AAA-DDD triple hydrogen bond complexes

Article abstract of DOI:10.1021/ja906061v

Experiment and theory both suggest that the AAA-DDD pattern of hydrogen bond acceptors (A) and donors (D) is the arrangement of three contiguous hydrogen bonding centers that results in the strongest association between two species. Murray and Zimmerman p

Full text of DOI:10.1021/ja906061v

Published on Web 09/11/2009
AAA-DDD Triple Hydrogen Bond Complexes
Barry A. Blight,† Amaya Camara-Campos,† Smilja Djurdjevic,† Martin Kaller,†
David A. Leigh,*,† Fiona M. McMillan,† Hamish McNab,*,† and
Alexandra M. Z. Slawin‡
Contribution from the School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West
Mains Road, Edinburgh EH9 3JJ, United Kingdom and the School of Chemistry, UniVersity of
St. Andrews, Purdie Building, St. Andrews, Fife, KY16 9ST, United Kingdom.
Received July 20, 2009; E-mail: david.leigh@ed.ac.uk; h.mcnab@ed.ac.uk
Abstract: Experiment and theory both suggest that the AAA-DDD pattern of hydrogen bond acceptors
(A) and donors (D) is the arrangement of three contiguous hydrogen bonding centers that results in the
strongest association between two species. Murray and Zimmerman prepared the first example of such a
system (complex 3•2) and determined the lower limit of its association constant (Ka) in CDCl3 to be 105
M-1 by 1H NMR spectroscopy (Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-4011).
The first cationic AAA-DDD pair (3•4+) was described by Bell and Anslyn (Bell, D. A.; Anslyn, E. A.
Tetrahedron 1995, 51, 7161-7172), with a Ka > 5 × 105 M-1 in CH2Cl2 as determined by UV-vis
spectroscopy. We were recently able to quantify the strength of a neutral AAA-DDD arrangement using
a more chemically stable AAA-DDD system, 6•2, which has an association constant of 2 × 107 M-1 in
CH2Cl2 (Djurdjevic, S.; Leigh, D. A.; McNab, H.; Parsons, S.; Teobaldi, G.; Zerbetto, F. J. Am. Chem. Soc.
2007, 129, 476-477). Here we report on further AA(A) and DDD partners, together with the first precise
measurement of the association constant of a cationic AAA-DDD species. Complex 6•10+[B(3,5-
(CF3)2C6H3)4-] has a Ka ) 3 × 1010 M-1 at RT in CH2Cl2, by far the most strongly bound triple hydrogen
bonded system measured to date. The X-ray crystal structure of 6•10+ with a BPh4 counteranion shows
-
a planar array of three short (NH · · ·N distances 1.95-2.15 Å), parallel (but staggered rather than strictly
linear; N-H· · ·N angles 165.4-168.8°), primary hydrogen bonds. These are apparently reinforced, as theory
predicts, by close electrostatic interactions (NH-·-N distances 2.78-3.29 Å) between each proton and
the acceptor atoms of the adjacent primary hydrogen bonds.
Introduction
result in particularly stable complexes because of favorable
secondary electrostatic interactions,3 have been prepared or
Multipoint hydrogen bonding motifs are the cornerstones of
the recognition processes of biology and increasingly feature
in the design of sophisticated functional organic materials and
synthetic supramolecular polymers.1,2 Fused-ring heterocyclic
systems are generally the scaffolds of choice for contiguous
hydrogen bonding centers, as geometrically well-defined arrays
of hydrogen bond donor (D) and acceptor (A) groups can be
presented along the edges of each rigid planar (or near-planar)
heteroaromatic unit. Unfortunately, accompanying solubility
issues and the possibility of multiple tautomeric forms for some
heterocycles can sometimes complicate the characterization of
their binding properties. Few receptor pairs with AA-DDD or
AAA-DDD hydrogen bonding motifs, which are predicted to
studied4,5 to date. Following the Jorgensen group’s calculations3
on the exceptionally strong binding in such hydrogen bond
(2) (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W.
Science 1997, 278, 1601–1604. (b) Beijer, F. H.; Siijbesma, R. P.;
Kooijman, H.; Spek, A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120,
6761–6769. (c) Gong, B.; Zeng, H.; Miller, S.; Flowers, R. J. Am. Chem.
Soc. 2000, 122, 2635–2644. (d) Corbin, P. S.; Zimmerman, S. C.;
Thiessen, P. A.; Hawryluk, N. A.; Murray, T. J. J. Am. Chem. Soc. 2001,
123, 10475–10488. (e) Folmer, B. J. B.; Sijbesma, R. P.; Meijer, E. W.
J. Am. Chem. Soc. 2001, 123, 2093–2094. (f) Tokunaga, Y.; Seo, T.
Chem. Commun. 2002, 970–971. (g) Wang, X. Z.; Li, X. Q.; Shao, X. B.;
Zhao, X.; Deng, P.; Jiang, X. K.; Li, Z. T.; Chen, Y. Q. Chem.sEur. J.
