Intramolecular Cannizzaro desymmetrization of tetraethylene glycol assisted by a cation binding template

Article abstract of DOI:10.1016/j.tetlet.2004.11.093

The synthesis of desymmetrized tetraethylene glycol possessing a benzyl alcohol and a benzoic acid end group via a Cannizzaro reaction is reported. The barium cation template used was found to be essential for a successful transformation.

Full text of DOI:10.1016/j.tetlet.2004.11.093

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1575–1577
Intramolecular Cannizzaro desymmetrization of
tetraethylene glycol assisted by a cation binding template
Yolanda Vida, Ezequiel Perez-Inestrosa* and Rafael Suau
Department of Organic Chemistry, Faculty of Sciences, University of Malaga, 29071 Malaga, Spain
Received 22 October 2004;revised 12 November 2004;accepted 16 November 2004
Dedicated to Professor Henri Bouas-Laurent
Abstract—The synthesis of desymmetrized tetraethylene glycol possessing a benzyl alcohol and a benzoic acid end group via a Can-
nizzaro reaction is reported. The barium cation template used was found to be essential for a successful transformation.
Ó 2004 Elsevier Ltd. All rights reserved.
Desymmetrization of macromolecules is an effective
method for the preparation of functional nanoparticles
for a variety of potential applications.1 The development
of efficient routes for the directed stepwise synthesis of
desymmetrized functional oligoethylene glycols (OEGÕs)
continues to be a major challenge in organic chemistry.
Derivatization with a stoichiometric equivalent of a pro-
tecting group reagent generally yields a statistical pro-
portion of the monosubstituted product in addition to
unreacted and disubstituted starting material. Reported
examples provide moderate yields of up to 50%.2 Disub-
stitution can be avoided by using a vast excess of glycol
relative to the reagent. This can be accomplished by
using inexpensive, easily removed starting materials
such as ethylene glycols of up to four units.3
mesylate derivative usually involves a time-consuming
column chromatography procedure. Recently, this
shortcoming has been circumvented by using a straight-
forward method with orthogonal end-functionalized
OEG that yields a mono-N-protected diamino OEG di-
rectly in fewer steps.5 OEGÕs are converted to bisazides
via bismesyl derivatives, and the crucial monoreduction
is accomplished by reacting the bisazide in a bilayer sys-
tem (PPh3, EtOAc/1 M HCl). Monoreduction of one of
the azide groups is followed by rapid protonation;the
water-soluble polar OEG-monoamine derivative mi-
grates to the water layer and further reduction is thus
hindered. However, purification of the compound in-
volves passing the aqueous layer thorough a C-18 solid
phase extraction column, which provides a 65% yield.
A synthetic route for preparing OEG-terminated alkan-
ethiol-amides was recently developed4 that starts with
the monomesylation of the OEG, followed by conver-
tion into the corresponding monoazides and reduction
of the azide function to the amine function by catalytic
hydrogenolysis on Pd/C. The conversion of one of the
hydroxyl groups in the OEG to the monomesylate deriv-
ative proved inefficient owing of the concomitant gener-
ation of the bismesylate product and small amounts of
unprotected starting material. Separating the mono-
The synthesis and characterization of multivalent recep-
tors for the binding of metal ions was recently reported
by the authors.6 One of the prerequisites for developing
an effective synthetic approach here is the availability of
practical methods for variably end-substituted tetraeth-
ylene glycol (TEG). Our primary interest was to obtain
TEGÕs end-substituted with aromatic groups with a view
to preparing chromophoric ditopic receptors.
The synthesis of compound 1, the reference system for
the ditopic receptors reported,6 provided crystals suit-
able for X-ray structure analysis of their Ba2+ ꢀ 1 com-
plex.6a,c Although the barium cation is Ôwrapped upÕ by
the TEG chain in a hexagonal fashion, both aromatic-
end groups point in the same direction—but are not
parallel.
Keywords: Tetraethylene glycol;Desymmetrization;Cannizzaro reac-
tion;Barium template.
