pK(a) values and geometries of secondary and tertiary amines complexed to boronic acids-implications for sensor design.

Article abstract of DOI:10.1021/ol0156805

[structure in text] The pK(a) values and the geometries of secondary and tertiary amines adjacent to boronic acids were determined using potentiometric and (11)B NMR titrations. The studies showed that the secondary ammonium ion has a pK(a) similar to that of the tertiary ammonium species, which leads to the formation of tetrahedral boron centers at pH values above approximately 5.5. Therefore, secondary amines as well as tertiary amines, when placed proximal to boron centers, can be used to create tetrahedral boronic acids at neutral pH for diol complexation.

Full text of DOI:10.1021/ol0156805

ORGANIC
LETTERS
2
001
Vol. 3, No. 9
311-1314
pK Values and Geometries of
Secondary and Tertiary Amines
Complexed to Boronic
a
1
AcidssImplications for Sensor Design
†
†
†
†
Sheryl L. Wiskur, John J. Lavigne, Hassan Ait-Haddou, Vincent Lynch,
‡
‡
,†
Yu Hung Chiu, James W. Canary, and Eric V. Anslyn*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712, and Department of Chemistry, New York UniVersity,
New York, New York 10003
anslyn@ccwf.cc.utexas.edu
Received February 7, 2001
ABSTRACT
The pK
NMR titrations. The studies showed that the secondary ammonium ion has a pK
a
values and the geometries of secondary and tertiary amines adjacent to boronic acids were determined using potentiometric and 11
similar to that of the tertiary ammonium species, which leads
B
a
to the formation of tetrahedral boron centers at pH values above approximately 5.5. Therefore, secondary amines as well as tertiary amines,
when placed proximal to boron centers, can be used to create tetrahedral boronic acids at neutral pH for diol complexation.
The boronic acid functional group is routinely incorporated
into synthetic receptors for the complexation of saccharides
and other guests that possess 1,2- and 1,3-diol groups.
pH. This is shown in the equilibrium between 1a and 1b
(eq 1), where the lone pair on the nitrogen associates itself
5
1
-4
The boronic acids form reversible covalent bonds with
the diols, creating boronate esters. The kinetics of this
interconversion is fast when the boron is tetrahedral, which
occurs in basic aqueous media. Since it is not always
advantageous to work at a high pH, Wulff has demonstrated
that the incorporation of an amine adjacent to the boronic
3
acid creates a tetrahedral sp boron at or near neutral
with the empty p orbital on the boron. It was found that the
complex 1b allowed for rapid boronate ester formation at
†
The University of Texas at Austin.
New York University.
neutral pH. This boron-nitrogen interaction raises the
‡
6
boronic acid’s pK
the pK
. These changes in the hybridization of boron are reflected
a
from near 9 to near 12 and can lower
(
1) Yoon, J.; Czarnik, A. W. J. Am. Chem. Soc. 1992, 114, 5874-5875.
(2) James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. J. Chem. Soc.,
of a tertiary ammonium ion from around 9 to near
a
Chem. Commun. 1994, 477-478.
5
(
3) Lavigne, J. J.; Anslyn, E. V. Angew. Chem., Int. Ed. 1999, 38, 3666-
3
669.
(
4) Ward, C. J.; Patel, P.; Ashton, P. R.; James, T. D. Chem. Commun.
(5) Wulff, G. Pure Appl. Chem. 1982, 54, 2093-2102.
(6) Julliard, J.; Geugue, N. C. R. Acad. Paris C 1967, 264, 259-261.
2
000, 229-230.
1
0.1021/ol0156805 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

