Occurence of Charge-Assisted Hydrogen Bonding in Bis-amidine

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Occurence of Charge-Assisted Hydrogen Bonding in bis-amidine complexes generating macrocycles Lidia Pop, Niculina D. H#dade, Arie van der Lee, Mihail Barboiu, Ion Grosu, and Yves-Marie Legrand Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00246 • Publication Date (Web): 18 Apr 2016 Downloaded from http://pubs.acs.org on April 21, 2016

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Crystal Growth & Design

Occurence of Charge-Assisted Hydrogen Bonding in bisamidine complexes generating macrocycles Lidia Pop,† Niculina D. Hadade, † Arie van der Lee,‡ Mihail Barboiu,‡ Ion Grosu,*,† and Yves-Marie Legrand,*,‡ ‡

Adaptive Supramolecular Nanosystems Group, Institut Européen des Membranes, ENSCM-UM-CNRS UMR5635 Place Eugène Bataillon, CC 047, F-34095 Montpellier, France †

Supramolecular Organic and Organometallic Chemistry Center (SOOMCC), Babes-Bolyai University, 11 Arany Janos str., 400028 Cluj-Napoca, Romania KEYWORDS supramacrocycles • salt bridge • H-bonding • multicomponent self-assembly • amidine ABSTRACT: Bis-amidine and bis-carboxylate derivatives have been studied in this work to extend the knowledge on Charge-Assisted Hydrogen Bonding (CAHB) which counts among the strongest noncovalent bonding observed so far and arises from the combination of two well identified types of interactions namely electrostatic attraction and H-bonding. The formation of such bridges and the associated formation of macrocycles were screened for substituted (1) and nonsubstituted (2) bis-benzamidines through the use of isomeric proton acceptors aromatic bis-carboxylic (3-6) and bis-sulfonic acids (7-8). A library made from the combination of amidines and carboxylic/sulfonic acids were assessed both in solution and in the solid state. The formation of the CAHB motif was found to be highly dependent on the E,Z isomerization of the amidine moiety. Interesting double dipolar motifs were identified in the solid state.

INTRODUCTION H-bonding plays an important role in molecular self-assembly and lead to exciting supramolecular architectures1-4 such as macrocycles,5-8 cryptands,9-13 catenanes14,15 or polymers.16-23 These superstructures are built up using polyvalent ligands displaying several proton-acceptor (A) or proton-donating (D) groups. These ligands have been classified considering the number, type and positions of the donor and acceptor groups (e.g. AA, DD, AD, DDD, AAA, DAD, ADA, etc). The ability of carboxylic compounds to associate via H-bonding was largely explored24,25 to build nicely organized supramolecular frameworks such as triangles, squares, hexagons or heptagons.26-28 Surprisingly, the bis-amidine molecular associations are not investigated. The carboxyl and amidine groups are DA bidentate ligands, while the carboxylate anion and the amidinium cation (i. e. formed in carboxyl-amidine reaction) are AA and DD ligands, respectively (Scheme 1). The association of amidine and carboxyl groups involves, besides two hydrogen bonds, a favorable electrostatic attraction between the positive (dispersed on the amidinium group) and negative (dispersed on the carboxylate group) charges. This peculiar interaction named "salt bridge" or CAHB (Charge-Assisted Hydrogen Bonding) can strongly connect different building blocks and led to the formation of exciting supramolecular architectures. In a recent work on amidinium-carboxylate interaction, published by Portalone,29 the contact between the

simple benzeneamidinium and some methoxy -substituted benzoates were investigated. The single crystal X-ray molecular structures revealed short distances in the CAHB N+1/2-H--O-1/2units between N+1/2 and O-1/2 [in the range 2.751(3)– 2.850(2) Å] similar to the N to O distances measured in classic N-H---O or O-H---N units (e.g. dN-O = 2.731-2.794 and 2.7062.771 Å in the supramolecular cyclic dimer and trimers dioximes, respectively30 or dN-O = 2.6 - 3.0 Å in proteins31). On the other side the bond angles in the N+1/2-H---O-1/2 unit are crucial and in Portalone's compounds the values of these angles are close to 180° [161(2)-180(2)°], while the dihedral angle between the plans of the amidinium and carboxylate groups ranges from 5.7(1) to 14.2(1)°.

Scheme 1. CAHB motif between the amidinium and the carboxylic acid moieties and the three possible conformations (E/E, E/Z and Z/Z) of the amidinium binding site.

