Cation template assisted oligoethylene glycol desymmetrization by intramolecular Cannizzaro reaction of topologically remote aldehydes

Article abstract of DOI:10.1016/j.tet.2008.10.015

Oligoethylene glycol chains containing 2-5 ethylene glycol units, and possessing a benzyl alcohol and a benzoic acid end groups, can be quantitatively obtained by intramolecular Cannizzaro reaction of the corresponding remote benzaldehyde end groups. The process is quite effective if a complex with an appropriate cation is formed to allow the two aldehyde groups to be spatially confined near enough each other for the intramolecular redox process.

Full text of DOI:10.1016/j.tet.2008.10.015

Tetrahedron 64 (2008) 11661–11665
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cation template assisted oligoethylene glycol desymmetrization by
intramolecular Cannizzaro reaction of topologically remote aldehydes
*
Antonio J. Ruiz-Sanchez, Yolanda Vida, Rafael Suau, Ezequiel Perez-Inestrosa
Department of Organic Chemistry, Faculty of Sciences, University of Malaga, 29071 Malaga, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2008
Received in revised form 3 October 2008
Accepted 8 October 2008
Available online 14 October 2008
Oligoethylene glycol chains containing 2–5 ethylene glycol units, and possessing a benzyl alcohol and
a benzoic acid end groups, can be quantitatively obtained by intramolecular Cannizzaro reaction of the
corresponding remote benzaldehyde end groups. The process is quite effective if a complex with an
appropriate cation is formed to allow the two aldehyde groups to be spatially confined near enough each
other for the intramolecular redox process.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Luis Castedo on the
occasion of his 70th birthday
Keywords:
Oligoethylene glycol desymmetrization
Cannizzaro reaction
Cation template
1. Introduction
Desymmetrizing symmetric compounds involves altering them
in such a way as to suppress one or more elements of symmetry of
The development of supramolecular chemistry and, more
recently, nanochemistry and nanotechnology, has relied on the
design of effective chemical tools with a view to connecting
chemical subunits in order to construct more complex and exten-
sively developed superstructures; the ability to connect units lying
at well-defined distances can help develop useful devices.1
Immobilizing (bio)chemical substrates onto solid surfaces and
controlled skeletal growth of chemical architecture for the con-
struction of, for example, (bio)sensors, require the use of accurately
defined spaces.2
A number of chemical species have been tested as potential
spacers. Oligoethylene glycols (OEGs) are especially attractive for
this purpose by virtue of their unusual, frequently amphiphilic
properties in solution, which have promoted their widespread use
in this context. The ability to prepare OEG chains of a specific length
possessing a high chemical flexibility, thanks to their bearing two
different functional groups at the ends of the chain, is a major
current challenge for organic chemists and a growing demand of
the scientific community.3 Meeting such a demand will require
developing effective chemical methodologies to desymmetrize
specific OEG derivative chains.
their structures. Some chemical4 and biological methods5 have al-
ready proved effective for this purpose and raised the demand for
new desymmetrizing technologies for use in large-scale industrial
processes.
The pharmaceutical sector has made great efforts at developing
chemical methodologies and transformation procedures for
desymmetrizing pairs of equivalent chemical groups in compounds
such as diols and diamines, among others.6 For structural reasons,
however, the end groups in these molecules usually lie at relatively
close positions precluding far-reaching conformational rearrange-
ment. As a result, large polymeric (oligomeric) materials, where the
equivalent groups are normally located at the two ends of the
macromolecule, require using special methodologies for desym-
metrizing their topologically remote functional groups.
Derivatization with one stoichiometric equivalent of a protect-
ing-group reagent generally yields a statistical proportion of the
monosubstituted product in addition to disubstituted and unreac-
ted starting material, thereby requiring tedious purification and
detracting from products’ yields.7–9
The intrinsic nature of the Cannizzaro reaction makes it the ideal
candidate for desymmetrizing nonenolizable dialdehydes via an
intramolecular process. We have conducted basic and applied re-
search into this process10 with a view to developing a standardized
procedure for application to various OEG derivatives as a general
method for desymmetrizing these oligomeric materials. Previously,
* Corresponding author. Tel.: þ34 952 13 7565; fax: þ34 952 13 1941.
