Quantifying the electronic effects of carbohydrate hydroxy groups by using aminosugar models

Article abstract of DOI:10.1002/chem.201100020

Methyl amino-deoxy-glycosides with α- and β-gluco, α-galacto, or α-manno stereochemistry with the amino functionality in each of the four possible non-anomeric positions have been synthesized and their pK_a values determined by titration. These

Full text of DOI:10.1002/chem.201100020

DOI: 10.1002/chem.201100020
Quantifying the Electronic Effects of Carbohydrate Hydroxy Groups by
Using Aminosugar Models
Christian M. Pedersen,* Jacob Olsen, Azra B. Brka, and Mikael Bols*[a]
Abstract: Methyl amino-deoxy-glyco-
sides with a- and b-gluco, a-galacto, or
a-manno stereochemistry with the
amino functionality in each of the four
possible non-anomeric positions have
been synthesized and their pKa values
determined by titration. These model
compounds were chosen because they
are the amino derivatives of the most
common glycosyl acceptors. From this
study it was possible to evaluate the
electron density at each of the given
positions in the carbohydrate and com-
pare them. Some general trends were
observed: The basicity of the amino
groups decreases in the order 6-NH2 >
3-NH2 >2-NH2 >4-NH2 (referring to
the position). The basicity of a of an
amino-deoxy-sugar generally increases
when one or more substituents on the
sugar ring are axial. The basicity de-
creases when the amine is antiperipla-
nar to an oxygen atom. These findings
are in agreement with the observations
obtained from glycosylation chemistry
and the regioselective protection of
sugars.
Keywords: acidity · amines · carbo-
hydrates · reactivity · stereoelec-
tronic effects
Introduction
sumably due to unfavorable 1,3-diaxial steric interactions,
and the 4-OH is often observed to be the least reactive.
Most of these rules build on the knowledge gained from the
glycosylation chemistry of partially protected acceptors and
regioselective protective group manipulations.[4] Some of the
conclusions on hydroxy group reactivity, obtained from stud-
ies on the acylation of methyl glycosides, are misleading be-
cause they do not take into account the effect of monoacyla-
tion of the remaining hydroxy groups[5] and the effect of dif-
ferent solvents[6] and reagent systems. In an early NMR
study by Horton and Lauterback, the relative distribution of
acetyl groups in the partial acetylation of methyl a-d-gluco-
pyranoside using acetic anhydride–[D5]pyridine was found
to be 0.4 (O-6) to 0.2 (for each of the secondary hydroxy
groups), that is, the secondary hydroxy groups have a similar
reactivity.[7] Williams and Richardson came to the conclusion
that the order of reactivity in acetylation is 2-OH>3-OH>
4-OH for methyl a-d-glucoside and 3-OH>2-OH>4-OH
for methyl a-d-mannoside, whereas for the galactoside the
3-OH and 2-OH have a similar reactivity and the 4-OH is
still the least reactive.[8] From the ditosylation, acetylation,
and benzoylation of pyranosides, 3,6-substitution has been
observed to be dominant for a-mannosides and b-glucosides,
whereas a-glucosides resulted in 2,6-substitution and a-gal-
actosides in mixtures.[9] Studies of the differences in the re-
activity of the different positions on the sugar ring have
almost only been performed with hydroxy groups and only
very few studies on the differences between amino-deoxy-
sugars have appeared. Inouye compared the NMR shifts of
different aminosugars and by looking at the shifts of the hy-
drochloride salts he estimated the order of decreasing basici-
ty to be 6-amino>3-amino>2-amino in the glucopyranoside
series.[10] We have earlier used aza-sugars as model com-
pounds to investigate the effects of substituents on a given
With the increased knowledge of the interactions of carbo-
hydrates in biological systems the need for complex oligo-
saccharides and glycoconjugates has increased. So far, the
best way to obtain these desired molecules for biological
evaluation and drug discovery has been by synthesis. This is,
however, often very complicated due to the many function-
alities present and expertise within the field is a must. Gly-
cosylation[1,4] is often the most critical reaction type in which
stereoselectivity (a vs. b), regioselectivity, moisture sensitivi-
ty, and poor nucleophilicity of the acceptor (often an OH
nucleophile) complicate the outcome and purification of the
reaction. To improve these reactions there has been increas-
ing interest in studying the reactivity and selectivity of the
glycosyl donor, and recently several methods to quantify the
reactivity of donors containing different protective groups
have appeared.[2] The reactivity of the glycosyl acceptor is,
however, less studied and it is difficult to find a specific pat-
tern in the different reactivities of the hydroxy groups,[3] al-
though there are some rules of thumb, such as the greater
reactivity of the 6-OH relative to the secondary hydroxy
groups for steric reasons. Of the secondary hydroxy groups,
the axial are normally less reactive than the equatorial, pre-
[a] Dr. C. M. Pedersen, J. Olsen, A. B. Brka, Prof. Dr. M. Bols
Department of Chemistry, University of Copenhagen
2100 Copenhagen Ø (Denmark)
Fax : (+45)35320212
E-mail: cmp@chem.ku.dk
bols@chem.ku.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100020.
