Electrophilicity Of Carbonyl Group Research Articles

Initial Amino Acid:Codon Assignments and Strength of Codon:Anticodon Binding.

The ribosome brings 3'-aminoacyl-tRNA and 3'-peptidyl-tRNAs together to enable peptidyl transfer by binding them in two major ways. First, their anticodon loops are bound to mRNA, itself anchored at the ribosomal subunit interface, by contiguous anticodon:codon pairing augmented by interactions with the decoding center of the small ribosomal subunit. Second, their acceptor stems are bound by the peptidyl transferase center, which aligns the 3'-aminoacyl- and 3'-peptidyl-termini for optimal interaction of the nucleophilic amino group and electrophilic ester carbonyl group. Reasoning that intrinsic codon:anticodon binding might have been a major contributor to bringing tRNA 3'-termini into proximity at an early stage of ribosomal peptide synthesis, we wondered if primordial amino acids might have been assigned to those codons that bind the corresponding anticodon loops most tightly. By measuring the binding of anticodon stem loops to short oligonucleotides, we determined that family-box codon:anticodon pairings are typically tighter than split-box codon:anticodon pairings. Furthermore, we find that two family-box anticodon stem loops can tightly bind a pair of contiguous codons simultaneously, whereas two split-box anticodon stem loops cannot. The amino acids assigned to family boxes correspond to those accessible by what has been termed cyanosulfidic chemistry, supporting the contention that these limited amino acids might have been the first used in primordial coded peptide synthesis.

Condensation reactions of dialkoxy-2-phenylchroman-4-ones with 1,2-diamines: A method for the preparation of chromenoquinoxalines

Reactions of dialkoxy-2-phenylchroman-4-ones (2,3-diethoxy-3-hydroxy-2-phenylchroman-4-one (1) and 2,3-dimethoxy-3-hydroxy-2-phenylchroman-4-one (2)) with various phenylenediamines in refluxing chloroform led to quinoxaline ring formation to produce racemic mixtures of chromenoquinoxaline molecules in good to moderate yields (3–10). The proposed mechanism involves the hemiacetals (1 and 2) rearranging upon heating to form a reactive dione intermediate that subsequently reacts with phenylenediamine derivatives to produce the title compounds. Reactions of 1 and 2 with asymmetric phenylenediamines led to mixtures of two regioisomers, for which the major products were dictated by the relative reactivity of the nucleophilic amine and the electrophilic carbonyl groups. The chromenoquinoxaline products were characterized by 1H, 13C, 19F (when necessary), nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, melting point determination, and in some cases (compounds 6–10) single crystal X-ray diffraction studies. Herein, the synthesis, characterization, and reactivity of this new class of molecules are discussed.

Redox Reorganization: Aluminium Promoted 1,5‐Hydride Shifts Allow the Controlled Synthesis of Multisubstituted Cyclohexenes

AbstractAn efficient synthesis of cyclohexenes has been achieved from easily accessible tetrahydropyrans via a tandem 1,5‐hydride shift–aldol condensation. We discovered that readily available aluminium reagents, e.g. Al2O3 or Al(OtBu)3 are essential for this process, promoting the 1,5‐hydride shift with complete regio‐ and enantiospecificity (in stark contrast to results obtained under basic conditions). The mild conditions, coupled with multiple methods available to access the tetrahydropyran starting materials makes this a versatile method with exceptional functional group tolerance. A wide range of cyclohexenes (>40 examples) have been prepared, many in enantiopure form, showing our ability to selectively install a substituent at each position around the newly forged cyclohexene ring. Experimental and computational studies revealed that aluminium serves a dual role in facilitating the hydride shift, activating both the alkoxide nucleophile and the electrophilic carbonyl group.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Covalent modification of poly(vinyl chloride) via organometallic Barbier reaction