E-mail address: inestrosa@uma.es (E. Perez-Inestrosa).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.015

11662
A.J. Ruiz-Sanchez et al. / Tetrahedron 64 (2008) 11661–11665
we converted the tetraethylene glycol (TEG) chain in its dialdehyde
derivative and found the intramolecular Cannizzaro reaction to be
readily accomplished and provide a simple, effective method for
preparing desymmetrized diaryl-TEG. It avoids the need for several
protection–deprotection reactions and tedious workup while pro-
viding quantitative yields that facilitate isolation of the desired
product in pure form (Scheme 1).
of the corresponding ditosylate derivatives with 4-hydroxy benz-
aldehyde (4-HBA) in an alkaline medium gave the corresponding
OEG, functionalized with the nonenolizable benzaldehyde moiety
amenable to Cannizzaro reaction at the ends of their respective
chains. This condensation reaction was achieved in yields exceeding
90% in all cases.
The triethylene and pentaethylene glycol derivatives 4 and 5
were quantitatively desymmetrized to the corresponding 1-benzyl
alcohol, and
u-benzoic acid derivatives 6 and 7, respectively
CH2OH
(Scheme 3). The reaction was accomplished by refluxing a 0.15 M
aqueous solution of the starting dialdehydes containing 1 M
Ba(OH)2 for 24 h. Following neutralization and extraction with or-
ganic solvents, the desymmetrized products were isolated in
quantitative yields and pure enough for use in subsequent reactions.
CHO
O
HO2C
O
O
O
O
O
CHO
O
O
O
O
1
2
CHO
O
CH2OH
O
Mn+
Mn+
CH2OH
CHO
O
CHO
CO2H
Base
H2O /
Intramolecular
Cannizzaro
reaction
O
O
O
O
O
O
O
Mn+
O
Mn+
n
O
n
O
Base: Ba(OH)2 for 4 and 5
LiOH for 3
O
O
O
Mn+
1
Mn+
2
Scheme 1. Schematic depiction of the proposed desymmetrization strategy.
CHO
CO2H
This paper reports the experiments we used to examine the
effect of the OEG chain length on the binding efficiency of various
cations with a template effect on the desymmetrization process
with a view to standardizing the proposed approach as a general
method for obtaining desymmetrized di-, tri-, tetra-, and penta-
ethylene glycol chain derivatives (DEG, TrEG, TEG and PEG,
respectively) as a set of scalable, orthogonally ended functionalized
spacers. In addition, we examined the influence of ortho and meta
substituents in the aromatic aldehydes.
n = 1; 3
2; 4
8
6
4; 5
7
Scheme 3. Desymmetrization of OEG-dialdehydes by intramolecular Cannizzaro
reaction.