2003, 9, 2904–2913. (h) Laffite, V. G. H.; Aliev, A. E.; Hailes, H. C.;
Bala, K.; Golding, P. J. Org. Chem. 2005, 70, 2701–2707. (i) Ligthart,
G. B. W. L.; Ohkawa, H.; Sijbesma, R. T.; Meijer, E. W. J. Am. Chem.
Soc. 2005, 127, 810–811. (j) Ligthart, G. B. W. L.; Guo, D.; Spek,
A. L.; Kooijman, H.; Zuilhof, H.; Sijbesma, R. P. J. Org. Chem. 2008,
73, 111–117. (k) de Greet, T. F. A.; Ligthart, G. B. W. L.; Lutz, M.;
Spek, A. L.; Meijer, E. W.; Sijbesma, R. P. J. Am. Chem. Soc. 2008,
130, 5479–5486. (l) McGhee, A. M.; Kilner, C.; Wilson, A. J. Chem.
Commun. 2008, 344–346.
† University of Edinburgh.
‡ University of St Andrews.
(1) (a) Zimmerman, S. C.; Corbin, P. S. Struct. Bonding (Berlin) 2000,
96, 63–94. (b) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma,
R. P. Chem. ReV. 2001, 101, 4071–4097. (c) Prins, L. J.; Reinhoudt,
D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001, 40, 2383–2426.
(d) Schmuck, C.; Wienand, W. Angew. Chem., Int. Ed. 2001, 40, 4363–
4369. (e) Sherrington, D. C.; Taskinen, K. A. Chem. Soc. ReV. 2001,
30, 83–93. (f) Sijbesma, R. P.; Meijer, E. W. Chem. Commun. 2003,
5–16. (g) Zimmerman, S. C.; Park, T. Polym. Prepr. 2005, 42, 1159–
1160. (h) Wilson, A. J. Soft Matter 2007, 3, 409–425. (i) Fathalla,
M.; Lawrence, C. M.; Zhang, N.; Sessler, J. L.; Jayawickramarajah,
J. Chem. Soc. ReV. 2009, 38, 1608–1620.
(3) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008–
2010. (b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 2810–2819.
(4) (a) Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114,
4010–4011. (b) Zimmerman, S. C.; Murray, T. J. Tetrahedron Lett.
1994, 35, 4077–4080.
(5) Bell, D. A.; Anslyn, E. A. Tetrahedron 1995, 51, 7161–7172.
9
14116 J. AM. CHEM. SOC. 2009, 131, 14116–14122
10.1021/ja906061v CCC: $40.75  2009 American Chemical Society

AAA-DDD hydrogen bond complexes
A R T I C L E S
Figure 1. Early experimental examples of AA-DDD and AAA-DDD
hydrogen bonding arrays: (a) AA-DDD complex 1•2;4 (b) AAA-DDD
complex 3•2;4 (c) AAA-DDD(cationic) complex 3•4+[B(3,5-(CF3)2C6-
H3)4-].5 Primary hydrogen bonds shown with dashed lines; additional
attractive secondary electrostatic interactions shown with hashed lines.
arrangements, the first experimental systems were realized4 by
Murray and Zimmerman who reported the association constants
(Ka) of AA-DDD complex 1•2 to be Ka ) 3 × 103 M-1 (Figure
1a) and that of AAA-DDD system 3•2 to be g105 M-1 (Figure
1b) in CDCl3. Variations of the contiguous hydrogen bond
acceptor-donor arrangements were consistent with cooperative
secondary hydrogen bonding interactions playing a prominent
role in the stabilization energy of these complexes.6 However,
AAA-DDD system 3•2 proved to be chemically reactive and
required the presence of proton sponge (1,8-bis(dimethylami-
no)naphthalene) during the binding studies to prevent a hydride
shift occurring from C-4 of 2 to C-10 of 3. An attempt to
simultaneously increase the chemical stability and binding
affinity of a contiguous AAA-DDD pair was reported by Bell
and Anslyn,5 who described the properties of the AAA-
Figure 2. AA(A)-DDD systems featured in the present study.
In 2007 we made a preliminary report7 on the synthesis and
complexation studies of AA and AAA units 5 and 6 with DDD
partners 2 and 7 (Figure 2). The extended aromatic system in 6
does not undergo the hydride transfer reaction that hindered
the study of 3 and is also probably a slightly stronger hydrogen
bond acceptor than the classic Zimmerman AAA system.7 Here
we extend the library of molecules with contiguous acceptor or
contiguous donor sites, providing an account of the synthesis
and complexation studies of six complementary pairs (Figure
2).
