Role of amide and urea moieties in molecular recognition t

The amide and urea moieties due to their unique stereoelectronic character interact with electron deficient centres through carbonyl group and with electron rich centers through N-H units. This dual character has been successfully U\ed for the design of urea/amide based receptors for recognizing variety of guests. This review discusses the salient examples of such receptors to bring out the unique scope of urea and amide units in designing receptors for recognition of cations, anions and neutral molecules.

Molecular recognition is quite essential to most of the biological and chemical processes. Enz'ymes, antibodies, membranes, and other receptors; carriers, and channels all involve molecular recognition as a key step in their biochemical functioning 1 . Molecular recognition in general involves multi molecular assemblies, called suprar.nolecular complexes, formed between two or more topologically complementary chemical entities which are held together by non-covalent forcesl. 2 . For a deep insight into the basis of' noncovalent interactions and biological functions of receptors and to emulate the basic principles of nature, the investigations on complementarity of various host guest interactions in structurally simpler model receptors have been canied out. In fact the concept of molecular recognition grew out of such studies in the mid-sixties from the observations of selective recognition of alkali metal cations by ionophoric antibiotics 3 -5 and synthetic macro(poly)cyclic polyethers 6 . Molecular recognition character of a receptor is goverened by its overall structural topology where primarily the constituent functionalities trigger and influence the nature of its bindings. Amongst various functional groups such as ethers, thioethers, sulphides, disulphides, imines, amines, ureas and am ides etc. used in the design of model receptors, amide and urea moieties enjoy a pre-eminent position because of their unique stereoelectronic character 7 • As depicted below amides elaborate electron rich 0, N centres and electron deficient N-H units, and thus can bind with both electron deficient guests (at 0, N) and electron rich guests through hydrogen bonding (at N-H unit). Resonance assists ami des to attain-more negative charge than any other neutral oxygen functionality and also provides desirable 1igid spatial geometry. The spatial orientation of the amide could  Urea moiety also owes its improtance to somewhat similar electronic character as the amide. Additional electron donation by the second nitrogen atom in the case of urea further increases the negative charge on the oxygen atom and provides rigidity to the geometry. Nature has quite generously used amides in evolving receptors such as valinomycin 3 , baeuvericin 4 , westiellamide5 etc. and many other molecules of biological importance.
Importance of urea moiety in biological systems is quite evident from the fact that out of the five nucleobases, all three pyrimidine bases i.e. cytosine, thymine and uracil have urea moiety in their structure, which efficiently p_articipates in double helix formation (H-bonds) and co-ordinates with metal ions 8 . In this article, the unique role of amide and urea moieties in molecular recognition of both electron rich and electron deficient guests in synthetic receptors has been highlighted. The presentation is categorized into cationic, anionic and neutral recognition and in each category the receptors in order of podands, coronands, cryptands, cyclophanes and calixarenes etc. are arranged. J. Indian Chern. Soc., Vol. 80, December 2003 Rat"uvPnrm R::t ~f'lf'CliVe l: Cationic recognition A pioneering effort to develop open chain amide based podands of utility in the development of ion selective electrodes was initiated by Simon and co-workers in ZUrich and as early as 1972, Ca 2 + selective carrier 1 9 was. reported.
Numerous other ligands such as 2-5 were developed. From amongst a series of N,N,N,N-tetrasubstituted diamides, the ionophores 3c and Sa-c showed a high Li+ selectivity with Sb showing highest Li+ selectivity over alkali (>1000 times) and alkaline earth (>100 times) cations. The ionophores Sb and Schave been used for Li+ assay detcrmi-nation10-12.

