An AAAA–DDDD quadruple hydrogen-bond array

Journal name:
Nature Chemistry
Volume:
3,
Pages:
244–248
Year published:
DOI:
doi:10.1038/nchem.987
Received
Accepted
Published online

Abstract

Secondary electrostatic interactions between adjacent hydrogen bonds can have a significant effect on the stability of a supramolecular complex. In theory, the binding strength should be maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other. Here, we describe a readily accessible AAAA–DDDD quadruple hydrogen-bonding array that exhibits exceptionally strong binding for a small-molecule hydrogen-bonded complex in a range of different solvents (Ka > 3 × 1012 M–1 in CH2Cl2, 1.5 × 106 M–1 in CH3CN and 3.4 × 105 M–1 in 10% v/v DMSO/CHCl3). The association constant in CH2Cl2 corresponds to a binding free energy (ΔG) in excess of –71 kJ mol–1 (more than 20% of the thermodynamic stability of a carbon–carbon covalent bond), which is remarkable for a supramolecular complex held together by just four intercomponent hydrogen bonds.

At a glance

Figures

  1. Examples of triple hydrogen-bond arrays and their association constants in various solvents.
    Figure 1: Examples of triple hydrogen-bond arrays and their association constants in various solvents.

    Different permutations of contiguous triple hydrogen-bonded complexes ADA–DAD 1·2 (ref. 9), ADD–DAA 3·4 (ref. 10), AAA–DDD 5·6 (ref. 13) and cationic AAA–DDD+ 7·6 (ref. 14). Arrows indicate secondary electrostatic interactions (black, attractive; red, repulsive).

  2. Examples of quadruple hydrogen-bond arrays and their association constants in various solvents.
    Figure 2: Examples of quadruple hydrogen-bond arrays and their association constants in various solvents.

    Different permutations of contiguous quadruple hydrogen-bonded complexes: ADAD–DADA 8·8 (ref. 16), AADD–DDAA 9·9 (refs 17,18,20), ADDA–DAAD 10·11 (ref. 23) and AAAA–DDDD+ 12·13. Arrows indicate secondary electrostatic interactions (black, attractive; red, repulsive).

  3. Synthetic routes to DDDD+ 12 and AAAA 13.
    Figure 3: Synthetic routes to DDDD+ 12 and AAAA 13.

    a,b, Synthesis of DDDD+ 12 (BArF salt) (a) and AAAA 13 (b). Reagents and conditions for a: (i) CS2, pyridine, 130 °C, 18 h, 81%; (ii) HgO, NH3/MeOH, CHCl3 25 °C, 3 h, 50%; (iii) NaBArF, 8 M AcOH, 25 °C, 2 h, 40%. Reagents and conditions for b: (i) NBS, DMF, –10 to 25 °C, 3 h, 60%; (ii) NHCH3(CH2CH2)N(CH3)2, BuLi then B(OMe)3, THF, –78 to 25 °C, 16 h, 36%; (iii) Na2CO3, H2O/DME (dimethoxyethane) 1:1, 80 °C, 1.5 h, 27%.

  4. UV/Vis titration of AAAA 13 with DDDD+ 12 in CH2Cl2.
    Figure 4: UV/Vis titration of AAAA 13 with DDDD+ 12 in CH2Cl2.

    UV/vis spectra of 13 (˜5 × 10–5 M) on addition of 12 (0 → 5 equiv.), maintaining the concentration of 13 constant, in CH2Cl2 at 298 K. Changes in absorbance reflect changes in the amount of 13 and 12·13 present during the titration experiment and differences in their UV/vis absorption spectra.

  5. 1H NMR spectra (500 MHz, CD2Cl2, 298 K) of 12 (top), complex 12·13 (middle) and 13 (bottom).
    Figure 5: 1H NMR spectra (500 MHz, CD2Cl2, 298 K) of 12 (top), complex 12·13 (middle) and 13 (bottom).

    Dashed lines show the changes in chemical shift of the resonances in 12 and 13 on formation of complex 12·13.

  6. UV/vis competition experiment in which 13 is displaced from 12·13 by a large excess of 6.
    Figure 6: UV/vis competition experiment in which 13 is displaced from 12·13 by a large excess of 6.

    UV/vis spectra of 12·13 (˜2 × 10–7 M) following addition of 6 (0 → 950 equiv., 50 equiv. aliquots) in CH2Cl2 at 298 K. Spectra at 0 equiv. (blue), 350 equiv. (green) and 940 equiv. (orange) of added 6 are shown with thicker linewidths for clarity. For comparison, the spectrum of free 13 (black) is also shown.

