Probing intramolecular B-N interactions in ortho-aminomethyl arylboronic acids

Article abstract of DOI:10.1021/jo900187a

(Chemical Equation Presented) This work investigates the interplay between the intramolecular B-N dative bonding and solvent insertion in various ortho-methylamino arylboronic acids in protic media. ¹¹B NMR experiments were conducted to study t

Full text of DOI:10.1021/jo900187a

Probing Intramolecular B-N Interactions in Ortho-Aminomethyl
Arylboronic Acids
Byron E. Collins, Steven Sorey, Amanda E. Hargrove, Shagufta H. Shabbir,
Vincent M. Lynch, and Eric V. Anslyn*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas,
1 UniVersity Station A5300, Austin, Texas 78712
anslyn@austin.utexas.edu
ReceiVed January 29, 2009
This work investigates the interplay between the intramolecular B-N dative bonding and solvent insertion
in various ortho-methylamino arylboronic acids in protic media. 11B NMR experiments were conducted
to study the effect that the degree of substitution of the amine group has on B-N bonding versus solvent
insertion. It was found that there is a slight increase in the amount of B-N dative bonding on going
from a tertiary to a secondary to a primary amine group, but that solvent insertion dominates in all cases
of the boronate esters. A X-ray crystal structure gives further insight into the structure of the solvent-
inserted boronate esters, showing that the inserted solvent has its hydrogen primarily on the amine. Lastly,
studies of the use of boronate esters as receptors for simple alcohols and carboxylic acids are described.
Introduction
incorporation of nitrogenous bases in an ortho-methyl position
to the phenyl boronic acid increases the rate of boronate ester
Boronic acids are known to reversibly form boronate esters
with various types of 1,2- and 1,3-diols.1 The covalent, yet
quickly reversible, nature of this interaction makes it a desirable
binding motif to incorporate into receptors for various hydroxy-
lated targets. For example, in recent years arylboronic acids have
been used for the molecular recognition of numerous diol
containing targets including catechols,2-6 R-hydroxy car-
boxylates,7-13 peptides,14 and saccharides.15-25 Boronic acids
have also been used for chromatographic protocols.26-31 The
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10.1021/jo900187a CCC: $40.75
Published on Web 04/24/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4055–4060 4055

Collins et al.
FIGURE 1. Upon formation of a boronate ester, 1 can form either
B-N bonded species, 2a, or a solvated species, 2b.
formation and diol exchange in neutral aqueous solution.32
Recent structural and mechanistic investigations have greatly
increased our understanding of these interactions.32-47
In a landmark study from Shinkai et al., sensor 1 displayed
a large fluorescence enhancement upon binding carbohydrates
such as glucose or fructose.46 The observed increase in
fluorescence upon analyte binding was attributed to a more
favorable B-N dative bonding interaction in the boronate ester
over the acid, which interrupted a photoinduced electron transfer
(PET) quenching mechanism between the amine and the
appended anthracene moiety (Figures 1 and 2a). Subsequently,
our own enantioselective sensor designs hinged on the belief
that a B-N dative bond is dominant in aqueous media.48-50
Recently, however, Wang et al. proposed a hydrolysis
mechanism whereby boronate ester formation caused a decrease
in the pKa of the boronic acid along with an increase in the pKa
of the amine group (Figures 1 and 2b).51,52 According to his
study, the change in pKa triggers the insertion of a solvent
molecule, increasing the extent of protonation of the amine.
Wang suggested that this change in protonation state would more
effectively occupy the nitrogen lone pair involved in PET
quenching than would dative bonding.
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FIGURE 2. 11B NMR spectra of (A) 3, (B) 4, and (C) 5, 10 mM in
methanol in the presence of 0, 10, 20, 30, 40, 50, 60, and 80 mM
catechol (catechol concentration increases from bottom to top). A is
reproduced from our previous report for comparison to B and C.53
4585–4593.
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4269.
