction with
binding site C (4-OH and 6-OH, as in compound 16).
Consequently, the complex is formed with 4-OH and
6-OH as suggested by the CIS values obtained for this
interaction. A J ob plot for this interaction gave a

1434 J . Org. Chem., Vol. 61, No. 4, 1996
Cotero´n et al.
Ta ble 6. Cou p lin g Con sta n ts for Com p ou n d s 12-18
befor e a n d a fter Com p lexa tion w ith 5a a
δ0
J exp
b
sugar
hydroxyl (ppm)
J 0
(%compl.) ∆J
â-D-glu 17
OH2
OH3
OH4
OH6
OH2
OH3
OH4
OH6
OH2
OH3
OH4
OH6
OH2
OH3
OH3
OH4
OH4
OH6
OH2
OH3
OH2
OH3
2.39
2.64
2.52
1.99
2.45
2.63
2.18
1.99
2.37
2.60
2.78
2.08
2.41
2.46
2.43
2.49
2.57
2.06
2.29
2.04
2.63
2.60
2.2 (5.0)
1.9 (4.7)
2.4 (5.0)
6.5c (5.8,6.0)
2.4
d
d
d
d
-
-
-
-
F igu r e 7. Most stable conformers obtained for 17 using
CHARMm 4.0 showing the most probable intramolecular
hydrogen bonding net for each conformer.
4,6-Bd-glu 12
2,3-di-Bn-glu 13
â-D-gal 18
3.0 (58)
3.0 (58)
4.2 (64)
6.8c (47)
d
1.0
2.2
1.0
3.0
0.2
-
3.0
1.6
2.3
6.7c
has in the vicinity an equatorial OH, an unprotected axial
OH, or a protected axial OH, respectively.
1.8
4.6
2.9
5.2/7.8
1.6
8.8
4.0
3.2
2.8
3.9/8.9
9.1
8.0
1.6
8.9
6.7 (72)
4.0 (71)
6.9c (63)
2.5 (48)
6.5 (55)
5.1 (26)
3.3 (27)
3.0 (45)
5.1c (37)
-
Molecular modeling21 was used to calculate the tor-
sional angles in the different conformers with intramo-
lecular hydrogen bonds in order to compare the experi-
mental values with the calculated ones. Compound 17
can be assumed to exist as two hydrogen bound species
as shown in Figure 7. In both conformers, 2-OH, 3-OH,
and 4-OH have torsional angles around 70°, with a small
coupling constant around 1 Hz according to eq 1. This
is in line with the experimental values around 2 Hz. The
6-OH signal appears as a triplet with very close J value
for both 6-HOCHa (6a-OH) and 6-HOCHb (6b-OH). In
conformer A, the calculated Φ values are 160° for 6a-
OH and 70° for 6b-OH corresponding to J values of 11
and 1 Hz, respectively, while, in conformer B, these
values are -80° for 6a-OH and -171° for 6b-OH. The
average experimental value (6 Hz) suggests similar
stabilities for both conformers. The same situation is
observed in the partially protected sugars 12 and 13
before complexation with small coupling constants for
2-OH, 3-OH and 4-OH close to 2 Hz. The coupling
constant value increases slightly in these protons when
the complex is formed, suggesting a change in the
torsional angle due to complexation.
-
4,6-Bd-gal 14
1.9
4.2
4.2
0.4
0.4
2,6-di-Bn-gal 15
2,3-di-Bn-gal 16
4,6-Bd-R-gal 19
4,6-Bd-â-gal 20
-
-
-
-
-
-
-
-
a
In CDCl3 at 298 ( 1 K. Compounds 12-18 are n-dodecyl â-D-
derivatives. Compounds 19 and 20 are methyl glycosides. Values
given for compounds 19 and 20 have been taken from reference
b
3
18. Numbers in brackets correspond to J HOCH in DMSO and
have been taken from reference 22. c Unresolved triplet. Coupling
d
constant not distinguishible.
maximum at x ) 0.5. If only one 1:1 complex is formed
between the acceptor and 4- and 6-OH, the observed CIS
values for 2- and 3-OH are due to the strengthening of
the intramolecular hydrogen bonding network in the
sugar after the complex has been formed. The difference
in the CIS value between 2- and 3-OH reflects then that
3-OH is closer to the main interaction than 2-OH and,
therefore, exhibits a higher CIS value.