CAHB or "salt bridges" are also encountered in other systems. The guanidinium cation forms CAHBs with carboxylates in proteins, in the classic arginine-glutamate (aspartate) bridg-

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es31,32 and its interaction with receptors bearing carboxylate, sulphonate or phosphate units is used to develop biomedical applications.33 2-Aminopyridines24 or pyrimidines34 somewhat mimic amidines in reaction with acidic groups, while amidines can give salt-bridges even with anions35 or tetrazoles.36 Amidininium (or amidine-like) - carboxylate (sulfonate, phosphate) salt-bridges are involved in the building of complex supramolecular macrocycles,37 cyclophanes,38 cryptands,39 catenanes,40,41 double and multiple helixes42-49 or different devices50 revealing a powerful tool to access exciting selfassembled architectures. In this context, herein we considered of interest to investigate the non-covalent associations of dications of p-benzenediamidine 1 and 2 with the dianions of several dicarboxylic (3-6) and disulfonic (7 and 8) acids and to monitor the influence of the relative positions of the carboxyl (ortho, meta, para) or sulfonic (1,5 or 2,6) groups and of the steric hindrance introduced by the substituents (N,Ndiisopropyl) of the amidinium units (Scheme 2). R HN

N R COOH COOH

R HN

COOH

N R 3

R = i-Pr (1), H (2) HOOC

COOH

3

COOH

COOH

6

COOH 5

4 SO3H

1

HO3S 2

N

6

5

6

7

SO3H

SO3H

8

Scheme 2. Chemical structure of diamidines 1 & 2 and diacids 38

EXPERIMENTAL SECTION Materials and Methods. Excepting 1 and 6 which were obtained in the laboratory using already reported synthetic ap-

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proaches,51-53 all the other compounds were purchased from Sigma-Aldrich and were used without further purification. Crystals were grown by slow evaporation from aqueous solutions. NMR spectra (room temperature) were recorded at Babes-Bolyai University, in CD3OH or D2O as solvents at concentration of 0.5 M, on Bruker Advance instruments operating at 300, 400 or 600 MHz for 1H and 75, 100 or 150 MHz for 13C. Chemical shifts (δ) are reported in parts per million (ppm) using residual solvent peak as internal reference. Melting points were determined in open capillary tubes using an electric melting point apparatus and are uncorrected.

X-ray crystallography. The crystal structures of compounds have been measured on an Agilent Technologies Gemini-S four circle diffractometer using Mo-Kα radiation (λ = 0.71073 Å) and equipped with a Sapphire3 detector at 175 K at the joint X-ray scattering facility of the Pôle Balard at the University of Montpellier, France. The structures have been solved using the ab-initio charge flipping method as implemented in SUPERFLIP.54 Hydrogen atoms could be in all cases located from difference Fourier maps. All structures were initially refined using non-linear least-squares methods as implemented in CRYSTALS,55 in which the hydrogen atoms were treated as riding on their parent atoms and with Uiso(H) constrained to in general 1.2-1.5 times Ueq(H) that of the parent atom. The crystallographic data and structure refinement details for P1,3-4, P1,7-8, P2,3-4 and P2,7-8 are shown in Table 1 and have been deposited in the Cambridge Crystallographic Data Centre CCDC 1453100-1453107 for P1,3-4, P1,7-8, P2,3-4 and P2,7-8 respectively. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif Ab initio calculations. DFT calculations were performed using the Gaussian 09 computational package.56 The B3LYP functionals and standard Pople 6-311+g(d) basis sets were used as implemented in Gaussian. All calculations were performed using the Integral Equation Formalism Polarizable Continuum Model variant (IEFPCM) as the default SCRF method and water as a solvent.