The templated influence of the cation was clearly confirmed by
the results shown in Tables 1 and 2. With the triethyleneglycol 4,
a 2 M solution of the alkaline hydroxides of Table 1 provided poor
yields of the corresponding desymmetrized product, 6dthe differ-
ence in yield was always recovered as starting materiald, which
exhibited a marked decrease in yield with increasing cation radius
from Liþ to Kþ. Increasing the concentration of the bases to 4 M
raised the cation concentration capable of displacing the association
equilibrium in order to increase the concentration of complexed
species triggering the intramolecular Cannizzaro reaction. With
compound 5, the 2 M solutions of the previous alkaline hydroxides
exposed the increased complexing ability of sodium cation relative
to lithium and potassium. However, raising the cation concentration
to 4 M provided an increased yield of the desymmetrized product 7
as a result of the complexing equilibrium being displaced to the
complexed formdmainly with potassium as cation. However, the
lithiumcomplexof this pentaethylenederivative musthaveretained
2. Results and discussion
Our primary goal was to extend the ability of alkaline and/or al-
kaline-earth cation metals to facilitate the spatial rearrangement of
remote benzene-carbaldehyde groups in such a way that the Can-
nizzaro reaction would operate preferentially in an intramolecular
manner. We found barium cation to arrange a tetraethylene glycol
chain end decorated with benzene-carbaldehyde 1 optimally in
space for the Cannizzaro reaction to occur exclusively via its intra-
molecular pathway (Scheme 1).10 With this in mind, we prepared
a series of related oligoethylene glycols including diethylene glycol
3, triethyleneglycol 4 and pentaethylene glycol 5 with two benzene-
carbaldehyde groups at their chain ends (Scheme 2). Condensation
O
TsO
OTs
n
Table 1
Yields (%) of desymmetrized compounds 6 (from dialdehyde 4) and 7 (from dia-
ldehyde 5) as a function of the alkaline base used in the intramolecular Cannizzaro
reaction
n = 1
Compound = 3
4
CHO
2
4
5
Starting
dialdehyde
Concentration
of base (M)
Base
LiOH
OH
NaOH
KOH
O
4
5
2
4
2
4
32
92
33
45
31
89
88
92
17
89
33
90
OHC
O
O
CHO
n
Scheme 2. Synthesis of the starting dialdehydes from the corresponding oligoethylene
ditosylates.

A.J. Ruiz-Sanchez et al. / Tetrahedron 64 (2008) 11661–11665
11663
Table 2
R2
R3
R4
Influence of the nature of the cation (added as a chloride salt), and its concentration,
on the yield (%) of desymmetrized compound 6 as obtained by pouring dialdehyde 4
(0.15 M) over an aqueous 2 M solution of LiOH
R1
O
O
Salt
Added
Concentration
(M)
Yield (%) of
compound 6
Ba(OH)2
H2O /
O
O
LiCl
4
6
8
1
76
83
88
3
3
O
O
BaCl2
Quantitative
R1
R2
R5
R6
a high degree of freedom, so the required arrangement of the alde-
hyde groups for intramolecular Cannizzaro reaction was not as
stable as in the other complexes and the yield was lower as a result.
That the well-complexed forms of the starting dialdehydes were
responsible for the high yields obtained in the intramolecular
Cannizzaro desymmetrization was confirmed by the data of Table 2.
As stated above, a 2 M solution of LiOH provided a yield of only 32%
in the conversion of dialdehyde 4 into the desymmetrized product
6 (Table 1). However, adjusting the final concentration of lithium
cation in this solution to 4 M by addition of LiCl raised the yield of 6
from 32 to 76%. Higher concentrations of lithium such as 6 or 8 M
further increased the reaction yields up to 88%. Also, simply
adjusting the barium cation concentration to 1 M with BaCl2 in
a 2 M LiOH solution raised the desymmetrization yield from 32%
(Table 1) to a quantitative value (Table 2).
The compound with the shortest ethylene glycol chain, 3, can
also undergo intramolecular desymmetrization by Cannizzaro re-
action to give 8. However, the difficulty of dissolving the starting
dialdehyde 3 in water compelled us to use a higher dilution. All
desymmetrization attempts performed with a 0.15 M concentra-
tion of 3 resulted in the recovery of unreacted starting material.
Compound 3 was quite insoluble in pure water; also, the water–
ethanol and water–tetrahydrofuran mixtures assayed were useless
to obtain the desymmetrized derivative with the alkaline (sodium
and lithium) and alkaline-earth metals (barium) used. Only after
treating the resulting slurry of 3 at a 0.15 M concentration with an
extremely concentrated (6 M) aqueous solution of LiOH the
desymmetrized product 8 was isolated, in a 42% yield, following
tedious workup (8% of unreacted 3 was also recovered). This in-
dicates that, if LiD33 is forced to be present, then it will be
properly arranged for intramolecular Cannizzaro reaction. In fact,
more dilute (0.005 M) 3 in 6 M aqueous LiOH provided a 85% yield
of the desymmetrized product 8.