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Our group, prompted by Wang’s findings, conducted our own
investigation into these two proposed mechanisms via X-ray
crystallography, 11B NMR, and pH titrations.53 Boron NMR
experiments were performed by titrating 3 with various guests:
4056 J. Org. Chem. Vol. 74, No. 11, 2009

Probing Intramolecular B-N Interactions
catechols, diols, and R-hydroxy carboxylic acids, in chloroform
and methanol. These experiments revealed the dominant species
in these solvents as a function of the concentration of added
guests. We demonstrated that in methanol the preferred species
is the solvated species for both free boronic acids as well as
boronate esters. In each crystal structure obtained from methanol,
a solvent molecule was seen coordinated between the boron
and the nitrogen. However, the 11B NMR spectra often displayed
the B-N bonded species as a minor component of the mixtures.
The concentrations of the B-N bonding species were pH as
well as guest dependent. For example, a solution of 3 with
catechol in methanol showed a small detectable peak assigned
to B-N bonded boronate ester, while a mixture of 3 with
R-hydroxyisobutyric acid in methanol displayed no such species.
FIGURE 3. Titration of 4 with catechol under the same conditions as
in Figure 2 performed on a 300 MHz NMR instrument.
of B-N bonding on going from a tertiary amine to a secondary
or a primary amine. For 3, 4, and 5, the initial boron peak
displayed a chemical shift of around 9.8 ppm, which is indicative
of the solvated boronate ester. Upon addition of catechol, this
peak shifts slightly downfield to 10.2 ppm due to the increased
electron withdrawing ability of catechol over methanol. As with
3, there was also formation of a small amount of dative bonded
boronate ester with 4 and 5. Integration after baseline correction
revealed that in 3, the B-N bound species accounted for about
4% of the boron species present. Comparatively, the B-N bound
species in 4 and 5 represented 11 and 10% of the boron in
solution (same values within experimental error for NMR
integration). The peak at 8.5 ppm in Figure 2C is due to the
solvated catechol ester of residual boric acid (see Supporting
Information) and was not included in the values presented above.
Similar titrations were performed with meso-hydrobenzoin and
no discernible B-N bond formation was observed.53 This
observation is also in agreement with previous work done with
3. Finally, in all of the experiments performed, boronate ester
formation was complete by the end of the titration, and
competition with methanol was not a hindrance.
In the work presented herein we further explore the depen-
dence of the B-N bond interaction as a function of structure,
but we now focus on changes in the structure of the amine.
Further, we report a new crystal structure that allows us to
elucidate the position of the proton of the solvent this is inserted
in the boronate esters. Lastly, we explore the use of boronate
esters themselves as receptors for simple alcohols and carboxylic
acids.
Results and Discussion
(A) Extent of B-N Bonding as a Function of Sterics. In
an effort to further understand the conditions in which B-N
bonding is favored, we decided to investigate the effect that
the degree of substitution at the ortho-aminomethyl group has
on B-N dative bonding in protic media. A better understanding
of the nature of this interaction could lead to improvements in
rationally designed boronic acid-based receptors exploiting
PET-based fluorescence quenching.
Notably, when performing titrations with 4 and catechol on
a 300 MHz instrument (operating at 96 MHz for 11B), there is
only a single boron resonance, which shifts slightly downfield
(Figure 3). However, when the same experiment is performed
on a 500 MHz instrument (operating at 190 MHz for 11B) a
distinct second boron peak indicative of the catechol bound
species is seen (Figure 2B). This observation allows us to
calculate that, under these conditions, boronate ester exchange
takes place at a rate corresponding to a half-life of between
11.1 and 54.7 ms.
(B) X-Ray Analysis. In our previous work, we obtained an
X-ray crystal structure of 3 grown from methanol. It showed
the presence of a solvent inserted boron species, such as depicted
for either 6 or 7 below. In the crystal structure it was apparent
that a hydrogen was bound between the pyrrolidine nitrogen
and one of the boron bound methoxides. However, we were
unable to determine whether that hydrogen was closer to the
nitrogen or the oxygen. The position of the hydrogen is a subtle
issue, but it defines whether the solvent inserted structure should
be best considered as a neutral complexed boronic acid (6), or
whether the methanol is closer to being fully dissociated creating
a zwitterionic structure (7).