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FULL PAPER
position, normally the anomeric, and piperidines have
turned out to be very good model compounds.[21]
values obtained by titration. From these data the relative
electron density at each position was obtained and used to
create a picture of the reactivities in each position.
Hydrogen bonding within the glycosyl acceptor is another
important factor to consider when looking at the reactivity
and selectivity of unprotected carbohydrates. The influence
and pattern of the hydrogen bonding are a matter of
debate,[11] but they are generally accepted to play a role in
the reactivity of hydroxy groups. This also explains to some
extent the observed solvent effects in regioselective protec-
tion, apolar solvents such as CH2Cl2 and CHCl3 tending to
give higher selectivity than more polar solvents.[12,15] The hy-
drogen-bonding network in carbohydrates has ingeniously
been used to increase or change the regioselectivity in reac-
tions. Hence, the intrinsically less reactive 4-OH in glucose
can selectively be functionalized[13] or shielded[14] depending
on the approach. As an example, selective functionalization
at the 3-position was achieved by having a directing pyridyl
residue at the 6-position shielding the 4-OH by hydrogen
bonding. Internal hydrogen bonds have been shown to
reduce the reactivity of the hydroxy groups in partially pro-
tected N-acetylglucosamine derivatives towards glycosyla-
tion, which is a significant problem in the synthesis of bio-
logically important oligosaccharides.[15]
Another point to consider when looking at the reactivity
of the acceptor towards the donor is the fact that the glyco-
sylation often involves two chiral reactants. Therefore the
reaction is subject to double diastereodifferentiation,[16] also
referred to as the “match–mismatch concept”[17] or “recipro-
cal donor–acceptor selectivity”[18] in carbohydrate chemistry.
The outcome of a glycosylation reaction clearly also de-
pends on this and not only the nucleophilicity of the accept-
or.
Results and Discussion
Preparation of model compounds: We began our study by
preparing model compounds. From the work on glycosyl
donors, amines had proved to be an excellent functional
group for investigating the charge distribution within the
ring system. We applied this approach to acceptors and de-
cided to prepare the four possible amino derivatives of each
sugar in the study. To limit the number of compounds we
decided to study the most common carbohydrate acceptors,
that is, a- and b-glucosides, a-galactosides, and a-manno-
sides. With both glucoside anomers we can obtain informa-
tion on the influence of the anomeric configuration on the
charge distribution in the sugar ring.
The 6-amino sugars 9–12 with gluco,[23] galacto,[24] and
manno[25] stereochemistry were synthesized from the corre-
sponding methyl glycosides 1–4 by selective monotosylation
of the 6-OH followed by acetylation of the remaining hy-
droxy groups and substitution of the tosyl with azide in
DMF. Deacetylation using sodium methoxide in methanol
and nickel-catalyzed azide reduction gave the desired 6-ami-
nosugars 9–12 in excellent yields (96–99%; Scheme 1).