F . Com p lexa tion a n d HOCH NMR Cou p lin g Con -
st a n t s. As shown recently by Vasella et al.,19 H-O-
C-H coupling constants can provide valuable insight into
the geometries of intramolecular hydrogen bond network
in carbohydrates. Bonar-Law and Sanders5 have de-
scribed the HOCH coupling constants of R- and â-alkyl
glycosides of glucose, galactose, and mannose in chloro-
form. We observed changes of these coupling upon
complexation which can be used to derive information
on the underlying geometries. Table 6 contains both the
observed maximal value 3J max as well as the one expected
for 100% complexation (3J cplx); these were obtained by
The galactose derivative 18 can be described by three
different conformers of very similar energy as shown in
3
Figure 8. The 2-OH group shows J HOCH very close to
the ones observed for 2-OH, 3-OH, and 4-OH in com-
pound 17, the reason being that 2-OH has only equatorial
vicinal oxygens and, consequently, torsional angles of 70°
in all conformers. 3-OH has one equatorial (2-OH) and
one axial (4-OH) neighbor; when 3-OH acts as a donor
to 2-OH the expected Φ is 70° corresponding to a J value
of 2 Hz, but when it acts as donor to 4-OH this value is
around 170° corresponding to a J value of 12 Hz. The
observed J (4.6 Hz) is close to the average value of the
three conformers. In the case of 4-OH, J is slightly larger
than in the case of 2-OH, likely due to an intramolecular
hydrogen bond with the pyran oxygen (conformer not
shown). In this conformer, the torsional angle of 4-OH
3
dividing J max over the complexation degree calculated
from the evaluated K values at the known concentrations
of host and guest. For the analysis of 3J we used a
Karplus type equation22 with empirically derived coef-
3
is close to -170° corresponding to a J of 12 Hz, and the
3
presence of a small concentration of this conformer would
ficients describing the variation of J with the torsional
3
explain the increase of J . 6-OH reflects two different
angle Φ in the system HOCH with the following form:
3J HOCH (Hz) ) 10.4 cos2 Φ - 1.5 cos Φ + 0.2 (eq 1)
coupling constants because the average of 3J in the three
conformers is different for 6-HOCHa and 6-HOCHb. The
coupling constants of the hydroxyls change after com-
plexation, indicating that their orientation is different
in the complex. The most remarkable change occurs in
the coupling constant observed for 3-OH. As it has been
shown before, the main interaction must take place
between the bromide and the hydroxyls 4 and 6 because
they show the largest CIS values, and, when the complex
Vasella et al.19 have studied the HOCH coupling
constants of some partially protected methyl glycosides
in chloroform, observing that an equatorial OH shows
3
characteristic J HOCH values of ca. 2, 4, or 9 Hz when it
3
is formed, J for 3-OH increases to a value close to the
(21) Bru¨nger, A. T.; Karplus, M. Acc. Chem. Res. 1991, 24, 54-61.
(22) Fraser, R. R.; Kaufman, M.; Morand, P.; Govil, G. Can. J . Chem.
1969, 47, 403-409.
(23) Gillet, B.; Nicole, D.; Delpuech, J . J .; Gross, B. Org. Mag. Reson.
1981, 17, 28-36.
one observed for compound 14, behaving as if 4-OH were
protected. On the other hand, when compound 14
interacts with the bromide 5a , the 3-OH coupling con-

Interactions of Hydroxy Compounds and Sugars with Anions
J . Org. Chem., Vol. 61, No. 4, 1996 1435
F igu r e 8. Most stable conformers obtained for 18 using CHARMm 4.0 showing the most probable intramolecular hydrogen
bonding net for each conformer.