Our hypothesis was that B-N bonding would be more
favorable for 1° amines than 2° amines, which in turn would
be more favorable than 3° amines. Our reasoning was that
decreased steric bulk on the nitrogen would encourage B-N
bond formation. To investigate this hypothesis, we examined
boronic acids 4 and 5 using 11B NMR in a manner identical to
that used previously with 3.53 Compound 4 was commercially
available and 5 was synthesized according to known literature
procedure via reductive amination with 2-formylphenylboronic
acid and methylamine.54 NMR titrations were performed in
methanol with 10 mM boronic acid 4 or 5 and catechol as the
guest in concentrations ranging from 0-80 mM. Catechol was
chosen because in our previous studies it showed the greatest
extent of B-N bond formation when complexed by 3.
When comparing to the previous results (Figure 2A), Figures
2B and C show that there is a very small increase in the extent
In the present study, we were able to grow crystals from
(54) Swamy, K. M.; Jang, Y. J.; Park, M. S.; Koh, H. S.; Lee, S. K.; Yoon,
Y. J.; Yoon, J. Tetrahedron Lett. 2005, 46, 3453–3456.
whose crystal structure we could locate the hydrogen atoms with
J. Org. Chem. Vol. 74, No. 11, 2009 4057

Collins et al.
SCHEME 1. Interruption of B-N Bonding by a Carboxylic
Acid
SCHEME 2. Benzyl Alcohol Binds Host 9 with a Weak
Association Constant
FIGURE 4. View of molecule 1 of 7 showing the atom labeling
scheme. Displacement ellipsoids are scaled to the 50% probability level.
The dashed line is indicative of a H-bonding interaction with geometry:
N1-H1N · · · O1, N · · · O 2.630(3)Å, H · · · O 1.69(3)Å, N-H · · · O
161(2)°.
TABLE 1. Various Conditions Used to Investigate Interactions
between Either Alcohol or Carboxylate with Boronic Acid Hosts
boronic
acid
ester
Catechol
Catechol
Catechol
Catechol
Catechol
4-chlorocatechol
solvent
CDCl3
CDCl3
DMF
Toluene
Acetonitrile Acetic acid
Acetonitrile Acetic acid
guest
Ka (M-1
)
3
3
3
3
3
3
Benzyl alcohol
Acetic acid
Acetic acid
Acetic acid
0.3
1.3
N/A
N/A
7.6
good confidence (Figure 4). These hydrogens were observed in
an ∆F map and refined with isotropic displacement parameters.
The crystals formed consisted of a three molecule asymmetric
unit. In the units analyzed, the hydrogen atoms resided on the
nitrogen atoms in all three cases. The three N-H bond distances
were found to be 1.02(3), 1.03(3), and 1.04(3)Å. Comparatively,
the H-O bond distances were 1.734, 1.693, and 1.668 Å.
(C) r-Amino Methyl Phenyl Boronates as -OH Recep-
tors. During our investigations of structural and solvent effects
on B-N interactions in ortho-aminomethyl aryl boronic acids,
we often observed a second diol “insertion” when an excess of
diol was present in aprotic media. This insertion is analogous
to the solvent insertion that is observed in protic solvents that
was discussed in the preceding two sections. This interaction
was most prominent with R-hydroxycarboxylic acids in chlo-
roform (Scheme 1). Chloroform is a solvent that gives pre-
dominantly the B-N dative bonding interaction until an excess
of the protic guest species is present.
