Lithium cation enhances anion binding in a tripodal phosphine oxide-based ditopic receptor

Article abstract of DOI:10.1039/c1cc12475g

A tripodal ditopic receptor presents H-bond donors and a phosphine oxide to potential guests. In the idealized binding conformation, an endohedral PO functionality provides enhanced halide binding in the presence of lithium with the greatest ΔΔG° observed for bromide, while minimal changes in K_a are observed in the presence of sodium.

Full text of DOI:10.1039/c1cc12475g

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COMMUNICATION
Lithium cation enhances anion binding in a tripodal phosphine
oxide-based ditopic receptorw
Jesse V. Gavette, Juven Lara, Orion B. Berryman, Lev N. Zakharov, Michael M. Haley*
and Darren W. Johnson*
Received 27th April 2011, Accepted 18th May 2011
DOI: 10.1039/c1cc12475g
A tripodal ditopic receptor presents H-bond donors and a
phosphine oxide to potential guests. In the idealized binding
Receptor 2 was synthesized via reaction of Boc-protected
glycine with 1b (obtained from the trihydrobromide salt 1a)
under common peptide coupling conditions in DMF
(Scheme 1). The desired product was isolated in 76% yield
as a white powder upon precipitation from ethyl acetate.
Single crystals of 2 suitable for X-ray diffraction analysis were
obtained by slow evaporation of methanol.15 In the solid state
receptor 2 forms an up-down-up conformation and accepts
two hydrogen bonds from a bound water molecule (Fig. 1). A
second water molecule also forms a hydrogen bond to the
bound water molecule (hydrogen bond distances and angles
are provided in the cif filesw).
Q
conformation, an endohedral P O functionality provides
enhanced halide binding in the presence of lithium with the
greatest DDG8 observed for bromide, while minimal changes in
Ka are observed in the presence of sodium.
Anion binding by synthetic receptors has garnered much
attention due to emerging applications in waste remediation
and studies aimed at elucidating biological structure and
function.1 Triamines such as 1,3,5-tris(aminomethyl)benzene2–4
and tris(2-aminoethyl)-amine (TREN)5 have proven to be
workhorse scaffolds for tripodal anion receptors. The popularity
of these scaffolds arises from the facile, modular synthetic
modifications of their primary amino groups into strong
hydrogen bond donors like secondary amines,6 amides,7 ureas,8
and thioureas.9 Furthermore, their C3v-symmetric geometry
allows for incorporation of multiple binding groups, which
is very attractive for host–guest chemistry and molecule/ion
recognition studies.
While single crystals of 2ꢀLi+ halide complexes unfortunately
remain elusive, the single crystal X-Ray structure of a related
receptor16 (Fig. S36w) exhibits a ‘‘bowl-shaped’’ cavity which
displays an endohedral phosphine oxide stabilized by three
DMSO solvates. This all up conformation shows that this
receptor class is capable of adopting a conformation that
presents an endohedral Lewis basic phosphine oxide to
create a ditopic binding pocket capable of binding ion pairs.
The possibility of such an endohedral binding geometry is
corroborated by a DFT model of 2ꢀLiBr (Fig. S37w).
Herein we introduce anion recognition to a core scaffold
based on the known tris(aminomethyl)phosphine oxide 1b.10
This scaffold provides for facile synthetic manipulation, a
tripodal geometry, and the incorporation of a Lewis basic
phosphine oxide as a possible endohedral11 cation binder or
hydrogen bond acceptor. We envisioned that the phosphine
oxide moiety could serve as a ligand for small cations such as
lithium. Lithium is an attractive target because of its roles in
the treatment of manic depressive behaviors,12 in battery
technologies,13 and as a surrogate probe for monitoring
Na+ ion channels.14 We report the preparation of a neutral
tripodal ditopic receptor derived from 1b that surprisingly
exhibits increased affinity for halides in the presence of Li+,
but not in the presence of Na+.
Anion binding studies of 2 with various halide salts were
performed via 1H NMR spectroscopy titrations in acetonitrile-d3
(MeCN-d3) (Table 1). Association constants were determined
by monitoring the downfield shift of the carbamate proton
signal and fitting the data to a 1 : 1 binding model17 using
WinEQNMR2.18 The amide NH resonances do not shift
Department of Chemistry and the Materials Science Institute,
University of Oregon, Eugene, OR 97403-1253, USA.