In previous work we were very interested in quantifying
the reactivity of glycosyl donors and finding ways to control
and, in particular, to increase their reactivity. By studying
various model systems we found a good correlation between
the reactivity of carbohydrates, that is, hydrolysis[19] and gly-
cosylation,[2e] and the pKa of piperidine analogues (aza-
sugars).[21] From this work it is clear that all substituents on
the sugar ring play a role and that the stereochemistry is
crucial. By using less electron-withdrawing protective
groups (silyl or alkyl) in combination with conformational
changes to the axial-rich conformation, highly reactive gly-
cosyl donors (super-armed) were prepared and used in gly-
cosylation reactions.[20] The use of highly reactive donors
solves many problems relating to the “difficult glycosyla-
tion” of acceptors with low nucleophilicity; ex. rhamonosy-
lation of the poor nucleophile benzyl 3-O-acetyl-6-O-
benzyl-N-acetyl-b-d-glucosamine was performed at À788C
to give a quantitative yield of the a-disaccharide.[22] From
the work carried out to gain an understanding of glycosyl
donors we became interested in glycosyl acceptors: Is it pos-
sible to quantify the reactivity of hydroxy groups by using
an amine model system and does it correlate with observa-
tions reported in the literature? In this study, model com-
pounds with a single amino group in one of the four avail-
able non-anomeric positions were prepared and their pKa
Scheme 1. Synthesis of the 6-amino model compounds (Pyr.=pyridine).
Methyl 2-amino-2-deoxy-a-d-glucopyranoside and methyl
2-amino-2-deoxy-a-d-galactoside were synthesized from d-
glucosamine and d-galactosamine, respectively, following
known procedures.[26] When applying the procedure to d-
mannosamine, purification became a problem and another
approach was necessary. Azidonitration of peracetylated
glucal following Paulsen and co-workerꢁs modification[27] of
the original Lemieux and Ratcliffe procedure[28] followed by
methanolysis gave a mixture of four possible compounds,
anomeric mixtures of methyl 2-azido-2-deoxy-gluco- and
-mannosides. The methyl 2-azido-3,4,6-tri-O-acetyl-b-d-man-
noside was removed by chromatography and after deacety-
lation using sodium methoxide the desired a anomer was
isolated in an overall yield of 17%.[28] Nickel-catalyzed re-
duction afforded the known[29] amine 15 in quantitative yield
(Scheme 2).
The 3-aminosugars[30] were prepared from the correspond-
ing 3-nitro compounds following a known procedure.[31] The
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C. M. Pedersen, M. Bols et al.
pKa values of methyl 3-amino-3-deoxy-a-d-glucoside,
methyl 3-amino-3-deoxy-b-l-glucoside, and methyl 3-amino-
3-deoxy-a-d-mannoside were already known.[32]
Scheme 4. Synthesis of the methyl 4-amino-4-deoxy-a-d-mannoside from
1,6-anhydro-b-d-mannoside.
Scheme 2. Synthesis of methyl a-d-mannosamine from glucal following
pKa measurements: With the aminosugars in hand their pKa
values were determined by titration. The results are present-
ed in Table 1 along with previously published data. En-
tries 1–4 show the four possible methyl aminosugars with a-
gluco stereochemistry, entries 5–8 the four aminosugars with
b-gluco stereochemistry, entries 9–12 the four aminosugars
with a-galacto stereochemistry, and entries 13–16 the four
aminosugars with a-manno stereochemistry. From this com-
plete data set for the model compounds representing the
most common carbohydrate acceptors, some general trends
can be observed. Because the pKa value is a measurement
of the electron density at a given position, in this study a
methyl amino-deoxy-glycoside, it can be correlated with the
nucleophilicity of the corre-
the procedure of Lemieux and Ratcliffe.[28]
The 4-aminosugars 19, 20, and 22 with gluco and galacto
stereochemistry were prepared by azide substitution of the
corresponding triflated hydroxy group. Methyl a- and b-d-
galactosides 3 and 16 were regioselectively benzoylated at
the 2-, 3-, and 6-positions[9] and then a triflate was intro-
duced on the free 4-OH. Treatment of this triflate with
NaN3 in DMF gave the 4-azido-d-glucosides, which were de-
benzoylated[33] and reduced to give the two target com-
pounds 19 and 20, respectively (Scheme 3).[34] The methyl 4-
sponding hydroxy group, that is,
the equivalent hydroxy accept-
or in glycosylation chemistry.
By measuring the pKa value of
the sugar with an ammonium
group at a given position, quan-
tification of the nucleophilicity
is achieved.
In general, the 6-amino
groups have a higher pKa value
Scheme 3. Synthesis of the methyl 4-amino-4-deoxygalacto- and -glucopyranosides from the 4-OH epimers.