NaHCO3 and then with water, dried over MgSO4, and con-
centrated. The residue was stirred with hexane for 20 min
and a gel was formed. The gel was filtrated and washed with
hexane (5 × 5 mL), and the final product was obtained (396
mg, 73%). 1H-NMR (400 MHz, CDCl3, 25 °C, TMS): δ ) 7.51-
7.28 (m, 5H, aromatic), 5.54 (s, 1H, benzylidene), 4.40 (d,
3J (H,H) ) 7.7 Hz, 1H; CH1), 4.35 (dd, 3J (H,H) ) 4.9 Hz,
3J ′(H,H) ) 10.5 Hz, 1H), 3.92-3.77 (m, 3H), 3.60-3.44 (m, 4H),
2.62 (d, 3J (H,H) ) 2.2 Hz, 1H; OH3), 2.44 (d, 3J (H,H) ) 2.4
Hz, 1H, OH2), 1.67-1.60 (m, 2H, CH2 â), 1.30-1.24 (m, 18H),
stant decreases from 8.8 to 4.2 Hz, indicating the partial
breakage of the intramolecular hydrogen bond OH(3)-
O(4) while forming the complex.
Exp er im en ta l Section
1H-NMR Spectra were obtained using a Bruker AM-400 (all
titrations) or a Bruker DRX-500 (2D experiments) spectrom-
eter. Molecular mechanics calculations21 were performed on
a Silicon Graphics Indy workstation using the QUANTA
program with the CHARMm force field.
3
0.88 (t, J (H,H) ) 3J ′(H,H) ) 6.6 Hz, CH3). C25H40O6 (436.6):
calcd C 68.78, H 9.23; found: C 68.85, H 9.10.
n -Dod ecyl 4,6-O-Ben zylid en e-2,3-d i-O-ben zyl-B-D-glu -
cop yr a n osid e. n-Dodecyl 4,6-O-benzylidene-â-D-glucopyra-
noside (800 mg, 1.83 mmol) was dissolved in a suspension of
NaH (338 mg, 14.7 mmol) in DMF (25 mL), and the mixture
was stirred for 1 h and then cooled to 0 °C. Benzyl bromide
(0.85 mL, 7,34 mmol) was added dropwise, and the reaction
mixture was stirred for 2 h at room temperature. MeOH (20
mL) was carefully added and, after all the NaH was quenched,
water (20 mL) was added. A white precipitate was obtained,
filtered, washed with methanol (5 × 5 mL), and dried. This
product was used in the next step without further purification.
Bin d in g Stu d ies. CDCl3 was deacidified with anhydrous
K2CO3 and dried with 4 Å molecular sieves. The water content
was checked by integration of the 1H-NMR peak at 1.6 ppm,
using DMSO as internal standard, and it was found to be 2.5-
3.0 mM. Self-association of 1,2-trans-cyclohexanediol and
dodecyl sugars was checked with dilution experiments and was
found to be negligible at or below the following concentra-
tions: 1,2-trans-cyclohexanediol, 10-2 M, n-dodecyl â-D-glu-
copyranoside, 1.7 mM, and n-dodecyl â-D-galactopyranoside,
2.0 mM. The dilution experiments could not be fitted to a 1:1
self-association mode, suggesting the presence of aggregates
different from a 1:1 stoichiometry in the self-association.
Wa ter Effects. A 1.7 mM solution of n-dodecyl â-D-
glucopyranoside in CDCl3 was titrated with wet chloroform;
it was found that the OH resonances were observable when
the water concentration was below 6.0 mM. In order to check
the influence of water on the K values, two titrations were
carried out with different water content (16 and 2.5 mM) for
the interaction of 1,2-trans-cyclohexanediol (11) with TBABr
(5a ), and the same association constant within the error was
obtained in both cases (10.7 and 11.3 M-1, respectively).
The assignment of the 3- and 4-OH signals in the case of
compound 17 was not clear by COSY45 when the concentration
of the sample was 1.7 mM, but it was possible to assign the
signals in a 2D experiment when the concentration was 13
mM (Figure 2). A dilution experiment showed that the relative
positions of both protons did not change in the range 20-1.5
mM, permitting the assignment of both signals.