Table 1. Crystallographic data and structure refinement details for P1,3-4, P1,7-8, P2,3-4 and P2,7-8 formula moiety T (K) space group crystal system a (Å) b (Å) c (Å) α (º) β (º) γ (º) V (Å3) Z ρ (gcm-3) Mr (gmol-1) µ (mm-1) Rint Θ (º) resolution (Å) Nref (measured) Nref (I>2σ(I) Nref (unique)

P1,3

P1,4

P1,7

P1,8

C36H46N4O8 C20H36N4,2(C8H5O4)

C28H48N4O8 C20H34N4,C8H6O4,4(H2O)

C30H42N4O6S2 C20H36N4,C10H6O6S2

C30H46N4O8S2 C20H36N4,C10H6O6S2,2(H2O)

175 P21/c monoclinic 10.02707(14) 11.84234(18) 15.3689(2) 90 98.8736(13) 98.8736(13) 1803.12(3) 2 1.221 662.77 0.709 0.065 68.125 0.83 15370 2899 3273

175 P1 triclinic 8.5305(6) 9.7737(5) 9.9298(8) 89.413(5) 72.702(7) 72.702(7) 788.61(7) 1 1.197 568.70 0.719 0.042 68.024 0.83 4995 3174 3350

175 P21/c monoclinic 8.6662(3) 14.3075(5) 12.6706(5) 90 94.225(3) 94.225(3) 1566.79(6) 2 1.312 618.82 1.938 0.064 64.567 0.85 4672 1974 2534

175 Pbca orthorhombic 14.2765(4) 11.7129(4) 19.5153(6) 90 90 90 3263.34(10) 4 1.333 654.85 0.218 0.042 29.271 0.73 10125 3097 3866


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Npar R1 (I>2σ(I)) wR2 (I>2σ(I)) R1 (all) wR2 (all) GOF ∆ρ (eÅ-3) crystal size (mm3)

226 0.0547 0.0460 0.0504 0.0512 0.0564 1.0961 -0.23/0.29 0.05x0.15x0.25 P2,3

391 0.0706 0.0549 0.0621 0.0574 0.0635 1.0583 -0.34/0.38 0.15x0.21x0.28 P2,4

P2,7

211 0.0676 0.0565 0.0601 0.0723 0.0655 1.0282 -0.52/0.45 0.05x0.27x0.32 P2,8

formula moiety T (K) space group crystal system a (Å) b (Å) c (Å) α (º) β (º) γ (º) V (Å3) Z ρ (gcm-3) Mr (gmol-1) µ (mm-1) Rint Θ (º) resolution (Å) Nref (measured) Nref (I>2σ(I) Nref (unique) Npar R1 (I>2σ(I)) wR2 (I>2σ(I)) R1 (all) wR2 (all) GOF ∆ρ (eÅ-3) crystal size (mm3)

C32H38N8O11 2(C8H12N4),2(C8H4O4),3(H2O)

C16H26N4O9 C8H12N4,C8H4O4,5(H2O)

C18H22N4O8S2 C10H6O6S2,C8H12N4,2(H2O)

C18H20N4O7S2 C10H6O6S2,C8H12N4,H2O

175 Pn monoclinic 13.3684(4) 9.2019(2) 14.6584(5) 90 109.138(3) 109.138(3) 1703.54(5) 2 1.385 710.70 0.106 0.037 27.818 0.76 11850 3281 3543 460 0.0492 0.0346 0.0377 0.0399 0.0398 1.1259 -0.22/0.19 0.05x0.15x0.30

175 P-1 triclinic 8.2967(5) 8.4124(4) 16.3294(8) 88.717(4) 77.272(4) 77.272(4) 1041.25(5) 2 1.334 418.41 0.110 0.025 32.580 0.66 11824 5570 6726 316 0.0439 0.0473 0.0385 0.0606 0.0410 1.1825 -0.26/0.42 0.08x0.25x0.30

175 P-1 triclinic 7.2562(7) 7.4409(7) 10.7885(10) 78.348(8) 73.338(9) 73.338(9) 504.99(5) 1 1.600 486.54 0.321 0.031 27.825 0.76 3332 1643 1965 163 0.0580 0.0443 0.0496 0.0557 0.0554 1.1174 -0.44/0.36 0.08x0.15x0.35

175 P-1 triclinic 7.8301(4) 9.7063(6) 13.4010(8) 77.285(5) 83.315(5) 83.315(5) 983.27(6) 2 1.582 468.52 0.323 0.039 32.627 0.66 15522 5284 6509 310 0.0645 0.0559 0.0620 0.0724 0.0715 0.9620 -0.82/0.89 0.05x0.25x0.30

