Synthesis of Glucose Based Water Soluble Molecular Tweezers as Molecular Recognition Scaffolds

Dry heating of 4,4’-methylenedianiline and N,N’-dimethyl-4,4’methylenedianiline with 5,6-anhydro-1,2-o-isopropylidene-α-D-glucofuranose afforded molecular tweezers having tertiary amino group linked to C-6 of the glucose moiety. These molecular tweezers on deprotection with dilute acid yielded water soluble analogs which were explored for the solubilization of neutral arenes viz. naphthalene, biphenyl, durene, fluorene, anthracene and phenanthrene in acidic aqueous medium. These solid liquid extraction studies revealed that 6,6’-(N,N’-dimethyl-4”,4”’-methylenedianilino) bis (α-D-glucopyranose) causes an approximate 31 fold increase in the solubility of biphenyl in aqueous medium and has best complementarity for naphthalene by forming 1:1 complex.


Introduction
Although, the modern field of molecular recognition began with Pederson's synthesis of crown ethers 1 , Emil Fisher used the analogy of a lock and key to describe the receptor-guest interaction 2 , more than a century ago.Later, the phenomenon of complex formation by organic molecules having an appropriate cavity to bind substrates was termed host-guest complexation by Cram 3 .For effective molecular recognition the host must provide a cavity that has molecular complementarity for the guest.Molecular tweezers 4 sometimes referred to as molecular clips 5 , are non-cyclic molecular hosts with open cavity capable of binding guests.The guest is held / gripped by the two pincers of the host using non-covalent bonding interactions but is not completely encapsulated.The term 'receptor' has come to be used synonymously with 'host' 6 .
There are only few reports of water soluble molecular tweezers [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] compared to otherwise reported molecular tweezers of variety of types, most of which are soluble in organic solvents.Water soluble molecular tweezers might be expected to complex a wide range of aromatic guests with the binding affinities dependent more on the extent of overlap between the host and the guest than on their electronic complementarity 25 .In particular, the hydrophobic effect in aqueous media can be very strong and can determine the stability of the associates to a substantial extent 26 .
This paper describes the synthesis of new 6-amino-6-deoxy-D-glucose derivatives as water soluble molecular tweezers and their use for the complexation of neutral arenes in aqueous medium.This type of studies have already been reported 11 by the author elsewhere exploring p-substituted 6-O-phenyl ethers of glucose as acylic hosts.The present studies report that 6-amino-6-deoxy-D-glucose based water soluble hosts recognizes neutral apolar arenes in aqueous medium more effectively than water soluble hosts pertained to p-substituted 6-Ophenyl ethers of glucose 11 .It seems that N + -π interactions, which were absent, in case of psubstituted 6-O-phenyl ethers of glucose based acylic hosts, also have some contribution for the complexation of present tweezers with neutral apolar arenes in aqueous medium.

Experimental
Melting points were determined in capillaries and are uncorrected.PMR and CMR spectra were recorded at 200 MHz on a Bruker FT NMR 200 Spectrometer.PMR spectra at 60 MHz were recorded on an JEOL JNM PMX 60 SI spectrometer.TMS was used as internal reference for solutions in deuteriochloroform.UV spectra were recorded with a Shimadzu UV-160 UV-VIS spectrophotometer and value of ε are in cm -1 /M.Optical rotations were measured with a JASCO DIP-360 digital polarimeter in a 1 dm cell.Column chromatography was performed on silica gel (60 -120 mesh) and TLC plates were coated with silica G.The spots were developed in iodine and /or charring with 1% sulfuric acid in water.Doubly distilled water and analytical grade n-hexane were used for spectroscopy.Distilled solvents were used for column chromatography.Other chemicals were of AR grade and used without further purification.

4,4'-Methylenedianiline (2)
The compound was prepared by the method given in literature 28

Water soluble molecular tweezers 2c, 2d, 3c and 3d
Compound 2a, 2b and 3a, 3b (500 mg) were taken in aqueous hydrochloric acid (20 mL, 1%) and refluxed for 20 minutes.The solvent was removed on reduced pressure and residue showed a homogeneous spot on TLC plate.The water soluble products (2c, 2d, 3c and 3d) were further used without purification.