Synthesis. There are few known examples of heterocycles
with multiple contiguous hydrogen bond sites in an AAA
pattern. Caluwe and Majewicz introduced9 methodology for the
synthesis of 1,9,10-anthyridines (three pyridine rings fused
together in a linear fashion through their 2,3/4,5 positions so
that the three nitrogen atoms are all presented on the same edge
of the molecule, e.g., 3) but most examples of these heterocycles
appear to be easily reduced to the corresponding 5,10-dihy-
droanthyridines (for example, by NaOEt/EtOH9 and during the
binding studies of 3 with DDD unit 24). Various aryl and
heteroaromatic groups have been introduced10 at the 5-position
of 3 in an attempt to overcome the instability of the central
ring, but binding studies with these modified systems have not,
to our knowledge, been reported. We decided to extend the
DDD(cationic) complex 3•4+[B(3,5-(CF3)2C6H3)4 ] (Figure 1c).
-
The cationic DDD species enhances the hydrogen bond donating
ability of the donor unit while also providing some electrostatic
stabilization of the DDD-AAA complex. The Ka of 3•4+[B(3,5-
(CF3)2C6H3)4-] was estimated from UV-vis titration experi-
ments to be greater than 5 × 105 M-1 in CH2Cl2; however, no
precise determination of the binding constant could be made
because excited state proton transfer in the AAA-DDD(cationic)
complex complicated the fluorescence spectra. Since these
seminal studies, until recently,7 relatively little progress8 had
been made in developing more robust and less chemically
reactive AAA-DDD systems.
(6) Some have cautioned against the use of the secondary interaction
hypothesis to explain the stability of hydrogen bonded complexes.
See: Popelier, P. L. A.; Joubert, L. J. Am. Chem. Soc. 2002, 124, 8725–
8729.
(7) Djurdjevic, S.; Leigh, D. A.; McNab, H.; Parsons, S.; Teobaldi, G.;
Zerbetto, F. J. Am. Chem. Soc. 2007, 129, 476–477.
(8) (a) Sugiyama, Y.; Adachi, K.; Kawata, S.; Kumagai, H.; Inoue, K.;
Katada, M.; Kitagawa, S. CrystEngComm 2000, 2, 174–176. (b)
Sugiyama, Y.; Adachi, K.; Kabir, M. K.; Kitagawa, S.; Suzuki, T.;
Kaizaki, S.; Kawata, S. Mol. Cryst. Liq. Cryst. 2002, 379, 419–424.
(c) Adachi, K.; Sugiyama, Y.; Yoneda, K.; Yamada, K.; Nozaki, K.;
Fuyuhiro, A.; Kawata, S. Chem.sEur. J. 2005, 11, 6616–6628.
(9) Caluwe, P.; Majewicz, T. G. J. Org. Chem. 1977, 42, 3410–3413.
(10) Murray, T. J.; Zimmerman, S. C. Tetrahedron 1995, 51, 635–648.
9
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A R T I C L E S
Blight et al.
Scheme 1. Synthesis of AA and AAA units 5, 6, 8 and 9 and
a
Cationic DDD Unit 10+
Figure 3. X-ray crystal structures of (a) 5·2H2O viewed from above the
molecular plane, (b) 5·2H2O viewed edge on, showing the significant (∼30°)
helical twist to the molecule, (c) 6 viewed from above the molecular plane,
and (d) 6 viewed edge on, showing the slight (∼7°) helical twist to the
molecule. Carbon atoms are shown in red; hydrogen white; nitrogen blue;
oxygen yellow. Hydrogen bond lengths (Å) and angles (°): N1 · · ·H2W2 )
2.121,N1 · · ·H2W2-O2W)175.5;N12 · · ·H1W1)2.094,N1 · · ·H1W1-O1W
) 166.0.
a Reagents and conditions: (i) Pd(PPh3)4, K2CO3, dioxane/water (1:1),
80%; (ii) methoxyamine hydrochloride, EtOH, 96%; (iii) FVP (flash vacuum
pyrolysis; furnace temperature ) 700 °C, inlet temperature ) 182 °C,
pressure ) 4.8 × 10-2 Torr, 10 min, 75%; (iv) N-iodosuccinamide, DMF,
86%; (v) 2-formylphenyl boronic acid, Pd(PPh3)4, Cs2CO3, dioxane/water
(1:1), 80%; (vi) 2-aminopyridine, Pd(OAc)2, 2,2′-bis(diphenylphosphino)-
1,1′-binaphthyl (BINAP), K2CO3, toluene, 70%; (vii) polyphosphoric acid,
95%; (viii) 2-aminopyridine, Pd(OAc)2, BINAP, K2CO3, toluene, 40%; (ix)
polyphosphoric acid, 85%; (x) HCl gas, CHCl3, 98%; (xi) NaB(3,5-
(CF3)2C6H3)4, CH3CN, 75%.
commercially available 2-chloro-3-cyanopyridine or previously
reported 2-chloro-3-cyano-1,8-naphthyridine13 yielded the pre-
cursors to 8 (Scheme 1c) and 9 (Scheme 1d). Ring closure of
these intermediates was achieved by heating in polyphosphoric
acid to give the acceptor molecules 8 and 9 in good yields (84
and 85%, respectively) without the need for further purification.