RESULTS AND DISCUSSIONS The compounds Px,y (x=1,2; y=3-8) resulted from combinations of diamidines 1 and 2 with diacids 3-8 (Table 2) were obtained either in solid state or in solution. The solid state preparation consisted in the vigorous grinding for 20 minutes of equimolecular quantities of diamidine and diacid with a pestle in a mortar. The obtained solid was then taken up in a limited amount of water for crystallization or was used for the preparation of NMR samples. The procedure in solution was based on the mixing of ≈1M solutions in water of diamidine dihydrochloride (1x2HCl or 2x2HCl) and disodium salts of dicarboxylic diacids 3-6 or of disulfonic diacids 7 and 8 giving rise to solution of 0.5 M of each species. The equimolecular ratio between diamidinium cations and diacid dianions was obtained using corrected volumes of the mixed solutions (in agreement with the precise concentrations of the stock solutions). The solutions exhibiting the two components were allowed to stay for 2 days, then were used either for the obtaining of crystals or for the preparation of NMR samples. Investigations in solution. The 1H NMR spectra of compounds P1,3-8 and P2,3-8 revealed significant shifting of the

196 0.0717 0.0663 0.0662 0.0815 0.0847 1.0141 -0.56/1.00 0.20x0.40x0.40

signals as compared to diamidine 1 or its chlorohydride 1xHCl in one side and diamidine 2 and its chlorohydride 2xHCl on the other side (Tables 2). The comparison of the 1H NMR spectra of compounds P1,3-8 with the spectrum of diamidine 1 (all spectra in CD3OD) or of its chlorohydride 1a (all spectra in D2O) revealed for the aromatic protons shifts of ∆δ = 0.37 0.46 ppm in CD3OD or up to ∆δ = 0.09 ppm in D2O. The protons of methyl groups of the i-C3H7 are different in NMR and they exhibit two signals (see Theoretical section below). The comparison of the spectra of P1,3-8 recorded in CD3OD with the spectrum of 1 show a shifting of the signals pertaining to the i-C3H7 units of ∆δ = 0.13 - 0.25 ppm, while the same analysis reveals a shifting up to ∆δ = 0.05 ppm for the spectra recorded in D2O (the spectrum of 1xHCl was taken as reference). The signals attributed to the diacid units also exhibit relevant shifting (Table 2). The signals belonging to the aromatic protons in P2,3-8 (spectra in D2O) are shifted up to 0.16 ppm compared to the spectrum of the diamidinium chlorohydride 2xHCl and the signals referring to the diacid exhibit also relevant shifting when the spectra of P2,3-8 were compared to the spectra of the sodium salts of these diacids (Table 2).



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Table 2. 1H-NMR chemical shifts for compounds P1,3-8 and P2,3-8 Product

Diamidine units Aromatic CH3 groups protons

1 1x2HCl (1a) P1,3

P1,7 P1,8

7.35 7.79 7.80 7.79 7.73 7.78 7.78 7.72 7.70 7.73 7.77

1.11 1.34, 1.26 1.33, 1.26 1.34, 1.26 1.30, 1.24 1.33, 1.25. 1.33, 1.25 1.25 1.29, 1.20 1.31, 1.22 1.33, 1.24

7.74→7.92, 7.58→7.44 7.52→7.79-7.74 (broad), 7.46→7.63 8.65→8.46, 8.23→7.94, 7.59→7.32 8.29→8.43, 7.99→8.11, 7.53→7.59 7.83→8.03 8.84→8.72, 8.19→8.13, 7.61→7.47, 4.52→4.46, 1.45→1.42 8.76→8.74, 8.10→8.08, 7.62→7.62, 4.47→4.47, 1.40→1.42 8.86→8.88, 8.23→8.24, 7.75→7.78 8.33→8.45, 8.06→8.20, 7.89→7.95

CD3OD D2O CD3OD D2O CD3OD D2O D2O CD3OD D2O D2O D2O

2x2HCl (2a) P2,3 P2,4 P2,5 P2,6 P2,7 P2,8

7.90 7.95 7.91 7.93 7.74 7.87 7.85

-

7.52→7.44, 7.46→7.39 8.29→8.23, 7.99→7.95, 7.53→7.50 7.83 → 7.86 8.76→8.66, 8.10→8.04, 7.62→7.56, 4.47→4.41, 1.40→1.34 8.86→8.85, 8.23→8.23, 7.75→7.71-7.80 (broad) 8.33→8.40, 8.06→8.16, 7.89→7.93

D2O D2O D2O D2O D2O D2O D2O

P1,4 P1,5 P1,6

Diacid units

Solvent

Figure 1. NMR spectra (CD3OD) of 1 (bottom), 3 & 4 (top) and P1,3 & P1,4 (middle)