Titr a tion s/Solven t Effect of Aceton itr ile. Titrations
were carried out as described before.15 All titrations were done
at least twice in order to ensure reproducibility, usually with
deviations below 10% in K and CIS values. A titration of the
interaction of compound 16 and bromide 5a in deuterated
acetonitrile gave K ) 17 ( 1 M-1, representing an energetic
advantage of 0.6 kcal/mol in respect to the same interaction
measured in chloroform (K ) 7.5 M-1). This result reflects
that acetonitrile is a weak acceptor while chloroform is a weak
donor; as the OHs are acting as donors, the K in chloroform is
smaller than the one in acetonitrile because chloroform
competes with the sugar for the acceptor.
n -Dod ecyl 2,3-Di-O-ben zyl-â-D-glu cop yr a n osid e (13).
The precipitate obtained in the last step was dissolved in
CHCl3-MeOH 1:1 (150 mL), and p-toluenesulfonic acid (20
mg) was added. The mixture was stirred for 10 h at room
temperature. Water (150 mL) was added, and the organic
phase was washed with saturated NaHCO3 (2 × 25 mL) and
then with water (2 × 25 mL). The organic phase was dried
over MgSO4, and the solvents were evaporated. Column
chromatography of the residue gave the final product as a
white solid (702 mg, 73% in two steps). 1H-NMR (400 MHz,
CDCl3, 25 °C, TMS): δ ) 7.38-7.29 (m, 10H, aromatic), 4.98
3
3
(d, J (H,H) ) 11.6 Hz, 1H, benzylic), 4.97 (d, J (H,H) ) 10.8
Hz, 1H, benzylic) 4.72 (d, 3J (H,H) ) 11.0 Hz, 1H, benzylic),
3
3
4.66 (d, J (H,H) ) 11.6 Hz, 1H, benzylic), 4.45 (d, J (H,H) )
7.3 Hz, 1H; H1), 3.95-3.85 (m, 2H), 3.77-3.70 (m, 1H), 3.58-
3.31 (m, 5H), 2.19 (d, 3J (H,H) ) 2.3 Hz, 1H, OH4), 1.99 (t,
3J (H,H) ) 3J ′(H,H) ) 6.7 Hz, 1H; OH6); 1.70-1.63 (m, 2H;
CH2 â); 1.45-1.20 (m, 18H); 0.88 (t, 1H, 3J (H,H) ) 3J ′(H,H) )
6.4 Hz, 1H; CH3). C32H48O6 (528.7): calcd C 72.69, H 9.15;
found: C 72.71, H 9.08.
Preparation of the corresponding galactose derivatives will
be reported elsewhere.24 All other substrates were com-
mercially available products and were used without further
purification.
Ack n ow led gm en t. Our work is supported by the
Deutsche Forschungsgemeinschaft, Bonn, and the Fonds
der Chemischen Industrie, Frankfurt. J .M.C. thanks
the Spanish Ministerio de Educacion y Ciencia for a
postdoctoral fellowship. We thank M. H. Abraham, K.
Connors, C. Laurence, and O. Raevsky for helpful
discussions, supported by a NATO CRG grant.
Solvents were refluxed and distilled using the following
drying agents: for dichloromethane, CaH2; for dimethylfor-
mamide, CaO; for acetone, K2CO3.
Syn t h esis. n -Dod ecyl 4,6-O-Ben zylid en e-n -â-D-Glu -
cop yr a n osid e (12). n-Dodecyl â-D-glucopyranoside (434 mg,
1.25 mmol) and R,R′-dimethoxytoluene (0.46 mL, 3 mmol) were
mixed in Cl2CH2 (70 mL). p-Toluenesulfonic acid (cat.) was
added, and the starting suspension became a clear solution
after 15 min. The mixture was stirred for 4 h. Water (70 mL)
was added, and the organic phase was extracted with 5%
J O951435L
(24) Ferna´ndez Gutie´rrez, P.; Schneider, H.-J . Manuscript in prepa-
ration.