The DDD arrays used in these studies include commercially
available 2,6-bis(hydroxyl-methyl)-p-cresol (7), the previously
reported4 2,6-diamino-1,4-dihydropyridine unit 2, and 2,6-
diaminopyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate
aromatic framework of the 1,9,10-anthyridine skeleton in the
form of the pentacene analogue 6,7,8-triaza-dibenzo[a,f]an-
thracene 6 and 1,6a,11,12-tetraaza-naphthacein-6-one 9 and their
AA (naphthyridine) analogues 5 and 8, each of which could be
prepared in three or less synthetic steps (Scheme 1).
The synthesis of AA unit 5 was accomplished via a Suzuki
coupling between 4-bromoisoquinoline and 2-formylphenyl
boronic acid followed by formation of the subsequent oxime
ether (Scheme 1a, steps i and ii). Flash vacuum pyrolysis (FVP,
step iii)11 then afforded compound 5 in 75% yield. AAA unit 6
was synthesized in two steps via iodination of the 3,5-positions
of 2,6-diaminopyridine with N-iodosuccinimide,12 followed by
a one-pot double Suzuki coupling-cyclization-aromatization
protocol with 2-formylphenyl boronic acid (80%, Scheme 1b).
Palladium catalyzed cross-coupling of 2-aminopyridine with
(10+[B(3,5-(CF3)2C6H3)4 ]). The cationic DDD unit (10+) with
-
the weakly ion-pairing tetraaryl borate anion [B(3,5-
(CF3)2C6H3)4-] (BARF14) was obtained in 75% yield (Scheme
1e) by protonation of 2,6-diaminopyridine with HCl gas
followed by anion exchange with NaB(3,5-(CF3)2C6H3)4 in
acetonitrile.
The solid state structures of 5 and 6 were determined by X-ray
diffraction analysis of single crystals obtained by slow evapora-
tion of saturated solutions of the AA and AAA molecules in
CH2Cl2/MeOH (Figure 3).7 AA unit 5 crystallized as the
dihydrate in space group Pbca (Figure 3a and b). A notable
feature of the structure is that the spatial requirements of the
(13) Baldwin, J. J.; Engelhardt, E. L.; Hirschmann, R.; Ponticello, G. S.;
Atkinson, J. G.; Wasson, B. K.; Sweet, C. S.; Scriabine, A. J. Med.
Chem. 1980, 23, 65–70.
(11) Duffy, E. M.; Foot, J. S.; McNab, H.; Milligan, A. A. Org. Biomol.
Chem. 2004, 2, 2677–2683.
(12) Koradin, C; Dohle, W; Rodriguez, A. L; Schmid, B; Knochel, P
Tetrahedron 2003, 59, 1571–1587.
(14) Yakelis, N. A.; Bergman, R. G. Organometallics 2005, 24, 3579–
3581.
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AAA-DDD hydrogen bond complexes
A R T I C L E S
Figure 4. (a) Structures, association constants, and (b) binding isotherms of receptor pairs 5•2, 8•2 and 6•7. 1H NMR titration analyses performed in CDCl3
using the change in chemical shift (∆δ) of the amino NH2 groups of 2 (10-3 M) upon addition of 5 or 8 and the hydroxyl groups of 7 (10-3 M) upon addition
of 6. The lines indicate best-fitting Ka’s for 5•2 (red), 8•2 (blue) and 6•7 (green).
hydrogen atoms attached to C6 and C7 require the quadruple-
ring system to adopt a pronounced helical twist (C6-C61-
C63-C7 torsional angle ) 29.9°) to accommodate them. AAA
system 6 (Figure 3c and d), which crystallized in space group
P21/c, exhibits a greatly reduced twist (C6-C61-C72-C8
torsional angle ) 6.9°) as the annulated phenyl rings are
separated by the width of an additional six membered ring.
AA-DDD pairs 5•2 and 8•2 are 1.8 and 2.0 kcal mol-1 more
stable than the previously reported4 AA-DDD system 1•2
(Figure 1a).
Association Constant Determinations for AAA-DDD
1
Complexes 6•2, 9•2 and 6•10+. H NMR titration experiments
with AAA-DDD complexes 6•2, 9•2 and 6•10+[B(3,5-
-
(CF3)2C6H3)4 ] gave binding isotherms that were steep, abruptly
changing and close to their maximum values at a 1:1 ratio (see
Supporting Information), typical of association constants outside
the range that can be accurately measured by standard NMR
methods.16 These observations are consistent with the previous
reports4,5 on AAA-DDD systems. In addition, the titration data
for 6•2 fitted a 2:1 stoichiometry at 10-3 M, confirmed by a
Job plot with a maximum at a molar ratio of 0.65 at this
relatively high concentration (see Supporting Information).