9: R1=CHO; R2=H
10: R1=H; R2=CHO
11: R3=R6=H; R4=CH2OH; R5=CO2H
12: R3=CH2OH; R4=R5=H; R6=CO2H
Scheme 5. Desymmetrization of the tetraethylene glycols 9 (ortho) and 10 (meta) by
intramolecular Cannizzaro reaction.
oligoethylene chain in order to assess the outcome of the intra-
molecular Cannizzaro reaction. To this end, we synthesized the
two isomers of the para-tetraethylene glycol 1 with an ortho-9 or
meta-10 arrangement on the aromatic ring, and reacted them
under the same conditions as in the intramolecular Cannizzaro
reaction of 1. Similar to 1, a quantitative yield of the desymme-
trized derivatives 11 and 12, respectively, was obtained for the two
isomers (Scheme 5). The more relaxed opposite conformation of
the complexed products 11 and 12 was comparatively less favor-
able for intramolecular Cannizzaro reaction than the more
congested parallel conformations. However, the concurrence of
the complexes 9 and 10 decisively facilitated intramolecular Can-
nizzaro reaction.
Neither dialcohol or diacid resulting from an intermolecular
process was detected under the conditions studied in this and
previous works.10 Only desymmetrized compounds and starting
material was detected. With complexed cations, the optimum sit-
uation is a vicinal arrangement of the skeletal remote atoms
involved. Experiments in presence of, for example, anisaldehyde
were carried out and no cross-over product has been detected,
providing that cations has only template effects.10
3. Conclusions
In summary, we found that a scalable collection of oligo-
ethylene glycol chains ranging from di- to pentaethylene glycol,
which possess two different, orthogonally functional groups at
their chain ends, can be directly synthesized and obtained with
no tedious workup simply by treating their corresponding aro-
matic-functionalized symmetric dialdehydes under conventional
Cannizzaro conditions. Such a simple procedure is effective pro-
vided by a cation templated spatially ordered arrangement of the
topologically distant end groups, which induces the intra-
molecular redox process. The results for the ortho-9 and meta-10
isomers confirm that this process is general for various sub-
stitution models of the aromatic ring. Also, the regiochemistry is
no limiting factor for successful desymmetrization and the
intramolecular Cannizzaro reaction is applicable to various types
of macromolecular systems.
All OEG-dialdehydes studied so far have been found to exhibit
a relative para arrangement of the carbaldehyde group and the
oxygen atom in the ethylene glycol chain. A unique situation is
therefore possible in the complexed form as regards the relative
arrangement of the two carbaldehydes (see MnD31 in Scheme 1).
On the other hand, the two carbaldehyde groups in the ortho and
meta analogs may face each other or adopt the nearest possible
arrangement (Scheme 4). We examined the influence of the rel-
ative position of the carbaldehyde group with respect to the
CHO
CHO
O
Mn+
O
CHO
OHC
O
O
O
O
O
O
4. Experimental
Mn+
O
4.1. General methods
O
parallel M n+ 9 or 10
opposite M n+ 9 or 10
All reagents were purchased from commercial sources and used
untreated unless otherwise stated. 1H NMR and 13C NMR spectra
were recorded at 25 ꢀC at 400 and 100 MHz, respectively, using
Scheme 4. Opposite versus parallel relative arrangements of the carbaldehyde groups
in the complexed forms of the ortho and meta models of tetraethylene glycols 9 and 10.

11664
A.J. Ruiz-Sanchez et al. / Tetrahedron 64 (2008) 11661–11665
TMS as internal standard. EIMS spectra were obtained at 70 eV via
direct insertion. HRMS and elementary analysis were recorded at
the C.A.C.T.I. service of the University of Vigo (Spain). To exclude
retention of complexed metals within the ethylene glycol chain and
counter ions of desymmetrized compounds, samples were ana-
lyzed by ICP-MS and no contaminants were detected (detection
limit is in parts per million). As additional purity control, HPLC
CDCl3, ppm) d 67.7, 69.0, 70.1, 70.4, 112.6, 120.4, 124.5, 127.6, 135.5,
160.8, 189.3. EIMS m/z (%) 402 (Mþ, 7), 149 (70), 148 (20), 121
(100), 120 (35).