E-mail: dwj@uoregon.edu, haley@uoregon.edu;
Fax: +1-541-346-0487; Tel: +1-541-346-1695
w Electronic supplementary information (ESI) available: experimental
details, spectroscopic data and X-ray analysis of receptors and titration
experiments for 2. CCDC 824327 and 824328. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc12475g
Scheme 1 Synthesis of ditopic receptor 2 using O-(benzotriazole-1-yl)-
N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU) and
Hunig’s base (DIPEA).
c
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Chem. Commun., 2011, 47, 7653–7655 7653

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Fig. 1 X-Ray crystal structure of 2. Red = O, orange = P, blue = N,
gray = C, and white = H.
Table 1 Association constants Ka (Mꢁ1) of 2, 2ꢀLi+ and 2ꢀNa+ with
TBA+ Xꢁ. Determined by an average of three 1H NMR titration
experiments in MeCN-d3 at 298 K. Data fit to a 1 : 1 binding model.
Errors o 10%.
Fig. 2 1H NMR spectra of methylene resonances of (a) receptor 2
with 0, 1 and 10 equiv. of Li+; (b) receptor 2 with excess iodide,
bromide and chloride; (c) complex 2ꢀLi+ with excess iodide, bromide
and chloride. Filled blue square = Ha and filled green circle = Hb.
Empty blue square = cation binding units and empty green circles =
anion binding units.
Clꢁ
Brꢁ
Iꢁ
a
2
320
50
—
2ꢀLi+
2ꢀNa+
DDG1Li
410b
450c
400b
90c
60b
—
a,c
+
(kcal molꢁ1 d
(kcal molꢁ1 e
)
)
ꢁ0.15
ꢁ1.2
ꢁ0.82f
—
DDG1Na
a
+
ꢁ0.16
ꢁ0.34
Association constant o 15 Mꢁ1 and could not be accurately
was observed for the triplet. These observations are consistent
with the coordination of lithium by the scaffold portion of 2
(Fig. 2a). Significant lithium coordination is further supported
by 31P NMR which shows a ca. 6.6 ppm downfield shift of the
phosphorus signal of 2 upon addition of ca. 30 fold excess of
lithium perchlorate to a solution containing 2 and ca. 30 equiv.
of TBA perchlorate.20
determined. Lithium perchlorate used as lithium source. c Sodium tetra-
b
phenylborate used as sodium source. d DDG1Li
+
= (DG12ꢀLi
+
ꢁ DG12).
e
f
DDG1Na
+
= (DG12ꢀNa
+
ꢁ DG12). Association constant of 15 Mꢁ1
was assumed for 2ꢀIꢁ.
downfield appreciably during the titrations with halides, indicating
that these protons do not contribute to the affinity of 2 for
anions. Association constants of 2 with tetrabutylammonium
(TBA) halides gave the expected Hoffmeister trend of
Clꢁ 4 Brꢁ 4 Iꢁ.
Conversely, addition of TBA halide to 2 induces significant
downfield shifting of Hb (green circles) as result of the anion
hydrogen bonding to the nearby carbamate protons, whereas
the triplet remained relatively unchanged (Fig. 2b). The shift
of this resonance was strongest for chloride followed by
bromide and then iodide which trends well with the observed
association constants. Titrations of 2 with lithium bromide
and lithium iodide also showed increased anion association
constants of 200 Mꢁ1 and 30 Mꢁ1, respectively, over the
analogous experiments with the halides alone, lending further
evidence that Li+ is promoting increased halide binding by 2.
Titrations of 2ꢀLi+ with TBA halides resulted in significant
downfield shifting of both methylene resonances. This
observation suggests binding by both lithium and halides
simultaneously, again consistent with the hypothesis that
Li+ binding modulates halide binding in this receptor class.
The magnitude of the downfield shifts in Hb (green circles)
again increases with increasing basicity of guest. The largest
binding enhancement is observed for bromide, with a DDG1 of
ꢁ1.2 kcal molꢁ1 (Table 1). Interestingly, in the case of chloride
the doublet resonance (Hb) shifts further downfield than for
iodide or bromide, whereas the triplet methylene resonance
(Ha) shows reduced shifting compared to iodide and bromide
(Fig. 2c). The diminished downfield shift of Ha in the presence
The affinity for several halides by 2ꢀLi+ was determined
using lithium perchlorate as a lithium source,19 and yielded
noticeable increases in the association constants of all the
anions tested. Remarkably, the affinity of 2 for bromide
increases one order of magnitude in the presence of Li+, even
in a polar coordinating solvent such as MeCN. The unusual
shift in anion binding trends between 2ꢀLi+ vs. 2 was
illuminated upon investigation of the methylene region of
the 1H NMR spectrum (Fig. 2). Addition of a lithium or
halide salt induces a downfield shift and divergence of the
eclipsed methylene resonances from a broad multiplet to a
triplet representing the Ha protons from the scaffold and a
doublet representing the Hb protons from the glycine unit. The
relative magnitude of the downfield shifts of the methylene
resonances are dependent on the identity of the guest.