Compound 2 exists as a mixture of 1,4-dihydro and 3,4-
dihydro tautomeric forms (Figure 5a) that are in slow exchange
in CDCl3 at room temperature, further complicating these
binding experiments. An illustration of the efficacy of 6 as an
AAA partner is provided by the observation that although ten
equivalents of AAA partner 3 are reported4 to fully convert 2
into the 1,4-dihydro DDD form at millimolar concentrations,
only 0.5 equivalents of 6 were required to convert the initial
67:33 ratio of the 1,4-dihydro:3,4-dihydro forms of 2 to greater
than 98:2 (Figure 5).
UV-vis titrations (see Supporting Information) of these
AAA-DDD complexes at 10-5 M concentrations (CH2Cl2, 293
K) also gave sharply changing isotherms, indicating that still
more dilute concentrations (and thus a more sensitive spectro-
photometric method) would be required to precisely measure
their binding strength.
The Ka values for complexes 6•2, 9•2 and 6•10+ were
successfully determined using titrations based on fluorescence
spectroscopy at nanomolar concentrations.17 Compounds 6 and
9 fluoresce with quantum yields of 0.94 for 6 and 0.25 for 9 in
CH2Cl2, determined by standard methods.20 Fluorescence titra-
tions were performed in CH2Cl2 at 293 K by adding a solution
of 2 (1 × 10-8 M) to 6 or 9 (initial concentrations 1 × 10-9 M)
and monitoring the increase in fluorescence intensity at 410 nm
(for 6•2) and 517 nm (for 9•2) upon excitation at 395 and 480
nm. The complexes are extremely strongly bound, with a Ka
value for 6•2 of 2 × 107 M-1 (Figure 6a)7 and 7 × 106 M-1 for
Association Constant Determinations for AA-DDD
Complexes 5•2 and 8•2 and AAA-DDD Complex 6•7. The
weaker complexes (Ka < 105 M-1) in this study could be
satisfactorily15 measured by standard 1H NMR titration
methods16,17 and these were used to determine the stabilities of
complexes 5•2, 8•2 and 6•7 (Figure 4). The titrations were
carried out in CDCl3 at 293 K under conditions where self-
association of 2, 5, 6, 7, and 8 was negligible (as determined
by 1H NMR). Plots for the change in chemical shifts of amino
(2) or hydroxyl (7) protons versus host to guest ratio for
complexes 5•2, 8•2 and 6•7 gave titration curves that fit18 to a
1:1 binding isotherm, giving association constants of 8 × 104
M-1, 6 × 104 M-1 and 2.4 × 104 M-1 respectively (Figure 4).
The AAA-DDD complex 6•7 employs hydroxyl protons as the
hydrogen bond donor source, which are significantly poorer
donors than heterocyclic amine protons.19 The three receptor
pairs show exceptionally strong binding for supramolecular
complexes held together with so few (5•2 and 8•2) or such weak
(6•7) noncovalent interactions. The binding energies for
(15) Although the Ka value of 8 × 104 M-1 for 5•2 was reproducible at
1
this concentration (close to the limit at which H NMR titrations are
accurate), and the error in data-fitting was <5%, the 1H NMR titration
binding isotherm (Figure 4b) is sufficiently steep and close to its
maximum value at a 1:1 ratio that the Ka may be an underestimate
and the value not as accurate as the others reported in this paper.
(16) (a) Wilcox, C. S. In Frontiers in Supramolecular Organic Chemistry
and Photochemistry; Schneider, H. J., Durr, H., Eds.; VCH: New York,
1991; pp 123-143. (b) Connors, K. A. Binding Constants: The
Measurement of Molecular Complex Stability; Wiley-Interscience: New
York, 1987; pp 24-68 and 141-216.
(17) Repetitions of the binding experiments for each of the reported
complexes gave Ka’s within 10% of the values shown (the error in
data-fitting for each run was <5%). See also ref 15.
(18) GAs-Fit: A program that uses an evolutionary algorithm to solve the
standard equations for titration methods, suitable even for large binding
constants (http://gasfit.djurdjevic.org.uk). In tests, for data in the Ka
102-105 M-1 range, GAs-Fit gave similar results to the binding
constant determination program available from the group of H.-J.
Schneider (http://www.uni-saarland.de/fak8/schneider/Links/down-
load.html).
(20) Lakowicz, J. R; Principles of Fluorescence Spectroscopy; Kluwer
Academic: New York, 1999; pp 52-53.
(19) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310–5324.
9
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A R T I C L E S
Blight et al.
Figure 7. Fluorescence spectra of 6 (ca. 1 × 10-10 M) upon addition of
10+[B(3,5-(CF3)2C6H3)4-] (0f 2.5 equiv), maintaining the concentration
of 6 constant, in CH2Cl2 at 293 K upon excitation at 395 nm.