4.3.5. 1,13-Bis-(m-benzaldehyde)-1,4,7,10,13,-penta-
oxatridecane (10)16
Oil. 1H NMR (400 MHz, CDCl3, ppm)
d 3.7 (m, 8H), 3.85 (t,
analyses (Col. Kromasil 100 C18 5.0
m
m, 250ꢁ3.0 mm; Mobile
J¼4.8 Hz, 4H), 4.16 (t, J¼4.8 Hz, 4H), 7.17 (dt, J¼7.5 Hz and J¼1.9 Hz,
phase: acetonitrile–water 30:70% vol containing a 0.1% of formic
acid; flow: 1.3 mL/min; detector: 254 nm) of the desymmetrized
compounds were performed and only single peaks were detected
for each compound. Melting points are given uncorrected. All re-
actions were monitored by TLC, using 60F 254 silica gel coated
plates. Column chromatography was performed by using silica gel
60 (0.040–0.063 mm) at an elevated pressure.
2H), 7.40 (m, 6H), 9.93 (s, 2H). 13C NMR (100 MHz, CDCl3, ppm)
d
67.2, 69.1, 70.2, 70.4, 112.6, 121.6, 123.0, 129.6, 137.3, 158.9, 191.6.
EIMS m/z (%) 402 (Mþ, 8), 149 (52), 148 (51), 121 (100), 77 (55).
4.4. General procedure for the desymmetrization of OEG-
dialdehydes
A
round-bottomed flask furnished with a condenser and
4.2. OEG-ditosylates
a magnetic stir bar was loaded with OEG-dialdehyde (1.2 mmol of
4, 5, 9, or 10), Ba(OH)2$8H2O (2.52 g, 8 mmol) and H2O (8 mL), and
the solution being refluxed for 24 h. After cooling, the flask was
immersed in a water–ice mixture and concentrated hydrochloric
acid added to pH 2. The resulting mixture was extracted with
dichloromethane, organics were dried with anhydrous MgSO4, and
filtered, and the solvent was removed on a rotary evaporator. The
corresponding desymmetrized products 6, 7, 11, and 12 were
obtained almost quantitatively and in a pure enough form for most
synthetic purposes. The procedure for dialdehyde 3 was identical
except that an amount of 0.3 mmol of the compound was treated
with a 60 mL solution of 6 M LiOH to obtain 8.
Diethylene glycol and triethyleneglycol ditosylates were syn-
thesized as described.11 Pentaethylene glycol ditosylate was
obtained from commercial sources.
4.3. OEG-Dialdehydes
An acetonitrile (400 mL) suspension of the sodium salt of the
corresponding hydroxybenzaldehyde (16 mmol) containing the
desired OEG-ditosylate (8 mmol) was refluxed until TLC confirmed
the disappearance of the starting material. The cooled reaction
mixture was then filtered off and the filtrate concentrated on a ro-
tary evaporator. In order to remove traces of unreacted products,
the crude residue obtained was dissolved in CH2Cl2 and extracted
with 10% aqueous NaOH and, finally, pure water. The organic so-
lution was then carefully dried with anhydrous MgSO4 and the
solvent evaporated to obtain the pure compound in almost quan-
titative yield.
4.4.1. Compound 6
Quantitative. White solid, mp 108–110 ꢀC; 1H NMR (400 MHz,
CDCl3, ppm)
d 3.74 (s, 4H), 3.85 (m, 4H), 4.09 (m, 2H), 4.18 (m, 2H),
4.59 (s, 2H), 6.86 (m, 2H), 6.92 (d, J¼8.8 Hz, 2H), 7.24 (m, 2H), 7.97
(d, J¼8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm)
d 65.0, 67.4, 67.6,
69.6, 69.8, 70.8, 114.6, 114.7, 121.8, 128.6, 132.2, 133.2, 158.4, 163.1,
170.0. HRMS m/z calcd for C20H25O7 [MþH]þ 377.1600, found
377.1612. Anal. calcd for C20H25O7$1⁄2 H2O: C, 62.33; H, 6.54. Found:
C, 62.56; H, 6.38.