(ranging from 8.6 to 9.0). This
is in accordance with the 6-OH
acceptor being the most reac-
amino-4-deoxy-a-d-galactoside 22 was prepared from the
known methyl 2,3,6-tri-O-benzyl-a-d-glucoside 21,[35] which
was triflated and treated with NaN3 in DMF to give the 4-
azide with galacto stereochemistry. Palladium-mediated hy-
drogenolysis afforded the 4-amino product 22 (Scheme 3).[36]
The preparation of the 4-amino-mannoside was more de-
manding because methyl a-d-talose (the 4-epimer of man-
nose) is not readily available and not straightforward to re-
gioselectively protect. Therefore another synthesis was plan-
ned starting from d-mannose, which was transformed into
the 1,6-anhydro-mannoside 23[37] and protected with an iso-
propylidene,[38] leaving the 4-OH free for tosylation. Remov-
al of the isopropylidene under acidic conditions and base
treatment gave the 3,4-epoxide 24,[39] which was opened
with the azide to give the 1,6-anhydro-4-azido-4-deoxy-man-
noside[40] with overall retention of stereochemistry. Acidic
hydrolysis gave an anomeric mixture of methyl mannosides,
which could be separated by flash chromatography. Nickel-
catalyzed reduction of the azide in the a anomer gave the
desired methyl 4-deoxy-4-amino-a-d-mannoside 25[50]
(Scheme 4).
tive/nucleophilic. This observation is not surprising and can
be explained by the fact that the 6-position is more remote
from the remaining electron-withdrawing substituents on
the sugar ring and only has one b-hydroxy group (the ring
oxygen), whereas the secondary hydroxy groups have two.
As mentioned in the Introduction the electron density will
both influence the nucleophilicity of a given hydroxy or
amino group and be influenced by the electron-withdrawing
capacity of nearby substituents.
Second to the 6-position, the 3-amino group is the most
basic and hence the 3-hydroxy group should be the most nu-
cleophilic. This is more surprising because the 2-OH is
sometimes found to be more reactive than the 3-OH in pro-
tective chemistry. These observations are probably due to
effects other than stereoelectronics and in most cases the
hydrogen-bonding pattern, other protective groups, and
steric effects can explain the outcome of these reactions.
The lower basicity of the 2-amino group can be explained
by being closer to the ring oxygen, which to a greater extent
pulls electron density away from the 2-position in compari-
son with the 3-position (inductive effect). The same trend
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Electronic Effects of Carbohydrate Hydroxy Groups
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Table 1. pKa values of the aminosugars.[a]
Table 1. (Continued)
Entry
Entry
Aminosugar
pKa
Aminosugar
pKa
1
7.5[32]
19
7.7
7.3
9.0
2
3
4
7.8[32]
20
21
22
7.4
9.0
6.8
7.4
8.8
8.9[32]
7.7[51][b]
8.1[52][c]
23
24
5
6
7
7.2[32]
7.6[32]
6.7
7.3[51][b]
7.9[52][c]
25
26
8.5[52][c]
8.1[52][c]
8
8.6
7.9
8.0
7.3
8.9
27
28
29
7.8[52][c]
9
8.4[52][c]
10
11
12
13.7[52][d]
30
31
32
13.2[52][d]
11.8[52][d]
11.6[52][d]
13
14
15
16
17
7.2
[a] References to the structures refer to the literature synthesis/data, ref-
erences to the pKa values refer to literature values. [b] Estimated values.
[c] Obtained from NMR studies; deuterium effects apply. [d] Estimated
from NMR studies in D2O.
8.1[32]
7.2
has been previously studied in a-mannosides, in which it
was found by calculation that the 3-OH is more nucleophilic
than the 2-OH, which was also confirmed by experimental
data.[41] As expected from knowledge of carbohydrate
chemistry, the 4-position is the least basic and therefore the
least nucleophilic in electronic terms. The lower electron
density at the 4-position results from the fixed antiperipla-
9.0
7.8
À
À
18
7.8
nar relationship between the C4 OH (here C4 NH2) and
À
C5 O5 bonds, which maximize the electron-withdrawing ca-
pacity of the O1 atom.[20a,21a] The electron-withdrawing ca-
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C. M. Pedersen, M. Bols et al.