Solubilization of neutral arenes in aqueous medium
10.0 mL of aqueous solution (5 mM L -1 ) of tweezer (2c, 2d, 3c and 3d) at pH 5 was shaken with respective arene (20 mg ) for 20 minutes and filtered.The filtrate was extracted with n-hexane (2x25 mL) and the arene concentration determined by UV VIS Spectrophotometer.Solubilities thus obtained were corrected for the solubility of the tweezer in n-hexane (tweezers 2c, 2d, 3c and 3d were found insoluble in n-hexane) and the stoichiometry of the tweezer-arene complex assigned.The solubilities of arenes in acidic aqueous medium without tweezer were determined in the same way.

Results and Discussion
Molecular tweezers synthesized and used for host-guest complexation studies are given in Figure 1.4,4'-Methylenedianiline (2) and N,N'-dimethyl-4,4'-methylenedianiline (3) were selected as building blocks for bent and hydrophobic part and appended at the para position with glucose moiety/ies to design the 'molecular tweezers'.The glucose moieties are expected to induce water solubility to these receptors and hydrophobic aromatic clefts would help complex non-polar guest molecules in aqueous medium.
The 'molecular tweezers' (2a, 2b, 3a and 3b) were prepared by dry heating of the appropriate amine and 5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose (1).These posses a tertiary amino group linked to C-6 of the glucose moiety and their reducing function blocked in a cyclic acetal group.Opening of the oxirane ring of 1 by the various amines is expected 30 to proceed by exclusive nucleophilic attack on C-6 and without inversion at C-5.
The NMR signal assignments were based on previous studies by Hall et al 31 (for 1 H NMR) and Vyas et al 32 (for 13 C NMR) on O-isopropylidene-D-hexoses.The chemical shifts (δ) for H-1 (5.91+0.3,doublet), H-2 (4.43 + 0.4, doublet), H-3 (4.29 + 0.3, doublet) and H-5 (3.98 + 0.3, s) were found constant and characteristic of these protons.The position of H-4 was also found constant, except in those cases where exact location could not be assigned because of overlapping signals.The most prominent shift was found in the H-6 signals.The methylene protons attached to aromatic moieties were found at δ 3.74 + 0.3.The spectra for 2a and 2b are different for the aromatic region.In the former the signal corresponding to these protons were assigned at δ 6.53-6.58 and 6.89-6.96as double doublets, whereas the later gave the same signals at δ 6.57 and 6.94 as AB quartet.In a similar manner, the spectra for 3a showed aromatic signals at δ 6.52-6.75 and 6.96-7.06 as double doublets, whereas same signals for 3b were found at δ 6.69 and 7.01 as AB quartet.The signal at δ 2.87-2.88 in tweezers 3a and 3b was assigned to methyl group attached to the tertiary nitrogen and the additional signal at δ 2.78 for 3a was assigned to the methyl attached to the secondary nitrogen.C NMR signal assignments of all the carbons in each entire molecule were supported by offresonance as well as by INEPT data.In the amino derivatives 2a, 2b, 3a and 3b the signals for the anomeric carbon, 1,3-dioxolane acetal carbon and methyl groups of the isopropylidene moiety were invariant at (104.8 + 0.1), (111.6 + 0.2) and (26.4 + 0.4), respectively.The chemical shifts (δ) for C-2 (85.0 + 0.2) and C-3 (75.3 + 0.2) were also found nearly identical.The methylene attached to aromatic moieties in these compounds was found constant at δ 40.0 + 0.1.The aromatic carbons for 2a were assigned at δ 113.9, 115.6, 129.6, 131.6, 132.3, 143.9 and 145.5, whereas being symmetrically substituted 2b gave aromatic carbons at 114.0, 129.6, 132.0 and 145.9 ppm, respectively.In 3a and 3b signal at δ 40.0 was assigned to methyl attached to tertiary nitrogen and additional signal at 31.0 in 3a was assigned to methyl attached to secondary nitrogen.The aromatic signals in 3b were found at 112.7, 114.0, 129.5, 130.7, 131.8, 147.4 and 148.2 respectively, whereas in 3a, these signals were assigned at 113.6, 113.9, 129.4, 129.7, 131.1, 131.4 and 147.9 respectively.
In mass spectra, for compounds 2a, 2b, 3a and 3b, a peak corresponding to the complete elimination of entire sugar moiety was found.The abundant fragment of mass corresponding to imine formation (RR'N=CH 2 ), after C-C cleavage of C-6 and C-5 of sugar moiety was found for compounds 2a, 2b and 3b respectively.