*
Corresponding author. Tel.: +34 952 13 7565;fax: +34 952 13
1941;e-mail: inestrosa@uma.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.093

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Y. Vida et al. / Tetrahedron Letters 46 (2005) 1575–1577
This led us into believing that dismutation (dispropor-
tionation) of appropriate functional groups (e.g., the
aromatic-end groups of a symmetric podand such as 1)
might provide a method for controlled desymmetriza-
tion of skeletal remote positions that can be induced
to adopt confined spatial vicinity by use of appropriate
templates.
We chose the Cannizzaro reaction for disproportionat-
ing desymmetrization as in its simplest form, it involves
the reaction of aromatic aldehydes (viz. aldehydes with
no a-hydrogen in general) to form RCH2OH and
RCO2H as major products.7 The synthetic approach
adopted starts from commercially available TEG and
is shown in Scheme 1. Briefly, TEG is converted to the
bistosyl derivative in 90% yield, using phase transfer
catalysis.8 Conversion of the bistosyl derivative to the
bis-aryloxyaldehyde 2,9 in 96% yield, is achieved by
reacting it with the sodium salt of 4-hydroxy benzalde-
hyde (4-HBA) in acetonitrile at reflux. Although com-
prehensive studies on the influence of [HOÀ] and
nature of the cation are discussed later on the decisive
desymmetrization reaction was best accomplished by
reacting a 0.15 M solution of 2 with 1.5 M Ba(OH)2 in
boiling water for 22 h. Subsequent neutralization with
5% HCl to protonate the carboxyl group and extraction
with CH2Cl2 gave 3 in almost quantitative yield.
Figure 1. (a) Yields of the intramolecular Cannizzaro reaction of 2 to
the desymmetrized 3 using Ba(OH)2, NaOH and KOH as hydroxylic
bases at different [HOÀ]. (b) Increase in yields of the desymmetrization
reaction resulting from the presence of a final [Ba2+] of 1.5 M for 0.5 M
Ba(OH)2, 3 M NaOH and 6 M KOH.
[NaOH] = 3 M, where the reaction does not occur and
only the starting material is quantitatively recovered
(Fig. 1a), the addition of BaCl2 at a final concentration
of 1.5 M increases the yield to 84%. The reaction can
also be made quantitative by using a medium consisting
of 1.5 M BaCl2 and 6 M KOH. On the other hand, the
reaction is completely inhibited in the absence of Ba2+
(Fig. 1a).
Figure 1 illustrates the crucial role of the complexing
cation. As can be seen in Figure 1a, using a Ba(OH)2
concentration of 1.5 N ([HOÀ] = 3 mol/L) or higher
ensured quantitative yield in the intramolecular
Cannizzaro desymmetrization reaction;also, lower
concentrations (0.5 M Ba(OH)2;[HO À] = 1 mol/L) sig-
nificantly decreased the reaction yield. However, this ef-
fect is appreciably displayed when the reaction is carried
out with NaOH or KOH. Thus, quantitative transfor-
mation was only accomplished at a 12 M NaOH concen-
tration, the yield decreasing to 84% at 6 M and the
starting material being quantitatively recovered at lower
NaOH concentrations. With KOH as the base, the yield
barely reached 63%, even at such a high concentration
as 12 M.
Therefore, the template provided by Ba2+, which is per-
fectly bound by the TEG chain, allows the two aldehyde
groups to be placed in a mutual spatial vicinity as re-
flected in the X-ray structure of the related compound
1.6c This preferred conformation of the complex is even
more crucial than the hydroxide concentration for effec-
tive hydride transfer in the Cannizzaro reaction. Thus,
at [HOÀ] = 6 mol/L (Fig. 1a) in the presence of Ba2+
the reaction is quantitative;on the other hand, in
,
the presence of Na+ and K+ the yield is 87% and zero,
respectively. At the same [HOÀ] as provided for KOH,
the yield is clearly increased by the presence of Ba2+
(Fig. 1b). The reaction is efficient at lowers [HOÀ];
although 3 M NaOH is inadequate for this purpose,
the presence of 1.5 M BaCl2 increases the yield to
84%. This reflects the ability of TEG to coordinate this
As can be seen from Figure 1b, the ability of the ethyl-
ene chain to bind the cation decisively influences the
course of the Cannizzaro reaction. The reaction yield
obtained with 0.5 M Ba(OH)2 ([HOÀ] = 1 mol/L), 22%
(Fig. 1a), can be raised to 33% simply by adding BaCl2
to a [Ba2+] concentration of 1.5 M. Significantly, at
Scheme 1. Reagents and conditions: (a) TsCl, CH2Cl2, 30% NaOH, TEBA;(b) 4-HBA, NaOH, CH 3CN, 85 °C;(c) i. alkaline or alkaline earth
hydroxide, H2O, 100 °C;ii. 5% HCl.