À
pacity of the C5 O1 bond has been noted to play a role in
tween the hydrogen-bond donor and acceptor is geometri-
cally impossible, the effect would be minimal. When dis-
solved in water it would be expected that all the amino and
hydroxy groups in the compounds are mainly hydrogen-
bonded to water molecules thereby further diminishing the
effects of internal hydrogen bonds.
protective group manipulations; Crich and Vinogradova ob-
served that 4-O-benzyl groups were more easily oxidatively
removed with DDQ under wet conditions than other benzyl
groups in perbenzylated mannosides. This was explained by
accelerated decomposition of the radical cation caused by
the above-mentioned effect.[42]
Analysis of the three diaminosugars (entries 20–22) and
comparison with the corresponding monoaminosugars, with
an amino group at the 3- or 6-position, shows there is no
change in the pKa of the 6-amino group. The 3-amino group
is more affected by the presence of a 6-ammonium group
(more EWD) and it is more difficult to protonate the
second amine, hence a lower pKa. The pKa is lowered by 0.3
pKa units for the altro and 0.7 pKa units for the manno. The
gluco isomer is in between with a difference of 0.5 pKa
units. This lowering can be explained by the field effect (+
I) of the 6-ammonium group and the fact that it is more
electron-withdrawing than the amine, which makes the 3-
amino groups more acidic. Hence, there is a smaller effect
on the altro because the amino is more distant from the am-
monium group.
In general, when there are axial hydroxy groups on the
sugar ring an increase in the pKa of the given ammonium
ion is observed. This can be explained by the dipole–dipole
interactions between a substituent and the sugar ring. When
the substituent, in this case a hydroxy group, is axial it is
perpendicular to the ring and the vector of the dipole
moment is relatively small and its electron-withdrawing ca-
pacity is minimized as well as the ring effects on the sub-
stituent (Scheme 5). When there is an equatorial substituent
the dipole moment is in almost the same plane as the ring
giving a relatively large dipole vector and hence a larger
effect on the other substituents as well as the other way
around.
By comparing the a-glucosides (Table 1, entries 1–4) with
the b-glucosides (entries 5–8), the influence of the anomeric
configuration on the electron density at different positions
can be observed. The differences in pKa values show that an
axial O-methyl group gives more basic amines at the 2- and
3-positions (0.2 to 0.3 pKa units; entries 1–8); the effect at
the 4-position is somewhat lower (ca. 0.1 pKa). The pKa of
the 6-OH group is surprisingly 0.3 units lower for the b
anomer. From these results it seems that a-glucosides
should be slightly more reactive at the 2- and 3-positions
compared with the b-glucosides. Looking at the a-manno-
sides (Table 1, entries 13–16) and a-galactosides (entries 9–
12) and comparing them with the a-glucosides (entries 1–4)
a general trend can be seen: When the amine has a neigh-
boring axial hydroxy group (see entries 2 and 10) the pKa in-
creases by about 0.2 pKa units. This effect is further in-
creased when comparing the 3-amino-mannosides and glu-
cosides (entries 2 and 14) for which the difference in pKa is
almost 0.3 units. Regarding the differences in the basicity of
the epimeric amines (entries 3 and 11, 1 and 13, 21 and 22,
17 and 18) it is difficult to find a trend. At the 2-position the
difference is about 0.3 pKa units (entries 1 and 13), with the
equatorial being the most basic. This can again be explained
by the antiperiplanar relation between the axial amino
group and the axial OMe, which is more electron-withdraw-
ing than the ring oxygen because it is antiperiplanar to the
equatorial amino group. At the 4-position (entries 3 and 11)
the difference is about 0.5 pKa units with the axial amine
being the most basic. This can again be explained by the O5
antiperiplanar to the equatorial amine (entry 3) drawing
electron density away from the 4-position; this can only
happen to a much smaller extent with the axial epimer
(entry 11) due to the geometry. The lower reactivity of the
axial 4-OH in acylation and glycosylation reactions seems to
be mainly influenced by steric effects and not to an intrinsi-
cally higher reactivity of the equatorial counterpart. At the
3-position (entries 14 and 19) there is a difference of about
0.5 pKa units when looking at the manno and altro epimer
pair. The effect is amplified by having the neighboring
group axial, which lowers the pKa of the axial epimer signifi-
cantly. This is in contrast to the 3,6-diamino derivatives (en-
tries 21 and 22) for which the pKa values are essentially the
same for the manno and altro derivatives.