The development of efficient synthetic methodologies for chemical functionalization and modification of existing polymers to improve or diversify the physicochemical and mechanical properties is an ongoing quest in macromolecular science. This is especially true for the generation of polymeric materials out of commercial/commodity polymers via structural tailoring since these polymers are produced in vast quantities and are structurally diverse. In this study, we report on benign chemical modification of an important commercial polymer, poly(vinyl chloride) (PVC) via Barbier reaction. The methodology is based on the employment of magnesium metal to generate nucleophilic alkyl-magnesium chloride groups on polymer backbone and addition of these nucleophilic centers to electrophilic carbonyl groups. The synthetic procedure can be implemented in a one-pot fashion by utilizing commonly available aldehyde or epoxide bearing compounds along with elemental magnesium. The Barbier addition of PVC backbone generated alkyl-magnesium chloride groups on the model aldehyde substrates with different structures were achieved with > 84 % functionalization degrees. It was shown that the functionalization degrees can easily be regulated by the simple alteration of employed magnesium ratio to backbone present alkyl chloride groups. Functionalization studies were investigated via 1H NMR, FT-IR and SEC analyses as well as contact angle measurements. Considering the wide industrial/ research utilization of poly(vinyl chloride) together with commercial availability, abundant reactive alkyl chloride bonds in backbone chains of this polymer offer easy to implement structural tailoring via proposed organometallic Barbier reaction.

Highly Stereoselective, Organocatalytic Mannich-type Addition of Glyoxylate Cyanohydrin: A Versatile Building Block for the Asymmetric Synthesis of β-Amino-α-ketoacids

β-Amino-α-ketoacids are important unnatural amino acids that exhibit unique bioactivity and reactivity derived from the highly electrophilic carbonyl group at the α-position. Despite the broad utility of the motif, reliable synthetic methods for β-amino-α-ketoacids have been limited to the oxidative homologation of α-amino acids based on a chiral-pool approach. In this article, we report an alternative practical method for the asymmetric synthesis of β-amino-α-ketoacid equivalents based on a highly stereoselective organocatalyzed Mannich-type addition using glyoxylate cyanohydrin. The optimal aminothiourea catalyst provides a wide variety of adducts from N-Boc imines in excellent yield and stereoselectivity (up to 100% yield, 99% ee, 94:1 dr), and the reaction can be applied to the direct use of α-amido sulfones as imine precursors, which significantly expands the substrate scope. The experimental structure–activity relationships and computational studies indicated that steric repulsion with the substituent on the amine moiety and the attractive interaction with the bis(trifluoromethyl)phenyl group might contribute to the high diastereoselectivity and that the thiourea scaffold provides a narrower catalytic pocket compared to benzothiadiazine due to the difference in the length of the intramolecular hydrogen bonding, which results in excellent enantioselectivity. The asymmetric adducts can be readily converted into β-amino-α-ketoacids that maintain their optical purity, and these can be used for the decarboxylative formation of amides without purification by column chromatography. Peptide-α-ketoacids were also prepared via intramolecular acyl migration as a key step and applied to decarboxylative peptide coupling with dipeptides that bear various unprotected functional groups and to [2 + 2 + 2] sequential peptide coupling. Furthermore, the efficient synthesis of peptide-α-ketoamides with retention of the stereo-information was achieved by using the cyanohydrin motif at the highly reactive α-carbonyl group, and the synthesis of an α-ketoamide-containing medicine, Telaprevir, was accomplished without any epimerization.

An in silico discovery of potential 3CL protease inhibitors of SARS-CoV-2 based upon inactivation of the cysteine 145-Histidine 41 catalytic dyad

Coronavirus disease 19 (COVID19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, several countries are at risk of the pandemic caused by this virus. In the absence of any vaccine or virus-specific antiviral treatments, the need is to fast track search for potential drug candidates to combat the virus. Though there are known drugs that are being repurposed to fight against the SARS-CoV-2, there is a requirement for the virus-specific drugs at the earliest. One of the main drug targets of SARS-CoV-2 is an essential non-structural protein, 3CL protease, critical for the life cycle of the virus. We have used molecular docking studies to screen a chemically diverse set of small molecules to identify potential drug candidates to target this protein. Of the 22,630 molecules from varied small molecule libraries, based on the binding affinities and physicochemical properties, we finalized 30 molecules to be potential drug candidates. Eight of these molecules bind in a manner allowing for the scope of a nearly orthogonal backside nucleophilic attack on their suitably placed electrophilic carbonyl groups by the thiol group of cysteine residue 145, while remaining inside a 4 Ǻ distance range. It is interesting since carbonyl groups are known to be attacked in a similar fashion by external nucleophiles and can be relevant when considering these molecules as potential mechanism-based irreversible inhibitors of the 3CLPro. Further, ADMET analysis and Molecular dynamics simulations and available bioactive assays led to the identification of three molecules with high potential to be explored as drug candidates/lead molecules to target 3CLPro of SARS-CoV-2. Communicated by Ramaswamy H. Sarma