These modifications are illustrated in Figures 1 and 2. The comparison of the spectra (in CD3OD) of diamidine 1 and diacid 4 with the spectrum of their complex (P1,4) reveals a shielding of the signals pertaining to the isophthalic acid moiety up to 0.27 ppm and a deshielding of 0.41 ppm of the signal belonging to the aromatic protons of the diamidine unit. In the case of P1,3 the spectrum reveals besides the shielding and deshielding of the signals of, respectively, the acidic and amidinic units, a broadening of the signals which suggests the dynamic behavior of the diamidinium-dicarboxylate associations in solution (Figure 1). Solid-state investigations - X-Ray crystallography. P1,3-8 and P2,3-8 were all screened by several crystallization techniques (cooling, slow evaporation, slow diffusion, non-solvent vapor) in an attempt to form cocrystals suitable for analysis. Eight crystals were obtained in total from compounds 3, 4, 7 and 8

together with both diamine 1 and diamine 2 (See Table 1). The single crystal X-ray molecular structures revealed some disparity in bond distances in the CAHB N+1/2-H---O-1/2units between N+1/2 and O-1/2 [in the range 2.751(3)–3.084(2) Å]. In some cases with diamine 2 (P2,3-4) the formation of the AA-DD motif was observed but not as often as expected and with diamine 1, this motif was not observed in the solid state. Interestingly, when the AA-DD motif is present, it occurs only on one of the two accessible sites. One can wonder if it is due to electronic reasons or simply packing constraints. The formation of large supra-macrocycles are less favorable than smaller ones, because higher in entropic energy; the formations observed in the crystals for (P2,3-4) represent the optimal compromise between the favorable CAHB and smallest possible macrocyclic rings.


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Figure 2. Hydrogen bonding arrays present in crystal structures for P1,3-4, P1,7-8, P2,3-4 and P2,7-8 and associated graph-set (Gda(r))57

P1,3 crystallizes from mQ water in the monoclinic space group P21/c. The asymmetric unit consists of one half 1 and one 3 molecule without any water molecule present. The acidic functions in 3 nearly sit in the same plane as the benzyl moiety (20.18° and 19.42°). While each amidine moitie is protonated and therefore dicationic, the acid 3 is in a monoacidic form, with a hydrogen molecule trapped between the two acidic moities. Crystal cohesion occurs only by intermolecular NH…O hydrogen bonds and no π-π stacking is observed. 1 and 3 form a H-bonded rhombic R88(54) macrocycle in the solid state involving four units of each species (Figure 2A). The

amidinium functions lies systematically in the (E,Z) conformation, preventing the expected amidinium-carboxylate synthon to form such as in the structures of P2,3 and P2,4. P1,4 crystallizes from mQ water in the triclinic space group P1. The asymmetric unit consists of one 1, one 4 and four water molecules. The acidic functions are nearly in the plane of the benzyl moiety (3.52° and 25.82°). The 3D structure assembles via intermolecular (amidinium) +N-H…O- (carboxylate) and amidinium/water or carboxylate/water hydrogen bonding. In this case, P1,4 is forming a rectangular H-bonded R911(48)



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macrocycle involving water molecules (Figure 2B). Again, the N-H bonds of the amidinium functions are systematically (E,Z), preventing the expected amidinium-carboxylate synthon to form. As expected, each amidinium function is hydrogen bonded to one carboxylate function. The organization in the solid state seems strongly governed by the hydrophobic interactions of the methyl groups and packing of phenyl rings. Remarkably, P1,4 is also forming chains made of supramolecular catenane (Figure 3).