Observation of this phenomenon led us to hypothesize that
it may be possible to exploit this interaction to create mono-
coordinate receptors for alcohols. To date, there exist only a
few receptors for mono-ols, and colorimetric sensing systems
capable of alcohol detection are rare.55 Those that exist are used
for the determination of ethanol concentration for quality control
purposes. To our knowledge, there are currently no synthetic
receptors capable of binding mono-ols at millimolar or lower
concentrations. Therefore, alcohol receptors are of both basic
scientific interest and have possible practical utility.
3.3
3
3
12
3-methoxycatechol Acetonitrile Acetic acid
2.9
9.2
N/A
4-nitrocatechol
4-nitrocatechol
Acetonitrile Acetic acid
Acetonitrile Acetic acid
was titrated into host 9 in deuterochloroform (Scheme 2).
Titrations were followed with 11B NMR, and an approximate
binding constant (Ka) of 0.3 M-1 was measured (Table 1). We
were able to measure this small value due to the fact that analyte
binding is slow on the NMR time scale and the boron signals
for both the B-N bonded and the anionic boron could be
measured by integration. As noted above, when methanol is
the solvent it is nearly 100% inserted. Of course with a large
excess of alcohol that naturally exists when the alcohol is the
solvent, even a binding constant near 1 M-1 results in near
quantitative insertion.
In our previous work, insertion of a guest into a preformed
boronate ester (the host) was most prominent with guests
possessing acidic functional groups. Therefore, we decided to
examine carboxylic acids as guests. When acetic acid was
substituted for benzyl alcohol as shown in Scheme 2, an
approximate Ka of 1.3 M-1 was measured.
We also screened several commercially available deuterated
solvents. The results, summarized in Table 1, show that with
acetic acid and catechol, acetonitrile is the best solvent for
host-guest interaction.
In addition, different catechols were screened for creating
different boronate ester hosts (see the second listing in Table
1). It was found that an electron withdrawing group meta- to
one of the catechol oxygens moderately enhanced binding of
acetic acid, while electron donating groups lowered binding
affinity. The most successful boronate ester host-guest com-
bination that we uncovered was that of 10 with acetic acid as
the guest in acetonitrile.
To test if a boronate ester of an R-aminomethyl phenyl
boronic acid could act as an alcohol receptor, benzyl alcohol
(55) (a) Wick, M. J.; Mihic, S. J.; Ueno, S.; Mascia, P. M.; Trudell, J. R.;
Brozowski, S. J.; Ye, Q.; Harrison, N. L.; Haris, R. A. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 6504–6509. (b) Mayes, A. G.; Blyth, J.; Kyro¨lainen-Reay, M.;
Millington, R. B.; Lowe, C. R. Anal. Chem. 1999, 71, 3390–3396. (c) Dubas,
S. T.; Iamsamai, c.; Potiyaraj, P. Sensors Actuators B 2006, 113, 370–375.
4058 J. Org. Chem. Vol. 74, No. 11, 2009

Probing Intramolecular B-N Interactions
SCHEME 3
excess diol guest, only one catechol species is created in solution
with no insertion of a second 4-nitrocatechol. This data lead us
to conclude that the increased steric bulk from the diisopropy-
lamine group actually shields the B-N bond, allowing it to
remain intact in the presence of guest. This appears to parallel
the observation that very hindered boronate esters formed from
diols such as pinacol are less hydrolyzable. Thus, the effect of
steric bulk on the extent of B-N bond formation and breakage
is minimal, which is analogous to the conclusion we reached
in part A of this manuscript where substitution on the amino
group was found to only have a small influence on B-N
bonding.
SCHEME 4. Synthesis of 12
Summary
We hypothesized that discouraging B-N bond formation
without decreasing the Lewis acidity of the boronic acid could
further encourage carboxylic acid association. The pyrrolidine
group on 3 was replaced with the more sterically hindered
diisopropylamino group. Boronic acid 12 was furnished through
nucleophilic substitution on bromomethyl boroxine in diiso-
propylamine followed by subsequent hydrolysis according to a
known literature procedure.56
The 11B NMR spectra of 12 with 4-nitrocatechol both in the
presence and absence of acetic acid showed the same chemical
shift at 12 ppm. The typical shift for a B-N bound boronic
acid is 14 ppm and that of an anionic boronate ester bound to
three -OR groups is typically 8-10 ppm. Therefore, it seemed
likely that there was either a very strong B-N (seemingly
unlikely due to sterics) bond or an inserted water. Any
tricoordinate B-O species [-B(OR)3] in the boronate ester prior
to addition of a guest alcohol, catechol, or carboxylic acid would
arise from the water liberated upon initial boronate ester
formation.