Figure 8. Fluorescence intensities of 6 (1 × 10-10 M) at 406 nm in CH2Cl2
-
at 293 K (λexcitation ) 395 nm) upon addition of 10+[B(3,5-(CF3)2C6H3)4
]
(0f2.5 equiv.), maintaining the concentration of 6 constant, using a 1:1
complexation model. (Inset) Job plot under the same conditions as the
titration experiment.
hydride shifts or excited state proton transfer phenomena were
observed during the association constant measurements of any
of these complexes.
Figure 5. 1H NMR (400 MHz, CDCl3, 298 K) spectra of (a) 2, (b) 2 +
0.13 equiv of 6, (c) 2 + 0.25 equiv of 6, and (d) 2 + 0.5 equiv of 6.
Experiments carried out at 1 × 10-3 M concentration of 2.
To precisely measure the association constant of the cationic
AAA-DDD pair 6•10+[B(3,5-(CF3)2C6H3)4-], fluorescence ti-
trations were performed in CH2Cl2 at 293 K by adding a solution
of 10+[B(3,5-(CF3)2C6H3)4-] (1 × 10-9 M) to 6 (ca. 1 × 10-10
M), while keeping the concentration of 6 constant, and monitor-
ing the increase in fluorescence intensity at 406 nm upon
excitation at 395 nm (Figure 7). The experimental data fit to a
1:1 isotherm,21 confirmed by Job plot experiment showing a
1:1binding(maximummolarratio)0.52).Complex6•10+[B(3,5-
-
(CF3)2C6H3)4 ] is the strongest triple hydrogen bonded complex
measured to date with a Ka ) 3 × 1010 M-1 in CH2Cl2 at 293
K (Figure 8). Treatment of 6•10+[B(3,5-(CF3)2C6H3)4-] with
solid K2CO3 deprotonates the pyridinium salt to generate 2,6-
diaminopyridine. 1H NMR titrations show no discernible com-
plexation between 6 and 2,6-diaminopyridine in CD2Cl2 at
millimolar concentrations (Ka < 10 M-1) and so protonation/
deprotonation offers a simple means to switch between the
extremely strongly bonded complex 6•10+[B(3,5-(CF3)2C6H3)4-]
and the uncomplexed, nonprotonated, components.
Single crystals of the 6·10+cationic AAA-DDD system were
obtained by slow diffusion of diisopropyl ether into a concen-
trated acetonitrile solution of 6·10+[BPh4 ]. The tetraphenylbo-
-
rate anion was used to lower the solubility of the AAA-DDD
complex and promote crystallization. X-ray diffraction analysis
of an amber colored single crystal revealed that the cationic
AAA-DDD system crystallized in space group Cc as
Figure 6. Change in the fluorescence intensities upon addition of aliquots
of 2 to (a) 6 at 410 nm (λexcitation ) 395 nm) and (b) 9 at 517 nm (λexcitation
) 480 nm) in CH2Cl2 at 293 K. The red lines show the best fitting. (Insets)
Job plots under the same conditions as the titration experiments.
9•2 (Figure 6b). Both sets of data fit to a 1:1 isotherm, while
Job plot experiments confirmed the 1:1 stoichiometry for both
complexes at this concentration (see insets in Figure 6). No
(21) Hunter, C. A. AllMaster14 host-guest titration fitting software;
University of Sheffield: Sheffield, U.K. 2008.
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AAA-DDD hydrogen bond complexes
A R T I C L E S
Figure 9. X-ray crystal structure of AAA-DDD(cationic) complex
6·10+[BPh4-].22 Carbon atoms of the AAA unit are shown in red, those of
the DDD unit pale blue and those of the anion gray; hydrogen atoms are
white (omitted from the anion for clarity); nitrogen blue; boron orange.
Primary and secondary hydrogen bonding interactions are denoted by dotted
and dashed lines, respectively. Selected primary hydrogen bond lengths (Å)
and angles (°): N1· · ·H24A ) 1.96, N1· · ·H24A-N24 ) 168.7; N21· · ·H23A
)2.15,N21 · · ·H23A-N23)168.8;N19 · · ·H28A)1.95;N19 · · ·H28A-N28
) 165.4. Selected secondary hydrogen bond lengths (Å) and angles (deg):
N1· · ·H23A ) 2.85, N1 · · ·H23A-N23 ) 135.1; N21 · · ·H24A ) 3.24,
N21· · ·H24A-N24 ) 133.0; N21· · ·H28A ) 2.78, N21· · ·H28A-N28 )
140.3; N19 · · ·H23A ) 3.29, N19 · · ·H23A-N23 ) 127.9.
Figure 10. Some literature examples of DAD-ADA and AAD-DDA
triple hydrogen bond complexes.
