Development of a Fluorogenic Reactivity Palette for the Study of Nucleophilic Addition Reactions Based on meso-Formyl BODIPY Dyes

Abstract

We describe herein a fluorescence-based assay to characterize and report on nucleophilic addition to carbonyl moieties and highlight the advantages a fluorescence-based assay and multiplex analysis can offer. The assay relies on the fluorogenic properties of meso -formyl boron-dipyrromethene (BODIPY) dyes that become emissive following nucleophilic addition. A reactivity palette is assembled based on the increasing electrophilic character of five meso -formyl BODIPY compounds tested. We show that increasing rates of emission enhancement correlate with the decreasing electrophilic character of BODIPY dyes in the presence of an acid catalyst and a nucleophile. These results are consistent with the rate-limiting step involving activation of the electrophile. Increasing product formation is shown to correlate with the increasing electrophilic character of the BODIPY dyes, as expected based on thermodynamics. In addition to providing rates of reaction, analysis of the fluorescence parameters for the reaction mixtures, including emission quantum yields and fluorescence lifetimes, enables us to determine the extent of reactant conversion at equilibrium (in our case the estimated yield of a transient species) and the presence of different products, without the need for isolation. We anticipate that our reactivity palette approach, combined with the in-depth fluorescence analysis discussed herein, will provide guidelines toward developing fluorogenic assays of reactivity offering multiplex information, beyond fluorescence intensity.

Tuning Photoinduced Electron Transfer Efficiency of Fluorogenic BODIPY‐α‐Tocopherol Analogues

“…Based on our recent work on estimating redox potentials for BODIPY cores , we propose a compound bearing CN at the 2 and 6 positions and no methyl groups at the 1 and 7 positions as the ideal candidate. Such a candidate, however, may have stability issues given the reported hydrolysis of nitrile BODIPY dyes .…”

3-Formylpyrazolo[1,5-a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores

“…The synthesis of N -heteroaryl aldehydes is an important focus of research for synthetic organic chemists due to their presence in biologically active compounds, as well as other functional molecules . In addition, the carbonyl group can undergo a variety of transformations such as C–C, C–N, and C–O coupling reactions and also participate in redox reactions; thus, the biological and physicochemical effect of such postfunctionalized compounds would be improved. In particular, pyrazolo­[1,5- a ]­pyrimidine derivatives have received augmented interest in recent years due to their broad range of biological and pharmacological activities .…”

Acetoxymethyl-BODIPY Dyes: A Universal Platform for the Fluorescence Labeling of Nucleophiles

“…In general, most post-functionalization strategies described for BODIPYs require the presence or prior introduction of a reactive atom or group (e.g. halogen, [9][10][11][12][13][14][15][16][17][18][19] formyl, [20][21][22][23][24] carboxyl, [25][26][27][28][29][30][31] thioether, [32][33][34][35][36] alkyne, [37][38][39][40][41][42][43][44] azide, [45][46][47][48] or tetrazine [49][50][51][52][53] ) that enables the final functionalization reaction. These reactive groups can be directly attached either to the chromophore backbone (at boron or carbon) or to peripheral positions separated by one or several bonds from the chromophoric nucleus.…”

“…(27,31) and tertiary(23) alkanols, as well as benzylic(21,34), allylic(24) and propargylic alcohols(19) could be successfully labeled in moderate to very good yields.The reaction is compatible with the presence of ester(26), nitrile(21), carbamoyl(26), carboxamido(32,33), imido(27)(28)(29), trialkylsilyl ether(27), isopropylidene acetal (29, 30), 1,2,4,5-tetrazino(34), disulfide(38), and chloro-/iodo-alkyl groups(20,32,33).…”