In the presence of ca. 1 equiv. of lithium perchlorate a small
but noticeable downfield shift for the triplet (Ha, blue squares)
was observed, while the position of the doublet (Hb, green
circles) was relatively unchanged. In the presence of
ca. 10 equiv. of lithium perchlorate further downfield shifting
c
7654 Chem. Commun., 2011, 47, 7653–7655
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of chloride and lithium suggests that lithium is not a good
guest in the presence of chloride, and therefore, lithium is not
enhancing the binding of chloride as significantly, resulting in
only a minor increase in association constant and a DDG1 of
ꢁ0.15 kcal molꢁ1 (Table 1).
7 For some recent examples of amide-based tripodal receptors see:
J. V. Gavette, J. M. McGrath, A. M. Spuches, A. L. Sargent and
W. E. Allen, J. Org. Chem., 2009, 74, 3706–3710; I. Ravikumar,
P. S. Lakshminarayanan and P. Ghosh, Inorg. Chim. Acta, 2010,
363, 2886–2895; K. J. Winstanley, S. J. Allen and D. K. Smith,
Chem. Commun., 2009, 4299–4301.
8 For some recent examples of urea-based receptors see:
I. Ravikumar and P. Ghosh, Chem. Commun., 2010, 46,
1082–1084; C. Jia, B. Wu, S. Li, X. Huang, Q. Zhao, Q.-S. Li
and X.-J. Yang, Angew. Chem., Int. Ed., 2011, 50, 486–490;
I. Ravikumar, P. S. Lakshminarayanan, M. Arunachalam,
E. Suresh and P. Ghosh, Dalton Trans., 2009, 4160–4168.
Lithium ion appears to modulate anion binding exclusively
in this receptor: the presence of sodium21 had little to no effect
on the affinity of the halides toward 2 (Table 1). Although a
small downfield shift of ca. 3.6 ppm in the 31P NMR was
observed upon addition of ca. 30 equiv. of sodium tetra-
phenylborate to a solution of 2 and ca. 30 equiv. of TBA
tetraphenylborate19 only downfield shifting of the Hb resonance
was observed by 1H NMR (Fig. S34w). The magnitude of these
shifts follows the same trend as titrations of the halides and 2
suggesting that sodium is not coordinated to 2 as strongly as
lithium. The preferential binding of lithium over sodium and
the resulting enhancement of bromide binding is presumably
due to a combination of optimum size fit, ion pairing strength,
and differences in solvation.
9 For
a recent example of a thiourea-based receptor see:
N. Busschaert, P. A. Gale, C. J. E. Haynes, M. E. Light,
S. J. Moore, C. C. Tong, J. T. Davis and W. A. Harrell, Chem.
Commun., 2010, 46, 6252–6254.
10 A. W. Frank and D. J. Daigle, Phosphorus Sulfur Relat. Elem.,
1981, 10, 255–259; D. J. Daigle, T. J. Decuir, J. B. Robertson and
D. J. Darensbourg, 1,3,5-Triaz-7-Phosphatricyclo[3.3.1.13,7]-
Decane and Derivatives, John Wiley & Sons, Inc, 2007; B. J. Frost,
J. L. Harkreader and C. M. Bautista, Inorg. Chem. Commun., 2008,
11, 580–583; B. J. Frost, W. C. Lee, K. Pal, T. H. Kim,
D. VanDerveer and D. Rabinovich, Polyhedron, 2010, 29,
2373–2380; R. Huang and B. J. Frost, Inorg. Chem., 2007, 46,
10962–10964.
In conclusion, we have presented the use of a tris-
(aminomethyl)phosphine oxide as a scaffold for the neutral
ditopic tripodal receptor 2. This unusual receptor shows a
greater enhancement in the binding of bromide over chloride
and iodide in the presence of ca. 1 equiv. of a lithium source,
while sodium has little to no effect on anion association.
Determination of association constants of lithium and sodium
by 2ꢀXꢁ are currently underway as are investigations into
possible cooperative effects of other positively charged species
on anion binding.
11 P. H. Liao, B. W. Langloss, A. M. Johnson, E. R. Knudsen,
F. S. Tham, R. R. Julian and R. J. Hooley, Chem. Commun., 2010,
46, 4932–4934; R. J. Hooley, T. Iwasawa and J. Rebek, J. Am.