Figure 3. CPK representation of supramolecular catenane of P1,4

P1,7 crystallizes from mQ water in the monoclinic space group P21/c. The asymmetric unit consists of one 1 and one 7 molecule without any water molecule present. The two amidinium functions of one 1 molecule are both nearly in the same plane and form an angle of 56.23 and 59.39° respectively with the phenyl ring. Crystal cohesion occurs only by intermolecular N-H…O hydrogen bonds and no π-π stacking is observed. 1 and 7 form a H-bonded compact rhombic R88(42) macrocycle in the solid state involving four units of each species (Figure 2C). The N-H bonds of the amidinium functions are systematically (E,Z). P1,8 crystallizes from mQ water in the monoclinic space group Pbca. The asymmetric unit consists of one 1, one 8 and one water molecule. The two amidinium functions of one 1 molecule are both approximatly in the same plane and form an angle of 62.76 and 64.87° respectively with the phenyl ring. Crystal cohesion occurs only by intermolecular N-H…O hydrogen bonds and no π-π stacking is observed. 1 and 8 form a H-bonded R66(32) macrocycle in the solid state involving two units of each species (Figure 2D). The N-H bonds of the amidinium functions are all (E,Z). P2,3 crystallizes from water in the monoclinic space group Pn. The asymmetric unit consists of two 2, two 3 and three molecules of water. The crystal structure is maintained by a dense network of hydrogen bonds and ionic interactions forming a 3D hydrogen-bonded polymer. The two independent benzene dicarboxylic acid molecules are each hydrogen bonded in two different ways two different 2 moieties, i.e. by forming one double-hydrogen bonding synthon H-N-+C-N-H…O--C-O and one less specific +N-H…O- hydrogen bond with another neighboring 2 (Figure 2E). One of the two double-hydrogen bonding synthons is nearly planar, the N-+C-N and the O--C-O least-squares planes making a dihedral angle of only 10.56°, whereas for the other synthon this angle is 37.45°. The two amidinium moieties of each benzene dicarboxylic acid molecule are approximately in the same plane – the dihedral angles being 10.78° and 4.76°, respectively – and are tilted by 24.56° and 28.52° for one and by 46.75° and 35.98° for the other molecule with respect to the benzyl ring. In contrast the mean

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squared planes of the two acidic functions are not at all in the same plane, making angles of 72.86° and 66.31° with each other for the two benzene dicarboxylic acid molecules, respectively. The ortho-orientation of the benzoic-diacid generates a small H-bonding network, of rhombic shape, involving the two dibenzoate molecules and one amidinium moitie of two benzamidine molecules, R24(18). P2,4 crystallizes from mQ water in the triclinic space group P1. The asymmetric unit consists of one 2, one 4 and five water molecules. 2 and 4 are pi-stacked (centroid-centroid distance 3.61 Å, angle 6.03°, shift distance 1.16Å) with a parallel stacked carboxylate and amidinium moiety pair on the same position (dihedral angle 9.38°). The two other functions are rotated and link together through hydrogen-bonding H…O (2.00 A). This crystal structure is also maintained by a dense network of hydrogen bonds and ionic interactions forming a 3D hydrogen-bonded polymer. The molecular geometry of 2 in the structure of P2,4 is very similar to that in the structure of P2,3 (Figure 2F), except that the two acidic functions of 4 are now much more parallel to the benzyl plane (7.91° and 26.73°, respectively) and making an angle of only 27.37° with each other. As in the structure of P2,3, one acidic function is involved in a planar double-hydrogen bonding synthon, while the other is forming two less specific single-hydrogen bonding links with two neighboring acid molecules. The metaorientation of the benzoic-diacid generates a larger, this time, rectangular H-bonding R44(34) network (Cycle 1) involving the two acidic functions of two 4 and the two amidinium moities of two 2. The molecules of this tetramer are involved in more H-bonding. Interestingly, another rectangular H-bonding motif (Cycle 2) includes again two molecules of each species, which are this time pi-stacking. Moreover, a clear stacking of the ion-pairs form by the amidinium-carboxylate tecton can be observed, in an antiparallel fashion. P2,7 crystallizes from mQ water in the triclinic space group P1. The asymmetric unit consists of one 2, one 7 and one water molecule. Molecules 2 and 7 are pi-stacked (2centroid-7plane distance 3.57 Å, angle 6.03°). The two amidinium functions of one 2 molecule are both in the same plane and form an angle of 37° with the phenyl. This crystal structure is also maintained by a dense network of hydrogen bonds and ionic interactions forming a 3D hydrogen-bonded polymer. The molecular geometry of 2 in the structure of P2,7 is reminiscent to that in the structure of P2,4 (Figure 2G). A rectangular H-bonding R64(34) network (similar to Cycle B in P2,4) involving four sulfonic functions of two 7 and four amidinium moities of two 2 is formed. P2,8 crystallizes from mQ water in the triclinic space group P1. The asymmetric unit consists of one 2, two 8 and one water molecule. In this case no obvious pi-stacking between 2 and 7 can be observed. The two amidinium functions of one 2 molecule are not in the same plane (dihedral 66.87°) and form an angle of 26.75 and 39.85° with the phenyl ring. This crystal structure is also maintained by a dense network of hydrogen bonds and ionic interactions forming a 3D hydrogen-bonded polymer. A rectangular H-bonding R43(36) network involving two molecules of 7 and one 2 and a water molecule is formed (Figure 2H). Theoretical investigations. Model compound N,Ndiisopropyl-benzylamidinium was used in order to evaluate the variation in stability of isomeric forms of the amidinium


