Synthesis And Properties Of Thiosemicarbazone Derivatives From Camphene

As one of the main forest resource chemicals in China,turpentine is also the natural essential oil with the largest output.Camphene is an important primary derivative of turpentine and has the advantages of low cytotoxicity,good biocompatibility,and facile structural modification.So far,although camphene has been exploited to synthesize many highly value-added chemicals,which are mainly used in the fields of flavors and fragrances,and household chemicals.However,the development of small-molecule fluorescent probes using camphene has rarely been reported.As an important class of ligands,thiosemicarbazide compounds has good application value in many fields,such as medicinal chemistry,chiral synthesis,clinical medicine,environmental monitoring,etc.Herein,a series of novel camphene-based thiosemicarbazones have been synthesized from camphene via selective addition and condensation reactions,and their chemical structures were characterized by NMR,FT-IR,and HR-MS.The probing performances and antioxidation activities of these synthetic compounds were studied.The main research contents and results are as follows:(1)2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2yl)hydrazine-1-carbothioamide(2Ⅲa),2-(1-(6-methyl-2-oxo-2H-chromen-3-yl)ethylidene)N-(2,3,3-rimethylbicyclo[2.2.1]heptan-2-yl)hydrazine-1-carbothioamide(2Ⅲb),and 2-(1-(6fluoro-2-oxo-2H-chromen-3-yl)ethylidene)-N-(2,3,3-rimethylbicyclo[2.2.1]heptan-2yl)hydrazine-1-carbothioamide(2Ⅲc)were synthesized from camphene via a three-step reaction.Firstly,camphene was reacted with potassium thiocyanate to prepare 2-isocamphanyl isothiocyanate with concentrated sulfuric acid as a catalyst.N-(2,3,3trimethylbicyclo[2.2.1]heptan-2-yl)hydrazinecarbothioamide(2Ⅰ)was synthesized by the addition reaction of 2-isocamphanyl isothiocyanate and hydrazine hydrate.Finally,The target compounds 2Ⅲa,2Ⅲb,and 2Ⅲc were synthesized by reacting the compound 2Ⅰ with 3-acetyl coumarin with different substituents,and characterized by FT-IR,1H NMR,13C NMR,and HRMS.Three compounds 2Ⅲa,2Ⅲb,and 2Ⅲc have been successfully applied as probes for the colorimetric detection of F-in DMF solution.The experimental results displayed that probe 2Ⅲc demonstrated the highest selectivity and sensitivity,with a low detection limit of 0.63 μM,with binding constant values of 2.58×104 M-1,as well as the binding ratio of 2Ⅲc to F-was 1:1.When F-was added to the DMF solution of probe 2Ⅲc,an instantly dramatic color change from colorless to purple was observed.The decreased absorption peak at 355 nm was observed,while there was a concomitant appearance of a new peak at 557 nm.The recognition mechanism of the probe 2Ⅲc towards F-was determined by 1H NMR,HR-MS,and DFT calculation.The calculated results suggested that initial formation of a hydro gen-bonded host-guest complex and the subsequent deprotonation of probe 2Ⅲc upon the addition of excess F-,which was responsible for the remarkable changes in the absorption spectra of 2Ⅲc.In terms of application,a combination logic circuit of IMPLICATION and INHIBITION gates at the molecular level was fabricated using the reversibility of probe 2Ⅲc towards F-and Mg2+.The portable test strips coated with 2Ⅲc were prepared simply and applied for detection of F-in an aqueous solution.Apart from that,compound 2Ⅲc was loaded on solid KBr,which was used to detect solid samples containing F-contamination.Therefore,compound 2Ⅲc could serve as a colorimetric probe to realize the naked eye recognition and detection of F-.(2)2-(4-(diethylamino)-2-hydroxybenzylidene)-N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2yl)hydrazinecarbothioamide(3Ⅲ)was synthesized by a condensation reaction of N-(2,3,3trimethylbicyclo[2.2.1]heptan-2-yl)hydrazinecarbothioamide(21)and 4-(diethylamino)-2hydroxybenzaldehyde,and then characterized by FT-IR,1H NMR,13C NMR,and HR-MS.Compound 3Ⅲ has been successfully applied as a probe for the "turn-on" fluorescence detection of Ga3+ in H2O/DMSO(v/v=3/7)solution.Probe 3Ⅲ could specifically recognize Ga3+with strong blue emission at 447 nm in a wide pH range.The probe 3Ⅲ exhibited high selectivity and sensitivity toward Ga3+ with low detection limit of 1.18 μM,binding constant values of 5.34×103 M-1,as well as it was not interfered by other ions including Al3+ and In3+.Meanwhile,the binding ratio of probe 3Ⅲ with Ga3+was 1:1.The sensing mechanism of probe 3Ⅲ for Ga3+was confirmed by fluorescence spectral titration,1H NMR,and HRMS analysis.The chelationinduced enhanced fluorescence(CHEF)effects along with the inhibition of C=N isomerization were responsible for the fluorescence enhancement of probe 3Ⅲ.In addition,the spectral response behaviors were reasonably explained by DFT calculations.In terms of application,an INHIBIT logic gate at the molecular level was successfully constructed based on the reversible fluorescence response of probe 3Ⅲ to Ga3+and ATP.The portable test strips coated with 3Ⅲwere prepared simply and applied for rapid qualitative and quantitative detection of Ga3+in aqueous solution.Finally,the probe 3Ⅲ displayed low cytotoxicity and cell permeability,and it could achieve the detection and imaging of Ga3+in the MFC-7 cells and zebrafish.(3)Six 2-(2-hydroxybenzylidene)-N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)hydrazine1-carbothioamide derivatives(4Ⅲb-4Ⅲf and 3Ⅲ)were synthesized by a condensation reaction of N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)hydrazinecarbothioamide(21)and salicylaldehyde with different substituents,and characterized by FT-IR.1H NMR,13C NMR,and HR-MS.The antioxidant activities of these compounds were explored by both experimental testing and theoretical calculations.Compounds 3Ⅲ,4Ⅲb-4Ⅲf were able to scavenge DPPH free radicals to varying degrees in the DPPH free radical scavenging experiment.Among of them,the most prominent is compound 3Ⅲ with the highest clearance rate and the lowest IC50 of 0.208μM,which is lower than the 0.241 μM of the reference Trolox.In the DPPH kinetics experiment,compound 3Ⅲ could quickly scavenge DPPH free radicals with the maximum reaction rate constant value of 4218 M-1S-1,which is 1.18-fold higher efficacy than that of Trolox.In peroxyl radical scavenging capacity experiment,compound 3Ⅲ still provided the highest peroxyl radical scavenging activity with the lowest IC50 of 1.27 μM,which is 1.27 times higher than Trolox.Furthermore,the DFT calculations were carried out to further explain the experimental results and antioxidant mechanism.The theoretical data suggested that scavenging free radical activities of 3Ⅲ is attributed to hydrogen atoms transfer(HAT)mechanism.Compound 3Ⅲ formed stable free radicals after hydrogen extraction,and the structure changes from a non-planar structure to an almost planar structure which is conducive to electron delocalization and structural stability.Therefore,compound 3Ⅲ showed higher antioxidant activity.