Molecular Recognition Of Amide Naphthotubes And Cucurbiturils And Capture Of Hemiaminals In Water

Molecular recognition exists widely in nature,and is the basis of many complex biological functions.Aritificial molecular recognition based on macrocyclic hosts can not only help understand the complex phenomena of biological molecular recognition as a model system,but also can be used in various fieds,such as environmental science,analytical chemistry,biological medicine,fine chemical engineering,material science.The molecular recognition systems in organic phase are relatively easy to construct,and thus are widely studied.However,it is very difficult to construct aqueous molecular recognition systems capable of selectively recognizing hydrophilic molecules.By mimicking the structure of bioreceptors,scientists synthesized the biomimetic hosts amide naphthotubes,which can selectively recognize hydrophilic molecules in water,through putting the polar binding sites in a deep hydrophobic cavity.Although progress has been made in aqueous molecular recognition of hydrophilic molecules,it is still difficult to develop a new artificial hydrophilic molecular recognition system.Because recognition mechanism of hydrophilic molecules is still unclear.In addition,performing chemical reactions in water is required for modification of biomolecules,cost saving,and environmental protection.However,intermediates or products of some reactions are sensitive to water and the reactions are difficult to run in water.Moreover,it is also difficult to study the mechanism of aqueous chemical reactions,because water usually increase the difficulty of trapping the reaction intermediates.Here,we investigate the mechanism of hydrophilic molecular recognition in water in detail through biomimetic hosts amide naphthotubes and classical hosts cucurbiturils;Based on the aqueous recognition property of amide naphthotubes,we designed and synthesized an amide naphthotube derivative which can form water-sensitive aliphatic imines and stabilize the intermediate hemiaminals in water.The molecular recognition of cucurbiturils towards neutral hydrophilic molecules in water was investigated,and the important role of hydrophobic effects due to hydrophobic cavities in aqueous hydrophilic molecular recognition was revealed.It was found that cucurbiturils can effectively bind neutral hydrophilic molecules in water,such as 1,4-dioxane,crown ethers,and monosaccharides.The high binding constant of 10~7 L/mol is achieved between cucurbit[8]uril and12-crown-4 ether.Binding constant of cucurbit[7]uril towards 2-deoxy-D-ribose is10~3 L/mol.There is no obvious non-covalent interactions between cucurbiturils and these hydrophilic molecules.The binding was mainly driven by hydrophobic effects.The packing coefficients of the host-guests complexes is between 52%and 65%,indicating that the guest is well accommodated in the cavity,neither causing steric hindrance nor being too looseThe binding parameters of cucurbit[7]uril towards 35 neutral hydrophilic guests in water were further determined,and were compared to those of amide naphthotubes.It was found that the intrinsic binding strength of cucurbit[7]uril is positively correlated with guest volume,and negatively correlated with guest asphericity,that is,cucurbit[7]uril prefers a spherical guest whose molecular volume is matched with its cavity.While the intrinsic binding strength of amide naphthotubes is positively correlated with the number of heteroatoms in the guest and the overall hydrogen bond basicity of guest,and negatively correlated with the octanol:water partition coefficient of guest,that is,amide naphthotubes selectively bind hydrophilic molecules which can form matching hydrogen bonds.Amide naphthotube cannot bind most of amino acids,deoxyribonucleotides,D-glucose,and D-fructose.And the molecular recognition of amide naphthotube to neutral molecules in water are not influenced by salts,PBS and Tris-HCl buffers.While HEPES buffer can inhibit the binding strength of amide naphthotube to guest molecules through competitive binding.Based on the selectively recognition of hydrophilic molecules by amide naphthotubes,a mono-functionalized amide naphthotube with an amine side chain was designed and synthesized by simulating the structure of bioreceptor aldolase.The amine side chain of the mono-functionalized amide naphthotube is folded into the cavity in water,and can trap alphatic aldehydes or benzaldehyde in solution to form imines.These imines are quite stable upon heating,in highly basic condition or in the presence of nucleophiles or electrophiles.During the reactions of the host with acetaldehyde or propanal,the active intermediates hemiaminals can be detected by ~1H NMR spectroscopy and mass spectrometry.While for the reactions of the host with the aldehydes having a bigger hydrophobic group,such as n-butanal,n-pentanal,n-hexanal and benzaldehyde,the intermediates hemiaminals cannot be detected.The functional groups of the imines and the hemiaminals can form hydrogen bonds with the amides in the host cavity,and are well protected by the hydrophobic cavity.