Y. Vida et al. / Tetrahedron Letters 46 (2005) 1575–1577
1577
cation and its efficiency in bringing the two aldehyde
groups closes in the hydride transfer step.
References and notes
1. Grimsdale, A. C.;Baure, R.;Weil, T.;Tchebotareva, N.;
Wu, J.;Watson, M.;Mullen, K. Synthesis 2002, 1229–
1238.
2. (a) Bertozzi, C. R.;Bednarski, M. D. J. Org. Chem. 1991,
56, 4326–4329;(b) Lebeau, L.;Oudet, P.;Mioskowski, C.
Helv. Chem. Acta 1991, 74, 1697–1706;(c) Housemann, B.
However, the slightly increased yield obtained by adding
BaCl2 to a [HOÀ] = 1 mol/L solution containing 2 (Fig.
1b) suggests that this [HOÀ] is inadequate for the
Cannizzaro reaction to occur, even with the favourable
spatial vicinity promoted by barium complexation.
T.;Mrksich, M.
7555.
J. Org. Chem. 1998, 63, 7552–
Interestingly, no dialcohol—this compound was previ-
ously prepared by the authors, see Ref. 6c—or diacid
resulting from an intermolecular process was formed un-
der the conditions studied in this work. Only compound
3 (intramolecular process) or the starting material was
detected.
3. (a) Keegstra, E. M.;Zwikker, J. M.;Roest, M. R.;
Jenneskens, L. W. J. Org. Chem. 1992, 57, 6678–6680;(b)
Chen, Y.;Baker, G. L. J. Org. Chem. 1999, 64, 6870–
6873.
4. (a) Valiokas, R.;Svedhem, S.;Svensson, S. C. T.;
Liedberg, B. Langmuir 1999, 15, 3390–3394;(b) Svedhem,
S.;Hollander, C.-A.;Shi, J.;Kondradsson, P.;Liedberg,
B.;Svensson, S. C. T. J. Org. Chem. 2001, 66, 4494–4503.
5. Iyer, S. S.;Anderson, A. S.;Reed, S.;Swanson, B.;
Schmidt, J. G. Tetrahedron Lett. 2004, 45, 4285–4288.
6. (a) Desvergne, J.-P.;Bouas-Laurent, H.;Perez-Inestrosa,
E.;Marsau, P.;Cotrait, M. Coord. Chem. Rev. 1999, 185–
186, 357–371;(b) Desvergne, J.-P.;Perez-Inestrosa, E.;
Bouas-Laurent, H.;Jonosauskas, G.;Oberle, J.;Rulliere,
C. New Trends in Fluorescence Spectroscopy. Applica-
tions to Chemical and Life Sciences. In Phototunable
Metal Cation Binding Ability of some Fluorescent Macro-
cyclic Ditopic Receptors;Valeur, B., Brochon, J.-C., Eds.;
Springer: London, 2001, pp 157–169;(c) Perez-Inestrosa,
E.;Desvergne, J.-P.;Bouas-Laurent, H.;Rayez, J.-C.;
Rayez, M.-T.;Cotrait, M.;Marsau, P. Eur. J. Org. Chem.
2002, 331–344.
The mechanism of the Cannizzaro reaction involves a
hydride shift. First HOÀ adds to the C@O group to give
a tetrahedral, tetravalent oxy-anion intermediate that
can release a proton to the alkaline solution and give a
gem-di(oxy-anion).10 The strong electron-releasing char-
acter of OÀ is believed to greatly enhance the ability of
the aldehyde hydrogen to leave with its electron pair.
This effect is obviously stronger in the di(oxy-anion).
When the hydride does leave, it attacks another alde-
hyde molecule. However, the spatial vicinity of the sec-
ond aldehyde group appears decisive for the reaction.