R1
Rz  z~Bz .bo ad.. For similar lipophilicity but lower number of binding sites and smaller ring size, 20a extracts alkaline earth metal picrates better than the more flexible 19 in the order Ba 2 + -Sr 2 + > Ca2+ but 20b shows h1gher selectivity in extraction for Ba2+ ions23. Both 20a and 20b furnish I : 1 complexes with Ba 2 + picrate 24 . However, the increase in the ring size in 2la, 2lb over that of 20a reveals order Ca 2 + -Sr2+ > Ba 2 + but 21c is selective for Ba 2 + overCa 2 + and Sr 2 + ions25.
Macrocycles 23 and 24 with amine-amide combination undergo deprotonat1on at amide NH with divalent transition metal ions to form neutral complexes. r") The ionophore 23 acts as a carrier for proton coupled transport of Cu 2 + against concentration gradient 27 . Ligand Lignad 25(E) having photosensitive azobenzene cap shows selective binding to Na+ while 2S(Z) formed by photomerization, encapsulates K+ more strongly suggestmg the expansion of N 2 0 4 ring photoinduced by (E) to (Z) isomerization 29 . The ligand 26 in which azobenzene cap is replaced by pyridine unit, strongly binds to heavy metal cations particularly Cu 2 + and no such binding is encountered in 26(Z) 30 . Amide functionalized appendages to the macrocyclic backbone also influence the binding character. Among the series of chiral mono-and di-substituted 14-crown-4 derivatives, the macrocycles 27a and 27b with amides as appendages induce the best u+ to Na+ selectivity (630 : I) in liquid membrane electrodes3 1 .
In ligand 28 though amide groups do not participate in complexation but position the two 15-crown-5 units to form I : 2 host-guest complex with Na+ and 1 : 1 complexes with K+, Rb+, cs+ and NH;[ ions. The ligand reveals high selectivity forK+ over other cations 32 .
A series of ether-ester macrocycles and podands containing one or two cyclic urea oxygens show selective extraction of Sr 2 + picrate 33 over u+, Na+, K+, Tl+, Mg 2 + and Ca 2 + picrates with macrocycle 29 showing maximum selectivity. Macrocycles 30a and 30b selectively extract lead picrate over silver, alkali and alkaline earth metal picrates 34 . Pyridine based diamide-diester IS-membered macrocycle 31 extracts Ag+ picrate with remarkable selectivity over alkali, groups comple)\es with Ni2+, Cu2+ and zn2+ 39. alkaline earth, Tl+ and Pb 2 + picrates35. Octamides 32 of p-alkoxycalix [8]arenes extract alkaline earth metal pi crates from water to dichloromcthane, and the corresponding nitrates from acidic water solution simulating radioactive waste to 2-nitrophcnyl hcxJI cther(NPHE) 36 . In case of simulated waste solutions, the distribution coefficients for strontium removal by octamides are much higher than the corresponding value found for dicyclohexyl-18crown-6 (DC 18C6). Amongst various heterocalix [6]arenes with different number of uracil and benzimidazolone units and three aryl units, the heterocalix [6]arene 33 exhibits t-BuNH3 +;K+ selectivity37.  More recently, receptors have been appended with appropiiate fluorescent moieties and the change in fluorescence during complexation provides direct means of both qualitative and quantitative estimation of guest species. The solution of 43 42 in acetonitrile-water at pH 7.1 adjusted with 2,6-lutidine shows fluorescence quenching on addition of Cu 2 + whereas no decrease in fluorescence is observed with Ni 2 +, Mn 2 + and Co 2 + cations. 43 44 The chiral diaza-9-crown-3 derivative 44 displays "offon" switching 43 of fluorescence when treated with various lithium salts in organic solvents such as CH 3 CN and discriminates against a variety of group I and group II metal ions.
The optically 44 active cyclic hexapeptides 45a and 45b exhibit intense pyrene monomer emission at 375-418 nm and an additional pyrene excimer band at 487 nm (intramolecular) in 45a and 481 nm (intermolecular) in 45b. The addition of Ca 2 +/Ba 2 + perchlorate to a solution of cyclic peptide 45a causes a consider~ble increase of the excimer to monomer emission ratio (IiI m) which is more pronounced in case of Ca 2 +. Mg 2 + does not affect the emission of 45a. Peptide 45b shows analogous fluorescence characteristics but film ratio is much lower in comparison to that observed in 45a.  The calix [4]arene 47 46 shows fluorescence enhancement with Zn 2 + but fluorescence quenching with Ni 2 +.