B3LYP/6-31G* level calculations using the Gaussian03
program7,25 and may simply be a consequence of crystal packing
forces.
3(6·10+[BPh4-])•5CH3CN (Figure 9).22 The structure shows a
planar array of three short (NH· · ·N distances 1.95, 1.95, and
2.15 Å, compared to 2.03-2.21 Å typically found in the crystal
structures of other contiguous hydrogen bond arrays1,2), parallel
(but staggered rather than strictly linear; N-H· · ·N angles
165.4-168.8°), primary hydrogen bonds. These are apparently
reinforced by close electrostatic interactions (NH-·-N dis-
tances 2.78-3.29 Å) between each proton and the acceptor
atoms of the adjacent primary hydrogen bonds. Although only
the strongest types of hydrogen bonds (of virtually covalent bond
strength) tend to have 180° bond angles,23 the offset arrangement
observed in the crystal structure of 6·10+[BPh4-] is slightly
surprising as the primary hydrogen bond lengths and the
secondary interaction distances are not minimized by such an
arrangement. Strictly linear motifs are a common feature in the
X-ray crystal structures of other contiguous hydrogen bond
arrays(ADA-DAD,AAD-DDAandAADD-DDAAsystems)1,2
although “propeller-twisted” pairings24 are apparent in both
DNA24a and some synthetic systems.24b-d However, the stag-
gered coconformation of 6•10+ is not reproduced by various
Contribution of Secondary Interactions to Complex
Strength. Current dogma6 is that secondary electrostatic interac-
tions between adjacent hydrogen bonding sites play an important
role in determining the stability of contiguous hydrogen bond
arrays and rare experimental examples of AAA-DDD systems
add new data to the field. Experimentally determined Ka values
(Figure 10) for triple hydrogen bond complexes in halogenated
solvents (CHCl3, CDCl3 or CH2Cl2) range from 90-550 M-1
(-2.7 to -3.7 kcal mol-1) in neutral ADA-DAD type
complexes (which feature only repulsive secondary interactions),
to 1.2 × 104 - 105 M-1 (-5.8 to -6.8 kcal mol-1) for the AAD-
DDA type (which are stabilized by two attractive secondary
interactions but have an equal number of repulsive secondary
interactions).26-28 Neutral AAA-DDD complexes 6•2 and 9•2
contain four attractive secondary interactions each and exhibit
Ka’s of 2 × 107 and 7 × 106 M-1 in CH2Cl2 that correspond to
binding energies of -9.9 and -9.3 kcal mol-1, respectively.
(24) (a) Neidle, S. Nucleic acid structure and recognition; Oxford
University Press: Oxford, 2002. (b) ten Cate, A. T.; Dankers, P. Y. W.;
Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. J. Am.
Chem. Soc. 2003, 125, 6860–6861. (c) ten Cate, A. T.; Kooijman, H.;
Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. J. Am. Chem. Soc. 2004,
126, 3801–3808. (d) Ligthart, G. B. W. L.; Guo, D.; Spek, A. L.;
Kooijman, H.; Zuilhof, H.; Sijbesma, R. P. J. Org. Chem. 2008, 73,
111–117.
(22) Crystal data for 3[6·10+ ·BPh4-]·5CH3CN: C154H132B3N23, M )
2337.26, amber needles 0.15 × 0.05 × 0.05 mm3, monoclinic, space
group Cc; a ) 36.323(12) Å, b ) 10.166(3), c ) 34.552(10) Å; R )
90, ꢀ ) 99.372(9), γ ) 90°; V ) 12588(6) Å3, Fcalcd ) 1.233 Mg/m3,
µ ) 0.573 mm-1, Z ) 4; λ ) 1.54178 Å, T ) 173(2) K, 79150 data
(21718 unique, Rint ) 0.0798), R ) 0.0884 for 6199 observed data,
wR2 ) 0.2881, S ) 1.048 for 1643 parameters. Residual electron
density 0.592 and-0.353 eÅ-3. Data was collected using a Rigaku
MM007 High brilliance RA generator (Cu KR radiation, confocal
optics) and Saturn92 CCD system. Intensities were corrected for
Lorentz-polarization and for absorption. The structures were solved
by direct methods. Hydrogens bound to carbon atoms were placed in
chemically reasonable positions. Structural refinements were performed
with full-matrix least-squares based on F2 by using the program:
Sheldrick, G. M. SHELXTL 6.14; Bruker AXS: Madison, WI, 2004.
(23) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University
Press: Oxford, 1997.
(25) Newman, S. G.; Taylor, A.; Boyd, R. J. Chem. Phys. Lett. 2008, 450,
210–213.
(26) Kyogoku, Y.; Lord, R. C.; Rich, A. Proc. Natl. Acad. Sci. U.S.A. 1967,
57, 250–257.