Although the two oxy-anions directly attached to the
carbon atom increase the nucleofugal character of the
hydride, only when the second electrophilic aldehyde
group cooperates to enhance the nucleofugacity of the
hydride does the disproportionation occur. Its location
and distance from the site of nucleofugal reactivity are
critical. With complexed barium cation, the optimum
situation is a vicinal arrangement of the skeletal remote
atoms involved.11 Beyond these limits, the yield of the
Cannizzaro reaction gradually decreases, or the reaction
is inhibited, with increasing distance. The enhancement
of the nucleofugal character of the hydride is crucial
as the reaction fails at some [HOÀ] in a sodium or potas-
sium environment unless barium is present. On the other
hand, barium complexation makes the reaction possible
at [HOÀ] too low to be efficient in its absence. Other
hydroxides such as those of lithium and magnesium only
provided the starting material, even at [HOÀ] as high as
12 M.
7. For a recent study on the mechanism of the Cannizzaro
disproportionation reaction of benzaldehyde and pivalde-
hyde using ion cyclotron resonance, conventional reverse
sector mass spectrometry and ab initio calculations, see:
Sheldon, J. C.;Bowie, J. H.;Dua, S.;Smith, J. D.;O ÕHair,
R. A. J. Org. Chem. 1997, 62, 3931–3937.
8. Stibor, I.;Koian, O.;Holy, P.;Zavada, J. Collect. Czech.
Chem. Commun. 1987, 52, 2057–2060.
9. All compounds gave satisfactory spectral data. Selected
spectral data for compounds 2 and 3 are given below.
Compound 2: mp 49–51 °C. 1H NMR (200 MHz, CDCl3):
d 3.68 (m, 8H), 3.85 (m, 4H), 4.17 (m, 4H), 6.98 (d, 4H,
J = 8.8 Hz), 7.79 (d, 4H, J = 8.8 Hz), 9.84 (s, 2H). 13C
NMR (50 MHz, CDCl3): d 67.7, 69.4, 70.6, 70.8, 114.8,
130.0, 131.9, 163.7, 190.7. EI-MS m/z (%): 402 (M+, 2),
149 (57), 121 (84), 77 (100), 65 (58). HRMS m/z calcd for
C22H26O7 (M+) 402.1679, found 402.1690. Compound 3:
mp 76–78 °C. 1H NMR (200 MHz, CDCl3): d 3.69 (m,
8H), 3.84 (m, 4H), 4.09 (m, 2H), 4.16 (m, 2H), 4.58 (s, 2H),
6.88 (m, 4H), 7.24 (m, 2H), 7.98 (d, 2H, J = 9 Hz). 13C
NMR (50 MHz, CDCl3): d 64.9, 67.4, 67.6, 69.5, 69.7,
70.6, 70.8, 114.2, 114.6, 121.8, 128.6, 132.2, 133.2, 158.3,
163.1, 170.8. EI-MS m/z (%): 420 (M+, 10), 165 (70), 121
(100), 107 (50), 91 (50), 89 (90), 77 (90). HRMS m/z calcd
for C22H28O8 (M+) 420.1784, found 420.1780.
In conclusion, the proposed method is a simple, effective
choice for the synthesis of desymmetrized diaryl-TEG,
that avoids several protection–deprotection steps and te-
dious work-up while providing quantitative yields that
facilitate isolation of the pure desired product. Experi-
ments aimed at examining the effect of the OEG chain
length on the binding efficiency of various cations that
exploit the template effect in the desymmetrization pro-
cess are currently underway and will be reported in the
near future.
10. Doubly deprotonated ions of gem-diols have been
described as ligands in cobalt (II) clusters. Their formation
can be accomplished by simply using a 4:1 ratio of
MeCO2À, see: Tsohos, A.;Dionyssopoulou, S.;Rapto-
poulou, C. P.;Terzis, A.;Bakalbassis, E. G.;Perlepes,
S. P. Angew. Chem., Int. Ed. 1999, 38, 983–985.
11. Desymmetrization of compound 2 has also been run under
the reaction conditions described in the text in the
presence of anisaldehyde and no cross-over product has
been detected, proving evidence that the Ba2+ ions haven
only templating effect;this insight was provided by a
referee.
Acknowledgements
This work was supported by the Spanish DGES
(BQU2001-1890).