1
1
in its chemical shift in B NMR. When boron is tetrahedral,
its chemical shift is upfield from that of the trigonal planar
While several examples exist that locate tertiary amines
adjacent to boronic acids, for sensing applications, few are
available that incorporate secondary amines. The utility of
3
2
geometry, where pure sp and sp is approximately 0 and
0 ppm, respectively. Upon formation of the boronate ester,
7
3
this latter combination raises questions pertaining to the pK
a
the Lewis acidity of the boron is increased, creating a
of the secondary ammonium ion relative to its tertiary
counterpart (i.e., the strength of the B-N interaction at
neutral pH) as well as the geometry found at the boron and
nitrogen centers with varying pH. To address the questions,
model compounds 6 and 7 were synthesized. To answer these
questions, there are several equilibria to consider. The first
stronger boron-nitrogen interaction.8
Many boronic acid receptors exist that incorporate an
adjacent tertiary amine. The intramolecular coordination
between a tertiary amine and a boronic acid not only
improves the kinetics of exchange but also can be used to
modulate photoinduced electron transfer (PET), leading to
a sensing application. For example, Shinkai’s sugar sensor
pK
a
is undoubtedly deprotonation of the ammonium ion in
can be attributed to either
6a (Scheme 1A). The second pK
a
2
is a boronic acid linked to an anthracene moiety via a
2
proximal tertiary amine. The amine is able to quench the
receptor’s fluorescence through PET, even though it is
involved in the boron-nitrogen interaction. Upon complex-
ation with a sugar, the fluorescence of the anthracene is
regenerated as the formation of the boronate ester increases
the Lewis acidity of the boron, decreasing the PET.
Scheme 1
Recently, a secondary amine has been used in a nonfluo-
rescent boronic acid sensor. James has recently synthesized
4
a colorimetric sensor (3) for saccharides. The host was
generated by covalently attaching an azo dye to a phenyl
boronic acid through a proximal secondary amine. The use
of an aniline nitrogen gave a color change due to deproto-
nation upon sugar complexation.
Our lab is currently investigating the incorporation of
boronic acids in receptors such as 4 and 5 for recognizing
diols found in various natural products.3 Here, dye displace-
ment strategies are being developed to signal the presence
of guests3 as compared to the covalently attached signaling
moieties of 2 and 3. In our systems, the role of the secondary
amine is both structural and electronic, preorganizing the
cavity and enhancing the kinetics of exchange, respectively.
another deprotonation of the amine (6b to 6d) or coordination
of hydroxide to the boronic acid (6b to 6c). We expect that
the pK of the amine 6b should be above that of an
a
,9
,10
alkylammonium since the lone pair has no ability to
delocalize and is near a negative charge, yet this needed to
be confirmed. If the second deprotonation is of the amine,
this could lead to hydroxide elimination to give 6e, which
11
can be found under dehydrating conditions. This would not
be evident in a potentiometric titration since it is formally
the elimination of water, although it would be evident in a
(7) N o¨ th, H.; Wrackmeyer, B. Nuclear Magnetic Properties of Boron.
In Nuclear Magnetic Resonance Spectroscopy of Boron Compounds; Diehl,
P., Fluck, E., Kosfeld, R., Eds.; NMR Basic Principles and Progress Series
1
1
1
4; Springer-Verlag: Berlin, 1978; pp 5-14, 287.
B NMR spectrum. Importantly, if 6e does dominate at
(
8) Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769-774.
neutral pH, it would not be as effective for binding diols in
sensing applications as is a tertiary amine analogue.
(9) Ait Haddou, H.; Anslyn, E. V. University of Texas at Austin, Austin,
TX. Unpublished work, 2001.
10) (a) Metzger, A.; Anslyn, E. V. Angew. Chem., Int. Ed. 1998, 37,
(
6
49-652. (b) Niikura, K.; Metzger, A.; Anslyn, E. V. J. Am. Chem. Soc.
(11) (a) Hawkins, R. T.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82,
3863-3866. (b) Hawkins, R. T.; Blackham, A. U. J. Org. Chem. 1967, 32,
597-600. (c) Lavigne, J. J.; Anslyn, E. V. University of Texas at Austin,
Austin, TX. Unpublished work, 2001.
1
998, 120, 8533-8534. (c) Niikura, K.; Bisson, A. P.; Anslyn, E. V. J.
Chem. Soc., Perkin Trans. 2 1999, 1111-1114. (d) Cabell, L. A.; Monahan,
M.-K.; Anslyn, E. V. Tetrahedron Lett. 1999, 40, 7753-7756.
1312
Org. Lett., Vol. 3, No. 9, 2001