  7. UV/vis titration experiments in which K12·13 and K13·(12·13) are measured by addition of 12 to 13 in CH3CN or 10% DMSO in CHCl3.
    Figure 7: UV/vis titration experiments in which K12·13 and K13·(12·13) are measured by addition of 12 to 13 in CH3CN or 10% DMSO in CHCl3.

    a, UV/vis spectra of 13 (˜8 × 10−6 M) following addition of 12 (0 → 5 equiv.), while maintaining the concentration of 13 constant, in CH3CN at 298 K. Component distribution over the course of the titration experiment is also illustrated (inset). Association constants for 12·13, modelled with a 2:1 equilibrium, are K12·13 = 1.5 × 106 M−1G = –35.2 kJ mol−1) for 12·13 and K13·(12·13) = 2.4 × 105 M−1G = –30.6 kJ mol−1) for the binding of a second AAAA unit to this complex to form 13·(12·13). b, UV/vis spectra of 13 (˜1 × 10−5 M) following addition of 12 (0 → 4.5 equiv.), while maintaining the concentration of 13 constant, in a solution of 10% DMSO in CHCl3 at 298 K. Association constants are K12·13 = 3.4 × 105 M−1G = –31.6 kJ mol−1) and K13·(12·13) = 1.4 × 105 M−1G = –29.4 kJ mol−1).

Compounds

20 compounds View all compounds
  1. 5-Bromo-1-cyclohexyl-1H-pyrimidine-2,4-dione
    Compound 1 5-Bromo-1-cyclohexyl-1H-pyrimidine-2,4-dione
  2. 9-Ethyl-9H-purine-2,6-diamine
    Compound 2 9-Ethyl-9H-purine-2,6-diamine
  3. N-(7-Bromomethyl-[1,8]naphthyridin-2-yl)-acetamide
    Compound 3 N-(7-Bromomethyl-[1,8]naphthyridin-2-yl)-acetamide
  4. 6-Amino-3-benzyl-5-biphenyl-3-yl-1H-pyridin-2-one
    Compound 4 6-Amino-3-benzyl-5-biphenyl-3-yl-1H-pyridin-2-one
  5. 2,6-Diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester
    Compound 5 2,6-Diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester
  6. 6,7,8-Triaza-dibenzo[a,j]anthracene
    Compound 6 6,7,8-Triaza-dibenzo[a,j]anthracene
  7. 2,6-Diaminopyridinium [(3,5-trifluoromethyl)phenyl]borate
    Compound 7 2,6-Diaminopyridinium [(3,5-trifluoromethyl)phenyl]borate
  8. 1-(4-Amino-6-(3,4,5-tris-dodecyloxybenzene)-[1,3,5]triazin-2-yl)-3-(n-butyl)-urea
    Compound 8 1-(4-Amino-6-(3,4,5-tris-dodecyloxybenzene)-[1,3,5]triazin-2-yl)-3-(n-butyl)-urea
  9. 1-(n-Butyl)-3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)-urea
    Compound 9 1-(n-Butyl)-3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)-urea
  10. ((3aR,4R,6R,6aR)-6-(2-(3-Butylureido)-6-oxo-1H-purin-9(6H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 11-oxo-2,3,5,6,7,11-hexahydro-1H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxylate
    Compound 10 ((3aR,4R,6R,6aR)-6-(2-(3-Butylureido)-6-oxo-1H-purin-9(6H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 11-oxo-2,3,5,6,7,11-hexahydro-1H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxylate
  11. (7-Pentanoylamino-[1,8]naphthyridin-2-yl)pentanamide
    Compound 11 (7-Pentanoylamino-[1,8]naphthyridin-2-yl)pentanamide
  12. N,N'-Bis-(1H-benzimidazol-2-yl)guanidinium tetrakis[(3,5-trifluoromethyl)phenyl]borate
    Compound 12 N,N'-Bis-(1H-benzimidazol-2-yl)guanidinium tetrakis[(3,5-trifluoromethyl)phenyl]borate
  13. 2,13-Di-tert-butyl-6,7,8-tetraaza-dibenzo[a,l]naphthacene
    Compound 13 2,13-Di-tert-butyl-6,7,8-tetraaza-dibenzo[a,l]naphthacene
  14. 1H-Benzoimidazol-2-ylamine
    Compound 14 1H-Benzoimidazol-2-ylamine
  15. 1,3-Bis-(1H-benzoimidazol-2-yl)thiourea
    Compound 15 1,3-Bis-(1H-benzoimidazol-2-yl)thiourea
  16. N,N'-Bis-(1H-benzoimidazol-2-yl)guanidine
    Compound 16 N,N'-Bis-(1H-benzoimidazol-2-yl)guanidine
  17. [1,8]Naphthyridine-2,7-diamine
    Compound 17 [1,8]Naphthyridine-2,7-diamine
  18. 3,6-Dibromo-[1,8]naphthyridine-2,7-diamine
    Compound 18 3,6-Dibromo-[1,8]naphthyridine-2,7-diamine
  19. 5-tert-Butyl-2-formylboronic acid
    Compound 19 5-tert-Butyl-2-formylboronic acid
  20. 4-tert-Butylbenzaldehyde
    Compound 20 4-tert-Butylbenzaldehyde

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Affiliations

  1. School of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JJ, UK

    • Barry A. Blight,
    • David A. Leigh,
    • Hamish McNab &
    • Patrick I. T. Thomson
  2. Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK

    • Christopher A. Hunter
  3. Deceased

    • Hamish McNab

Contributions

P.I.T.T. carried out the experimental work. P.I.T.T., B.A.B., D.A.L. and H.M. contributed to the design of the experiments and analysis of the data. C.A.H. designed the complex stability models and calculations. All of the authors contributed to writing the paper.

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