4.3.1. 1,7-Bis-(p-benzaldehyde)-1,4,7-trioxaheptane (3)12
White solid: mp 134–136 ꢀC; 1H NMR (400 MHz, CDCl3, ppm)
d
3.95 (t, J¼4.6 Hz, 4H), 4.23 (t, J¼4.6 Hz, 4H), 7.00 (d, J¼8.8 Hz, 4H),
7.81 (d, J¼8.8 Hz, 4H), 9.86 (s, 2H). 13C NMR (100 MHz, CDCl3, ppm)
4.4.2. Compound 7
d
67.7, 69.7, 114.8, 130.1, 131.9, 163.7, 190.8. EIMS m/z (%) 314 (Mþ,
Quantitative. White solid, mp 73–75 ꢀC. 1H NMR (400 MHz,
89), 286 (68), 149 (91), 121 (100), 77 (99).
CDCl3, ppm) d 3.65 (m, 12H), 3.84 (m, 4H), 4.09 (m, 2H), 4.16 (m,
2H), 4.59 (s, 2H), 6.87 (m, 2H), 6.92 (d, J¼9.0 Hz, 2H), 7.24 (m, 2H),
4.3.2. 1,10-Bis-(p-benzaldehyde)-1,4,7,10-tetraoxadecane (4)13
7.97 (d, J¼9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm)
d 64.9, 67.5,
White solid: mp 72–74 ꢀC. 1H NMR (400 MHz, CDCl3, ppm)
67.6, 69.5, 69.7, 70.6, 70.8, 114.3, 114.7, 121.9, 128.6, 132.2, 133.3,
158.4, 163.1, 170.6. EIMS m/z (%) 464 (Mþ, 14), 446 (10), 297 (72),
165 (100), 95 (45). HRMS m/z calcd for C24H32O9 [M]þ: 464.2046;
found 464.2057.
d
3.74 (s, 4H), 3.87 (t, J¼4.7 Hz, 4H), 4.19 (t, J¼4.7 Hz, 4H), 6.99 (d,
J¼8.8 Hz, 4H), 7.80 (d, J¼8.8 Hz, 4H), 9.86 (s, 2H). 13C NMR
(100 MHz, CDCl3 ppm)
d 67.7, 69.5, 70.9, 114.8, 130.0, 131.9, 163.7,
190.8. EIMS m/z (%) 358 (Mþ, 77),149 (99), 121 (100), 77 (87). HRMS
m/z calcd for C20H23O6 [MþH]þ: 359.1495; found 359.1490.
4.4.3. Compound 8
85%. White solid, mp 175–180 ꢀC. 1H NMR (400 MHz, DMSO-d6,
4.3.3. 1,16-Bis-(p-benzaldehyde)-1,4,7,10,13,16-hexa-
oxahexadecane (5)14
ppm)
d
3.81 (m, 4H), 4.08 (t, J¼4.8 Hz, 2H), 4.19 (t, J¼4.8 Hz, 2H),
4.40 (d, J¼5.2 Hz, 2H), 5.04 (t, J¼5.2 Hz, 1H), 6.54 (s, 1H), 6.88 (d,
White solid: mp 44–46 ꢀC. 1H NMR (400 MHz, CDCl3, ppm)
J¼8.4 Hz, 2H), 7.02 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz, 2H), 7.87 (d,
d
3.63 (m, 12H), 3.85 (t, J¼4.5 Hz, 4H), 4.18 (t, J¼4.5 Hz, 4H), 6.98 (d,
J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm)
d 62.8, 67.4, 67.8,
J¼8.4 Hz, 4H), 7.80 (d, J¼8.8 Hz, 4H), 9.86 (s, 2H). 13C NMR
69.2, 69.4, 114.4, 114.6, 123.3, 128.2, 131.7, 135.0, 157.6, 162.4, 167.3.
(100 MHz, CDCl3 ppm)
d
67.1, 68.7, 69.9, 70.1, 114.3, 129.4, 131.2,
HRMS m/z calcd for C18H19O5 [MþH]þ: 315.1227; found 315.1200.