Scheme 5. Difference in the dipole moment vector between an equatorial
(galacto) and an axial (gluco) hydroxy group.
The pKa (H and D) values of the reducing sugars glucosa-
mine, galactosamine, and mannosamine have previously
been measured by various methods in which the mutarota-
tion has been taken into account. When comparing the dif-
ferences in the pKa values between the a- and b-2-amino-2-
deoxyglucopyranosides the same trend as with the methyl
glucosides is observed; the axial epimer is 0.2–0.4 units (de-
pending on the method) more basic than the equatorial
counterpart (entries 23 and 24). The same was observed
with the methyl glucosides and therefore it is appropriate to
compare the reducing sugars with the methyl glycosides in
this study. There is a difference of 0.5 pKa units between the
epimers of 2-amino-2-deoxy-galactosamine, again with the a
epimer being the most basic (8.1 vs. 8.5). The higher values
for the galactosamines are in line with more axial hydroxy
Conformational change is probably also the explanation
for the similar pKa values obtained for the 3-amino-pentoses
(entries 17 and 18). Internal hydrogen bonding might be
possible in the methyl 3-amino-a-glycosides, but because
this would stabilize an ammonium ion further and therefore
increase the pKa of the axial amines, this is probably not a
significant contribution. Because a linear relationship be-
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Electronic Effects of Carbohydrate Hydroxy Groups
FULL PAPER
groups on the sugar ring, as seen with previous model com-
pounds. A comparison with the anomers of mannosamine
shows that the a anomer is less basic than the b anomer,
with a difference of 0.6 units. This is in contrast to the glu-
cosamine and galactosamine described above, for which the
b anomers are the most acidic. This again illustrates the
strong effect of an anti-periplanar hydroxy group, which in
all cases have been shown to significantly lower the pKa
value and in this case over-rule the effect of an additional
equatorial substituent.
The 4-amino group is always the least basic and there-
fore the 4-OH sugar analogue the least nucleophilic. This
is even more pronounced in the gluco configuration,
which is known to be less reactive.
3) The 6-amino group is always the most basic and hence
the 6-OH sugar is the most nucleophilic. Therefore the
6-OH is the most reactive from the viewpoints of both
stereoelectronic effects and steric accessibility.
4) The 3-position is always more basic than the 2-position,
and so from a stereoelectronic point of view the 3-posi-
tion is more reactive than the 2-position. This can again
be explained by the antiperiplanar relationship between
the 2-OH and either the ring oxygen (galacto and gluco)
or the a-O-methyl (manno), and the effect is more sig-
nificant for manno stereochemistry. In carbohydrate
chemistry the 2-position is sometimes found to be more
reactive than the 3-position, but this is due to steric ef-
fects.
In entries 29–32 of Table 1 the pKa (D)[52] values of the
anomeric hydroxy group are listed. The values are estimates
from NMR studies, but the tendency for equatorial hydroxy
groups to be more acidic than the axial counterpart is con-
firmed. When in an equatorial position the EWD capacity
of the sugar ring with its electronegative substituents is
maximized. The dipole of the equatorial hydroxy group lies
in the same plane as the ring and the effect is therefore
maximized. An axial hydroxy group is almost perpendicular
to the plane of the sugar ring and only experiences a damp-
ened effect of the EWD capacity of the remaining hydroxy
groups on the ring. This is just one more example, but it has
to be underlined that the anomeric hydroxy group is special
compared with the amino-deoxy-sugars in this study and a
direct comparison is not appropriate. The difference be-
tween the pKa (D) values obtained for glucose and glucosa-
mine might arise from hydration[53]/solvation effects or dif-
ferent interactions with the counterion, respectively.
Experimental Section
For details regarding the synthetic and analytical procedures see the Sup-
porting Information.
Acknowledgements
We thank Dr. Steffen Jacobsen for providing model compounds and the
Lundbeck Foundation and the Danish Agency for Science, Technology
and Innovation for financial support.
Conclusion
pKa values have been obtained for 32 sugars representing
the most common sugar configurations. The pKa values give
information about the charge density at substituted positions
and hence provide a measure of the stereoelectronic influ-
ence of the sugar ring at the given positions. Some general
trends have been observed that enable the nucleophilicity to
be predicted.
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À
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Received: January 4, 2011
Published online: May 3, 2011
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Chem. Eur. J. 2011, 17, 7080 – 7086