II. Anionic recognition
Anions are larger in size than isoelectronic cations ( Table  I)   Additionally, anions are more sensitive to the pH (becoming protonated at lower pH), and therefore receptors must function within the pH range of the target anion. Anionic species have wide range of geometries and therefore a higher degree of design may be required to make receptors complementary to their anionic guest. Anionic receptors involving varied non-covalent interactions viz. electrostatic interactions, hydrogen bonding, hydrophilicity, co-ordination to a metal ion, and combination of these interactions have been ,developed. Receptors which use the amide moiety for bindmg anions, make use of the hydrogen bonds. Being direc-tiOnalm nature, hydrogen bonds allow the designing of receptors with specific shapes capable of differentiating anionic guests with different geometries.

48
In 1986, Pascal prepared the first purely amide based anion receptor 48 47  Receptors 49-55 are all C3-symmetric and are consequently organized to bind tetrahedral anions. Anslyn and co-workers have reported the synthesis of a cage like molecule 56 50 . Since the amide NH groups in 56 are arranged in a trigonal prismatic array, they are able to co-ordinate to then-electron system of planar anions such as carboxylates and nitrate.
Ureas and thioureas are particularly good hydrogen bond donors and are excellent receptors for Y -shaped anions such as carboxylates through the formation of two hydrogen bonds. The urea based receptor 57 forms highly stable complexes with bidentate ligands 51 . The acyclic cleft molecules 52   In evolving amide based anion receptors tris(2,2'bipyridyl)ruthenium(II) ([Ru(bpy) 3 ] 2 +), because of its chemical stability, redox properties, excited-state reactivity, and luminescent emission 55 had been one of the most extensively investigated platforms. Beer and co-workers have incorporated this moiety into acyclic, macrocyclic, and calix [4]arene structural frameworks to produce new class of anion receptors 64-68 capable of optical and electorchemical sensing 5 6-58 .

72
A structurally designed strategy for improving the binding ability of neutral urea and amide based receptors had been described 62 . A series of boronate ureas 73 and a related bis(boronate-amide), 74 were prepared. Their enhanced binding towards carboxylate anions is explained due to the co-operative polarization effect which is induced by intramolecular co-ordination of urea or amide carbonyl to a Lewis acidic boronate group. The interactions between a neutral (usually organic) molecular guest and the host framework may vary from very limited (e.g. van der Waals interactions) to significant stability (e.g. hydrogen bonds). Unlike charged species, neutral molecules are neither bound by strong permanent electrostatic forces, nor do they undergo well-defined co-ordination interactions, and hence their bindings are weaker. Also the sizes of the neutral guests are larger than metal cations or simple anions. Despite these features, the importance of this phenomenon in biological systems has lead to an enomous diversity of hosts or lattice compounds, which can bind neutral molecules through H-bonding 7 0-76 .
Hydrogen bonds are simulated in molecular mechanics as attraction between the bridge-forming proton and the donor and acceptor hetero element bearing negative partial charges. Many supramolecular systems have been devised which are based essentially on the simultaneous action of properly arranged hydrogen bond donors and acceptors. Amides because of facility of their modification and lipophilicity have been widely used asH-bond donors.
In combination with pyridine group, receptor 87 prepared Systems 89 possessing six-basic heteroarenes are tailor-made for encapsulating sterically and functionally complementary trihydroxybenzene 79 . Such hosts are sensitive to the introduction of methyl or ammonium groups into the guest molecules as 2,4,6-trihydroxytoluene or 2,4,6trihydroxytoluene hydrochloride are not complexed. The more strongly acidic nitrophloroglucinol simply forms, like picric acid, I : 3 complexe.
In contrast to the tris(bipyridine)hosts, the macrobicyclic ligand 90 has pronounced proton donor character, due to six hydroxyl groups of the catechol units. As a consequence, it complexes organic molecules with basic functional groups as long as the pK 5   The basket shaped molecule 94 in CDCJ 3 solubilizes ammonium p-nitrophenolate by the formation of the com-plex81. The water soluble macrobicyclic compound 97 (R =Me) constitutes a ditopic host for zwitterionic amino acid 85 and binds y-aminobutyric acid (GABA) with an association constant of3.2 x 10 3 M-1 (0 2 0). Glycine, which is too small, and 6-aminocaproic acid, which is too large, are only weakly bound.