(27) (a) Rebek, J., Jr.; Askew, B.; Ballester, P.; Buhr, C.; Jones, S.; Nemeth,
D.; Williams, K. J. Am. Chem. Soc. 1987, 109, 5033–5035. (b) Kelly,
T. R.; Maguire, M. P. J. Am. Chem. Soc. 1987, 109, 6549–6551. (c)
Kelly, T. R.; Zhao, C.; Bridger, G. J. J. Am. Chem. Soc. 1989, 111,
3744–3745.
(28) Kyogoku, Y.; Lord, R. C.; Rich, A. Biochim. Biophys. Acta 1969,
179, 10–17.
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A R T I C L E S
Blight et al.
Thus in this series each incremental increase of two cooperative
secondary interactions increases the stability of the neutral triple
prove useful for parametrizing these methods at the extremes
of strongly binding hydrogen bonding motifs.
hydrogen bonded complex by roughly 3 kcal mol-1
.
Conclusions
Various empirical methods have been formulated in order to
more precisely predict the binding energy data of hydrogen
bonding complexes.29,30 Schneider has developed an additive
approach for estimating ∆G of association by attributing energy
values of 1.9 kcal mol-1 for primary hydrogen bonds and 0.7
kcal mol-1 for cooperative secondary interactions.29 Applying
this method to an AAA-DDD type system, with three primary
hydrogen bonds and four secondary interactions, gives a
predicted value for the stability of such a complex to be 8.4
kcal mol-1 (Ka ) 5 × 106 M-1). Experimentally 9•2 is 0.6 kcal
mol-1 more stable and 6•2 is 1.4 kcal mol-1 more stable than
this predicted value. Zimmerman has formulated an alternative
empirical method to calculate the ∆G of linear arrays of
hydrogen bonds.30 This approach takes into account different
types of noncovalent interactions, such as differentiating between
NH· · ·N, NH · · ·O, and CH · · ·O hydrogen bonds, intramolecular
hydrogen bonds that must be broken to form new intermolecular
bonds, cooperative and repulsive secondary electrostatic interac-
tions, and the loss of rotational and translational entropy when
two species are complexed into a static geometry with restricted
molecular motion. Evaluation of 6•2 employing this formula
gives -7.7 kcal mol-1, which is 2.2 kcal mol-1 less than the
experimentally determined value. Both the Schneider and
Zimmerman predictive tools are based on measurements made
in CHCl3 or CCl4 whereas the data for 6•2 were obtained in
CH2Cl2, however one would not expect this to fully account
for the difference between the experimental and predicted values.
One contributing reason for the disparity could be that both
models are largely based on data extracted from DNA-base
pairs that are rather more flexible and much weaker than the
strong, rigid AAA-DDD systems reported here. The experi-
mental data for AAA-DDD hydrogen bond complexes may
Short and efficient synthetic routes to chemically stable AA
and AAA hydrogen bonding units have enabled the binding
constants of some supramolecular complexes of the AA-DDD
and AAA-DDD type to be measured. Neutral AAA-DDD
complexes 6•2 and 9•2 have Ka’s of 2 × 107 M-1 and 7 × 106
M-1, respectively, in CH2Cl2 at room temperature, as determined
by fluorescence spectroscopic titrations. The binding constant
of a cationic AAA-DDD system 6•10+ was determined to be
Ka ) 3 × 1010 M-1 under the same conditions, a remarkable
value for a triple hydrogen bond system and ∼108× greater
than the typical value for triple hydrogen bonded DNA base
pairs. The X-ray crystal structure of 6•10+ shows short
hydrogen-heteroatom distances for both the primary hydrogen
bonds and the secondary electrostatic interactions between each
proton and the acceptor atoms of the adjacent primary hydrogen
bonds, responsible for the exceptional strength of the AAA-DDD
motif according to the classic Jorgensen model. The binding
between 6 and 10+ can be switched off by deprotonation of the
pyridinium salt with K2CO3, providing a simple means of
controlling this exceptionally strong molecular recognition event.
This may prove useful in the construction of stimuli-switchable
supramolecular polymers, noncovalent adhesives and other
functional organic materials.
Acknowledgment. We thank Prof. Chris Hunter (University of
Sheffield, U.K.) for the use of his AllMaster14 host-guest titration
fitting software and for useful discussions. This work was supported
by the EPSRC. DAL is an EPSRC Senior Research Fellow and
holds a Royal Society-Wolfson research merit award.
Supporting Information Available: Experimental procedures
and spectral data for all compounds, details of X-ray analysis
of 6•10+ including cif file and additional experimental and
complexation studies. This material is available free of charge
via the Internet at http://pubs.acs.org.
(29) Sartorius, J.; Schneider, H.-J. Chem.sEur. J. 1996, 2, 1446–1452.
(30) Quinn, J. R.; Zimmerman, S. C.; Del Bene, J. E.; Shavitt, I. J. Am.
Chem. Soc. 2007, 129, 934–941.
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