Chem. Soc., 2007, 129, 15330–15339; R. J. Hooley, P. Restorp,
T. Iwasawa and J. Rebek, J. Am. Chem. Soc., 2007, 129,
15639–15643; A. R. Renslo and J. Rebek, Angew. Chem., Int.
Ed., 2000, 39, 3281–3283; K. Goto and R. Okazaki, Liebigs
Ann./Recl., 1997, 2393.
12 P. E. Keck, S. L. McElroy, S. M. Strakowski and C. A. Soutullo,
J. Clin. Psychiatry, 2000, 61, 33–38; C. Lennkh and C. Simhandl,
Int. Clin. Psychopharmacol., 2000, 15, 1–11.
13 D. Aurbach, J. Power Sources, 2000, 89, 206–218; F. Lantelme,
H. Groult and N. Kumagai, Electrochim. Acta, 2000, 45,
3171–3180; W. H. Meyer, Adv. Mater., 1998, 10, 439–448.
14 D. R. Hunter, R. A. Haworth and H. A. Berkoff, J. Mol. Cell.
Cardiol., 1984, 16, 1083–1090; V. V. Kupriyanov, B. Xiang,
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15 Crystal data for 2ꢀ2(H2O): C24H49N6O12P Mr = 644.66, 0.18 ꢂ
This research was supported by the NIH (GM087398-02)
and the University of Oregon (UO). O.B.B. acknowledges the
NSF for an Integrative Graduate Education and Research
Traineeships (DGE-0549503). The authors thank Professor
Brian J. Frost for helpful discussions on receptor design and
the synthesis of 1a.
%
0.05 ꢂ 0.02 mm, triclinic, P1 (N 2), a = 11.1651(19) A, b =
13.264(2) A, c = 13.360(2) A, a = 93.405(3)1, b = 109.288(3)1,
g = 111.239(3)1,V = 1704.3(5) A3, Z = 2, rcalcd = 1.256 g smꢁ1
,
Notes and references
m = 0.144 mmꢁ1, 2ymax = 50.001, T = 173(2)K, 16644 measured
reflections, 6003 independent reflections [Rint = 0.0446], 428
1 J. W. Steed and J. L. Atwood, Supramolecular Chemistry, John
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and W.-S. Cho, Anion Receptor Chemistry, Royal Society of
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2 D. M. Perreault, L. A. Cabell and E. V. Anslyn, Bioorg. Med.
Chem., 1997, 5, 1209–1220; K. J. Wallace, R. Hanes, E. Anslyn,
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Chem. Soc., 1992, 114, 6653–6661; S. Valiyayeettil, J. F. J.
Engbersen, W. Verboom and D. N. Reinhoudt, Angew. Chem.,
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6 For recent examples of 21 amine-based receptors, see: M. Mazik
and M. Kuschel, Chem.–Eur. J., 2008, 14, 2405–2419; M. Mazik
and C. Sonnenberg, J. Org. Chem., 2010, 75, 6416–6423; A. Arda,
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parameters, R1 = 0.0476, wR2 = 0.1097 (with I 4 2s(I)), R1 =
0.0729, wR2 = 0.1320 (all data), GOF = 1.012, max/min residual
electron density +0.226/ꢁ0.294 e Aꢁ3
.
16 Crystal data for 3ꢀ3(DMSO): C30H36N9O19PS3, Mr = 953.83 , 0.80 ꢂ
0.02 ꢂ 0.01 mm, hexagonal, R3 (N 146), a = b = 26.969(4) A,
c = 4.7896(9) A, 901, 901, 1201, V = 3016.8(8) A3, Z = 3, rcalcd
=
1.575 g smꢁ1, m = 0.315 mmꢁ1, 2ymax = 50.001, T = 173(2)K,
8003 measured reflections, 2156 independent reflections [Rint
=
0.0874], 191 parameters, R1 = 0.0474, wR2 = 0.0701 (with
I 4 2s(I)), R1 = 0.0686, wR2 = 0.0768 (all data), GOF =
0.838, max/min residual electron density +0.251/ꢁ0.226 e Aꢁ3
.
17 Job’s method of continuous variations was used to confirm the 1 : 1
host : guest binding stochiometry (Fig. S7–S9w).
18 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
19 No observable anion binding was observed with LiClO4 or
TBAClO4 indicating that the role of perchlorate is strictly as a
spectator anion.
20 The presence of excess TBA salt ensures that the observed chemical
shift is due to coordination and not changes in the ionic strength of
the receptor milieu.
21 NaB(Ph)4 was used as the source of sodium. 1H NMR titrations of
TBA tetraphenylborate with 2 furnished no measurable binding
event meaning the role of the tetraphenylborate anion is innocent.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7653–7655 7655