In summary, we have investigated the effect of amine
substitution on B-N dative bonding in ortho-aminomethyl aryl
boronic acids. Our results show that while the degree of
substitution does have a minor effect on the extent of B-N
bonding, the solvated species still dominates in protic media.
Also, the 11B NMR experiments provided qualitative insight into
the rate of boronate ester exchange. Further, we have shown
that while the presence of an excess amount of diol can interrupt
a B-N bond in boronate esters in nonprotic solvent, the binding
affinities that boronate esters have toward mono-ols and
carboxylic acids are very low. Moreover, increasing the steric
bulk around the ortho-aminomethyl group appears to sterically
shield the system from insertion of an hydroxy containing guest.
Finally, X-ray crystal data has provided greater structural
understanding of the solvated boronate esters indicating ioniza-
tion of the O-H group and the formation of a zwitterion.
Experimental Section
In order to correctly identify the dominant species, boronate
ester 13 was prepared, isolated, and dried using an Abderhalden
apparatus. This complex was analyzed by both 1H and 11B NMR.
1H NMR was used to monitor the aromatic hydrogens of the
catechol. The dried free boronic acid showed a single peak at
29 ppm, which is indicative of no B-N bond or -B(OR)3
species, while the boronate ester derived from 4-nitrocathechol
had a single signal at 11.8 ppm. This means that there is only
one boron species present upon addition of 4-nitrocatechol, and
that we must have originally isolated a water inserted form of
12.
N-Isopropyl-N-(2-(5-nitrobenzo[d][1,2,3]dioxaborol-2-yl)ben-
zyl)proban-2-amine (13). o-(Diisopropylaminomethyl)phenyl-
boronic acid (70 mg, 0.3 mmol) and 4-nitrocatechol (46.3 mg, 0.3
mmol) were stirred in dry chloroform (50 mL) at room temperature
form 20 min. Magnesium sulfate (50 mg, 0.4 mmol) was added,
and the reaction was stirred overnight. The reaction mixture was
filtered, and the filtrate was washed with chloroform (2 × 5 mL).
Solvent was removed under reduced pressure to provide 13 as a
yellow powder. The product was dried further using an abderhalden
apparatus with refluxing toluene in the presence of phosphorus
pentaoxide for 12 h. This gave 13 as a yellow solid (105 mg, 98%
1
yield). H NMR (400 MHz, CD3CN) δ (ppm) ) 1.34-1.38 (d,
The next experiment involved adding two equivalents of
4-nitrocatechol to test if excess catechol would lead to insertion
12H, CH3), 3.52-3.6 (m, 2H, CH), 4.41-4.44 (t, 2H, CH2),
6.55-6.58 (d, 1H, phenyl-H), 7.2-7.33 (m, 4H, phenyl-H),
7.57-7.59 (d, 1H, phenyl-H), 7.62-7.65 (dd, 1H, phenyl-H). 13C
NMR (500 MHz, CD3CN) δ (ppm) ) 18.9, 52.2, 52.3, 103.5, 107.5,
127.7, 129.2, 132.4, 133.4, 133.6, 140.2, 154.3, 161.8. HRMS
(ESI+): calcd. for C19H23BN2O4 [M + H]+ 355.1824; found m/z:
355.1829. mp 117-121 °C.