91·
Macrobicyclic host 9886 complexes flat, disk shaped aromatic guest pyrene in aqueous phase 87 . Several macrocyclic hosts such as 99-103 have been prepared 88 as domains for binding quinone, which play a key role in the photosynthetic energy conversion. Complexation of pbenzoquinone by the macrricycles was investigated using 1 H NMR titrations. The limiting change in chemical shift observed for the 1 : 1 complexes support the structure shown in the Fig. 3. The signals due to amide protons show -1 ppm downfield shifts characteristic of hydrogen bonding and the signals due to the quinone protons show -2.5 ppm upfield shifts, which indicate that they lie over the host side walls.
A lipophilic glucose derivative is known to form a mul- Aliphatic mono(poly)ols and even hydrocarbon adamantane can be bound as guests to well designed cyclophane hosts in water as trans-! ,4-cyclohexanediol, trans-! ,4-cyclohexanedicarboxylic acid, and adamantanecarboxylic acid bind to host 105 90 . 105' (+)-106 Cage like host 106 is an example of chiral hosts having L-or o-valine moieties as chiral building blocks. This host binds steroid harmones such as a-estradiol, ,8-estradiol and estratriol enatioselectively in water-methanol (75 : 25) 91 . Testosterone having no aromatic moiety can not be bound to host 106. Rebek has prepared a versatile series of rigid C-shaped tweezer hosts such as 107-109 92 . The imide tweezer host 109 forms l : l complex with adenine and is able to extract adenine, and even nucleosides such as adenosine and deoxyadenosine, from aqueous solution and transport them across liquid organic membranes.
One of the most effective early tiesigns for guest inclusion via hydrogen bonding was reported by Chang and x, x, Synthetic receptor 124 has been found via fluorescence titration to compete effectively with cytochrome c peroxidase for binding cytochrome c forming 1 : I complex 97 . Chiral imidazole cyclophane receptors 125 exhibit good chiral recognition toward the enantiomers of L-and D-amino acid derivatives in chloroform98_ 125 Encapsulation of guests in self-assembled tetraurea calix [4)arene 126 and 127 dimers in organic solvents has been probed by PGSE NMR technique 99 . New polypyridine-macrocyclic receptors 128-130 for glucopyranoside recognition were designed and synthe-sized100. The receptors possess a terpyridine skeleton as a hydrogen-bonding site and a flexible polyoxyethylene chain as a bridge for the macrocyclic structure, in which the cavity of the receptor is large enough to incorporate pyranosides. The receptors showed high affinities for n-octyi-/3-(D)glucopyranoside, and selective binding of the receptors was observed between epimeric pyranosides.
A new rationally designed receptor molecule 131 binds adrenaline derivatives in water. Its binding pattern imitates the interplay of non-covalent interactions operating in the nature. High shape selectivity is achieved for the slim dopamine skeleton, and leads to the rejection of substrates with an a~substituent, such as amino acid derivativesl0 1 . Thus, the pre-eminent role of amide and urea moieties in recognition of both electron-rich (anions and neutral molecules) and electron deficient (cations and neutral molecules) guest species exemplified here points to the scope of exploration of abiotic receptors of these categories for evolving sensors and new models for recognition.