The equilibria available to the analogous tertiary model
7) is more straightforward (Scheme 1B). Deprotonation of
In an effort to better understand the geometry at boron,
1
1
(
the B NMR spectra of 6 and 7 were recorded as a function
1
4
the ammonium ion (7a to 7b) and coordination of hydroxide
7b to 7c) can be assigned to the first and second pK
of pH (Figure 2). In our studies, both compounds 6 and 7
(
a
,
5
respectively. Given the equilibria presented in Scheme 1,
we performed potentiometric titrations and B NMR versus
11
a
pH studies on 6 and 7 to probe the pK values and the
geometries at boron as a function of pH.
Secondary model 6 was prepared in one step through a
reductive amination between benzylamine and 2-formylben-
zene boronic acid. Tertiary model 7 was prepared by
protecting the boronic acid of 2-methylbenzene boronic acid
with neopentyl glycol. The methyl group was then bromi-
nated and subsequently displaced through nucleophillic
substitution by N-methyl benzylamine. The boronic acid was
deprotected by hydrolysis on silica gel.1
2
Potentiometric titrations were performed to determine the
first pK values associated with 6a and 7a. The pK of an
a a
ammonium generally ranges between 9 and 10, but a boronic
acid adjacent to an ammonium will lower that significantly.
The titration curves for both models are shown in Figure 1.
Figure 2. 11B NMR chemical shifts of model compounds 6 (9)
and 7 (b) with increasing pH (10% d -methanol in water, 40 mM
and 7, 40 mM NaCl). Referenced to Et O‚BF in toluene as zero.
4
6
2
3
showed shifts from approximately 30 to 10 ppm as the pH
was raised. This indicates that the boron centers in both the
secondary and the tertiary model compounds are trigonal
planar at low pH and upon increasing the pH they become
a
tetrahedral, with pK values of 5.2 and 5.8, respectively.
These values are in agreement with those determined by
potentiometric titrations. Further, at neutral pH the chemical
shifts found for 6 and 7 are nearly identical. Since we are
confident in the assignment of form 7b at neutral pH for the
tertiary model, it indicates that the proper form for the
secondary counterpart is 6b at this pH. These data therefore
indicate that the dominant forms of the secondary and tertiary
compounds near neutral pH are 6b and 7b, respectively.
To further confirm the geometry of 6 near neutral pH, we
wanted to obtain a crystal structure, but our attempts to grow
crystallographic quality crystals were unsuccessful. However,
the geometry was clear from X-ray crystallography on
crystals of the polyaza compound 5 (Figure 3).9 Impor-
tantly, the boron is tetrahedral, as is the coordinated nitrogen,
Figure 1. pH profile of 6 (9) and 7 (b) upon addition of base
(
0.15 M NaCl in water, 0.1 M NaOH, and 4.5 mM (initial) 6 and
). The titration of 6 started with a higher concentration of acid,
and the first few data points were excluded.
7
,15
1
6 11
and the B-N bond lengths are 1.669 Å.
B NMR of the
a
From these curves, a pK of 5.7 was found for 7a, which is
crystals provide a chemical shift of 9.4 ppm, consistent with
our assignment of form 6b at neutral pH.
comparable to the known value of 5.2 for a dimethylam-
5
monium ion adjacent to a boronic acid. The titration of the
secondary model 6a produced a value of 5.3 for its pK
Hence, the pK values determined from the potentiometric
titrations of 6a and 7b are quite similar.1
a
.
(
14) 11B NMR spectra were obtained with a Bruker AMX-500 spec-
a
trometer. Quartz NMR tubes were used to limit background noise. The pH
values of the solutions were adjusted between 1.6 and 11 and measured
with an Orion 720A pH meter.
3
(
15) Toyota, S.; Futawaka, T.; Asakura, M.; Ikeda, H.; Oki, M.
(
12) Lavigne, J. J. Ph.D. Dissertation, University of Texas at Austin,
000.
13) Potentiometric studies were conducted with a Brinkmann Titrino
Organometallics 1998, 17, 4155-4163.
2
(16) Crystal data for 4. C33H37B2N7O4, M ) 617.32, monoclinic, space
group C2/c (No. 15), a ) 21.7733(9), b ) 16.3103(9), c ) 8.9580(3) Å, â
(
3
-1
7
3
2
02 autotitrator. A Metrohm combined pH glass electrode (Ag/AgCl) with
M NaCl internal filling solution was used. Measurements were taken at
5 °C under nitrogen. About 100 data points were collected for each titration,
and the analysis was carried out as described by Martell (see below).
Equilibrium constants were calculated using the program BEST. All
constants were determined using at least two independent titrations. Martell,
A. E.; Motekaitis, R. J. Determination and Use of Stability Constants; VCH
Publishers: New York, 1992.
) 99.049(3)°, V ) 3141.7(2) Å , Z ) 4, Dc ) 1.30 g/cc, µ ) 0.087 mm .
Data were collected at 123(2) K on a Nonius Kappa CCD using graphite
monochromatized Mo KR radiation (0.71073 Å). A total of 5976 reflec-
tions were collected, 3535 were unique (Rint ) 0.028). The structures were
2
refined on F to a wR2 ) 0.119 with an R1 [for 2497 reflections with Fo
> 4(σ(Fo))] ) 0.0549 and a goodness of fit ) 1.05. The molecule lies on
a crystallographic 2-fold rotation axis passing through the central pyridine
ring.
Org. Lett., Vol. 3, No. 9, 2001
1313

Further, at neutral pH, form 6b dominates. Therefore,
secondary amines can be used to coordinate boronic acids
for sensor applications with geometries appropriate for the
complexation of 1,2- and 1,3-diols, just as is now routinely
done with tertiary amines. Undoubtedly there will be a
difference in the extent of PET between a tertiary and second
amine that can be exploited for sensor applications,17 but
the use of secondary and tertiary amines are essentially the
same with regards to complexation geometry and pH
dependence.
Acknowledgment. This work has been supported by the
Welch Foundation and the National Institutes of Health.
Figure 3. View of 5 showing a partial atom labeling scheme.
Thermal ellipsoids are scaled to the 50% probability level. Hydrogen
atoms shown are drawn to an arbitrary scale. The molecule lies on
a crystallographic 2-fold rotation axis bisecting the pyridine ring
and passing through N1. Atoms with labels appended by ′ are related
by -x, y, 1/2 -z. The protons on the amines were located and
refined in the crystal structure.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 6 and 7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0156805
a
In conclusion, we have determined that the pK values of
secondary ammoniums adjacent to boronic acids are com-
parable to those of the analogous tertiary ammoniums.
(
17) Bissel, R. A.; de Silva, A. P.; Gunaratne, H. Q. N.; Lynch, P. L.
M.; Maguire, G. E. M.; McCoy, C. P.; Sandanayake, K. R. A. S. Top. Curr.
Chem. 1993, 168, 223-264.
1314
Org. Lett., Vol. 3, No. 9, 2001