1
of a second catechol as a guest. Comparison of the H NMR
spectra of 13 to that of 4-nitrocatechol showed that one of the
two hydrogens ortho- to the two hydroxyl groups was shifted
upfield by 0.3-0.4 ppm while one was only shifted by 0.05
ppm. Most importantly, there were no peaks arising from
additional catechol species in 13 that are not present in
uncomplexed 4-nitrocatechol alone. Hence, in the presence of
Crystal Structure Data. X-Ray Experimental for C18H22
-
BNO3. Crystals grew as colorless prisms by slow evaporation from
methanol. The data crystal was a prism that had approximate
dimensions; 0.35 × 0.17 × 0.09 mm. The data were collected on
a Nonius Kappa CCD diffractometer using a graphite monochro-
(56) Lauer, M.; Bo¨hnke, H.; Grotstollen, R.; Salehnia, M.; Wulff, G. Chem.
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J. Org. Chem. Vol. 74, No. 11, 2009 4059

Collins et al.
mator with Mo KR radiation (λ ) 0.71073Å). A total of 525 frames
of data were collected using ω-scans with a scan range of 0.8° and
a counting time of 153 s per frame. The data were collected at 153
K using an Oxford Cryostream low temperature device. Details of
crystal data, data collection and structure refinement are listed in
Table S1. Data reduction were performed using DENZO-SMN.57
The structure was solved by direct methods using SIR9758 and
refined by full-matrix least-squares on F2 with anisotropic displace-
ment parameters for the non-H atoms using SHELXL-97.50 The
hydrogen atoms on carbon were calculated in ideal positions with
isotropic displacement parameters set to 1.2 × Ueq of the attached
atom (1.5 × Ueq for methyl hydrogen atoms). The hydrogen atoms
on the nitrogen atoms were observed in a ∆F map and refined with
isotropic displacement parameters. The function, Σw(|Fo|2 - |Fc|2)2,
fit, S, are given in the Supporting Information. The data were
checked for secondary extinction effects but no correction was
necessary. Neutral atom scattering factors and values used to
calculate the linear absorption coefficient are from the International
Tables for X-ray Crystallography (1992).60 All figures were
generated using SHELXTL/PC.61 Tables of positional and thermal
parameters, bond lengths and angles, torsion angles, figures and
lists of observed and calculated structure factors are located in
Tables S1-S7, Supporting Information.
Acknowledgment. We acknowledge the work of Dr. Lee
Daniels of Rigaku America, The Woodlands, Texas for work
on the X-ray crystal structures presented herein. This work was
supported by the National Science Foundation (CHE-0616467)
as well as the Welch Foundation.
was minimized, where w ) 1/[(σ(Fo))2 + (0.0332*P)2
+
(2.7466*P)] and P ) (|Fo|2 + 2|Fc|2)/3. Rw(F2) refined to 0.122,
with R(F) equal to 0.0558 and a goodness of fit, S, ) 1.01.
Definitions used for calculating R(F), Rw(F2) and the goodness of
Supporting Information Available: Necessary NMR spec-
tra, and complete crystallographic information. This material
is available free of charge via the Internet at http://pubs.acs.org.
(57) DENZO-SMN: Otwinowski Z.; Minor W. Methods in Enzymology, 276:
Macromolecular Crystallography part A; Carter, C. W., Jr., Sweets, R. M., Eds;
Academic Press: New York, 1997; pp 307-326.
JO900187A
(58) SIR97: A program for crystal structure solution: Altomare, A.; Burla,
M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni,
A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115–119.
(59) Sheldrick, G. M. SHELXL97. Program for the Refinement of Crystal
Structures; University of Gottingen: Germany, 1994.
(60) International Tables for X-ray Crystallography; Wilson, A. J. C., Ed.;
Kluwer Academic Press: Boston, 1992; Vol C, Tables 4.2.6.8 and 6.1.1.4.
(61) Sheldrick, G. M. SHELXTL/PC, version 5.03; Siemens Analytical X-ray
Instruments, Inc.: Madison, WI, 1994.
4060 J. Org. Chem. Vol. 74, No. 11, 2009