163.2, 190.1. EIMS m/z (%) 446 (Mþ, 6), 149 (99), 148 (90), 121 (100),
120 (90). HRMS m/z calcd for C24H31O8 [MþH]þ: 447.2019; found
447.2010.
4.4.4. Compound 11
Quantitative. Oil. 1H NMR (400 MHz, CDCl3, ppm)
d 3.68 (m, 8H),
3.82 (m, 2H), 3.87 (m, 2H), 4.15 (m, 2H), 4.31 (m, 2H), 4.62 (s, 2H),
6.84 (d, J¼7.6 Hz, 1H), 6.91 (t, J¼7.4 Hz, 1H), 6.98 (d, J¼7.6 Hz, 1H),
7.10 (t, J¼7.2 Hz, 1H), 7.23 (m, 2H), 7.50 (ddd, J¼7.4 Hz, 7.2 Hz and
2.0 Hz, 1H), 8.10 (dd, J¼7.2 and 2.0 Hz, 1H). 13C NMR (100 MHz,
4.3.4. 1,13-Bis-(o-benzaldehyde)-1,4,7,10,13,-pentaoxatridecane (9)15
Oil. 1H NMR (400 MHz, CDCl3, ppm)
d 3.68 (m, 8H), 3.88 (t,
J¼4.8 Hz, 4H), 4.21 (t, J¼4.8 Hz, 4H), 6.95 (d, J¼8.0 Hz, 2H), 6.99 (t,
J¼7.2 Hz, 2H), 7.49 (dt, J¼7.2 Hz and J¼2.0 Hz, 2H), 7.79 (dd,
J¼8.0 Hz and J¼2.0 Hz, 2H), 10.48 (s, 2H). 13C NMR (100 MHz,
CDCl3, ppm) d 61.2, 67.4, 68.7, 69.1, 70.1, 70.2,111.7,113.1,118.1,120.6,
121.8, 128.3, 128.4, 129.8, 132.9, 134.4, 134.5, 156.4, 157.1, 165.6. EIMS

A.J. Ruiz-Sanchez et al. / Tetrahedron 64 (2008) 11661–11665
11665
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Weinheim, 2005.
3. (a) Hermanson, G. T. Bioconjugate Techniques; Academic: San Diego, CA, 1996;
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2191–2196.
m/z (%) 420 (Mþ, 6), 402 (15), 165 (22), 121 (100), 120 (30). HRMS
m/z calcd for C22H28NaO8 [MþNa]þ: 443.1676; found 443.1664.
Anal. calcd for C22H28O8: C, 62.85; H, 6.71. Found: C, 62.87; H, 6.80.
4.4.5. Compound 12
4. Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stuermer, R.; Ze-
linski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
Quantitative. Oil. 1H NMR (400 MHz, CDCl3, ppm)
d 3.70 (m,
5. Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354.
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8H), 3.84 (m, 4H), 4.11 (m, 2H), 4.15 (m, 2H), 4.64 (s, 2H), 6.81 (d,
J¼8.0 Hz, 1H), 6.89 (d, J¼8.0 Hz, 1H), 6.94 (s, 1H), 7.12 (d, J¼8.0 Hz,
1H), 7.21 (t, J¼8.0 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H), 7.58 (s, 1H), 7.65
(d, J¼8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, ppm)
d 64.3, 66.9,
67.2, 69.3, 69.4, 70.2, 70.3, 70.4, 112.6, 113.4, 114.8, 119.0, 120.2,
122.3, 129.1, 129.2, 130.6, 142.2, 158.3, 158.5, 169.8. EIMS m/z (%)
420 (Mþ, 27), 165 (37), 150 (46), 147 (53), 121 (100), 89 (32), 77
(38). HRMS m/z calcd for C22H28NaO8 [MþNa]þ: 443.1676; found
443.1675. Anal. calcd for C22H28O8: C, 62.85; H, 6.71. Found: C,
62.89; H, 6.86.
Acknowledgements
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This work was supported by Spain’s DGI (Project CTQ07-60190).
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