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moiety and the energy barrier between the (E,E) and the (E,Z) state (Figure 4A). Ab-initio modeling shows that the (E,Z) form of the simple model is slightly more stable than the (E,E) & (Z,Z) conformation (+1.28 and +2.09 kcal/mol respectively), which is in good agreement with previously reported data on similar E/Z energetics comparisons.58 Differences of around 1.3 kcal/mol can generate a 90/10 excess of the (E,Z) conformation, proportion that can be observed in solution NMR. Gibbs ∆E was also assessed and a potential energy barrier for the dimethyl moiety rotation of 21.98 kcal/mol. was obtained, without zero-point energy (ZPE) correction, which is consistent with experimental values obtained for substituted benzamidine.59 The imaginary frequency at the global maximum is 126.9i cm-1.

formed was significantly modified, for e.g. increased from P2,3 to P2,4. The steric hindrance introduced by the substituents (N,N-diisopropyl) of the amidinium units was also clearly evidenced in the solid state; in solution the NMR spectra confirmed the preference for the cis-trans structure of the diisopropyl-amidinium units in all cases. In all cases, the “organic salts” were favored to crystallize as no sodium or chloride ions were found in any crystals. In the solid state, the formation of the AA-DD motif was only observed in a few cases (P2,3-4) and never on both side of the symmetrical ditopic molecule

ASSOCIATED CONTENT Supporting Information Crystal data for the eight structures studied: CCDC 14531001453107. 1H/13C-NMR for reactants and products. Characterization Data

AUTHOR INFORMATION * e-mail: [email protected] * e-mail: [email protected] Note: The authors declare no competing financial interests. Funding This work was financially supported by ANR Blanc International DYNMULTIREC (13-IS07-0002-01) and CNCSUEFISCDI (PN-IIID-JRP-RO-FR-2012-0088)

REFERENCES Figure 4. (A) Calculated energy of E/E, Z/Z, E/Z conformation of model compound and TS between E/E and Z/Z. The lowest energy conformation E/Z was taken as the reference and differences of energy compared to E/Z are reported on the graph. (B) Electrostatic potential map of the CAHB salt bridge between 2 and 4 and (C) the schematic representation of the dipole moments involved within the complex. The atomic positions were taken from the crystal structure and the geometry optimized.

In order to evaluate the dipole moments that could be present in the case of P2,4, the electrostatic density map was generated. It is quite obvious that a double dipole is being formed, primarily from the CAHB salt bridge association between the acid and the amidinium moieties, secondly from the “up and down” salt interaction arising between superposed acid and the amidinium moieties and finally from pi-stacking between the electron poor and rich rings of 2 and 4 respectively (Figure 4B&C). This double dipole moment configuration was only observed in the crystal structures of P2,4 maybe due, in the other cases, to steric reasons preventing the pi-stacking to take place simultaneous with the CAHB salt bridge association.

CONCLUSIONS Supramolecular associations of dications of pbenzenediamidine (1 and 2) with the dianions of several dicarboxylic (3-6) and disulfonic (7 and 8) acids have been investigated in solution and in the solid state. The relative positions of the carboxyl (ortho, meta, para) or sulfonic (1,5 or 2,6) groups proved to play a crucial role in the affinity of the complementary units. In solution, the NMR investigations suggest significant CAHB associations involved in rapid exchanges. In the solid state, the size of the hydrogen bonded macrocycles

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"For Table of Contents Use Only," Occurence of Charge-Assisted Hydrogen Bonding in bis-amidine complexes generating macrocycles Lidia Pop,† Niculina D. Hadade, † Arie van der Lee,‡ Mihail Barboiu,‡Ion Grosu,*,† and Yves-Marie Legrand,*,‡

SYNOPSIS TOC: A library made from the combination of amidines and acids were assessed both in solution and in the solid state and revealed the presence of the CAHB motif responsible for the formation large supramolecular macrocycles.


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Occurence of Charge-Assisted Hydrogen Bonding in Bis-amidine

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