A Dipolar Cyclization/Fragmentation Strategy for the Catalytic Asymmetric Synthesis of Chiral Eight-Membered Lactams

A Dipolar Cyclization/Fragmentation Strategy for the Catalytic Asymmetric Synthesis of Chiral Eight-Membered Lactams

Curcumin induces expression of 15-hydroxyprostaglandin dehydrogenase in gastric mucosal cells and mouse stomach in vivo: AP-1 as a potential target

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the conversion of oncogenic prostaglandin E2 to non-tumerigenic 15-keto prostaglandin E2. In the present study, we found that curcumin, a yellow coloring agent present in the rhizome of Curcuma longa Linn (Zingiberaceae), induced expression of 15-PGDH at the both transcriptional and translational levels in normal rat gastric mucosal cells. By using deletion constructs of 15-PGDH promoter, we were able to demonstrate that activator protein-1 (AP-1) is the principal transcription factor responsible for regulating curcumin-induced 15-PGDH expression. Curcumin enhanced the expression of c-Jun and c-Fos that are functional subunits of AP-1, in the nuclear fraction of cells. Silencing of c-Jun suppressed curcumin-induced expression of 15-PGDH. Moreover, the chromatin immunoprecipitation assay revealed curcumin-induced binding of c-Jun to the AP-1 consensus sequence present in the 15-PGDH promoter. Curcumin increased phosphorylation of ERK1/2 and JNK, and pharmacologic inhibition of these kinases abrogated the curcumin-induced phosphorylation of c-Jun and 15-PGDH expression. In contrast, tetrahydrocurcumin which lacks the α,β-unsaturated carbonyl group failed to induce 15-PGDH expression, suggesting that the electrophilic carbonyl group of curcumin is essential for its induction of 15-PGDH expression. Curcumin restored the expression of 15-PGDH which is down-regulated by Helicobacter pylori through suppression of DNA methyltransferase 1. In addition, oral administration of curcumin increased the expression of 15-PGDH and its regulators such as p-ERK1/2, p-JNK, and c-Jun in the mouse stomach. Taken together, these findings suggest that curcumin-induced upregulation of 15-PGDH may contribute to chemopreventive effects of this phytochemical on inflammation-associated gastric carcinogenesis.

DFT characterization of the mechanism for Staudinger/aza-Wittig tandem organocatalysis

A computational simulation with DFT calculations and microkinetic modeling is carried out on a complete catalytic cycle, involving Staudinger ligation, aza-Wittig condensation and phosphine oxide recycle, for non-truncated substrates and catalyst. The Staudinger reaction produces phosphazenes (R3P = NR), also known as iminophosphoranes, from phosphines and organic azides. Electrophilic carbonyl groups react with phospazenes to produce imines and phosphine oxides. Recently the Staudinger reaction and the aza-Wittig condensation have been combined to spawn intramolecular tandems producing cyclic molecules of great pharmaceutical interest (e.g. benzoxazoles). The release of diatomic nitrogen combined with the formation of phosphine oxide represents the driving force of the reaction. The implementation of in situ recycling of the exhausted phosphine oxide into the Staudinger/aza-Wittig tandem improves the scopes and the applicability of the reaction, transforming it into a powerful and versatile synthetic tool.

A new study of iodine complexes of oxidized gum arabic: An interaction between iodine monochloride and aldehyde groups

Gum arabic, a plant polysaccharide was oxidized with periodate to produce aldehyde groups by the cleavage of diols present in the sugar units. The oxidized gum was then iodinated with iodine monochloride (ICl) and the interaction between electrophilic iodine, I+ and reactive carbonyl groups of the modified gum was studied.Results of titrimetric estimation performed to determine the extent of oxidation and aldehyde content in the oxidized gum showed that degree of oxidation ranged between 19.68–50.19% which was observed to increase with periodate concentration; the corresponding aldehyde content was calculated to be 5.15–40.42%. Different strengths of ICl were used to iodinate the oxidized gum and the iodine content of the complexes varied from 6.11–11.72% as determined by iodometric titration. Structure elucidation of the iodine complexes conclusively established the attachment of ICl molecules to CHO groups. A reaction scheme has been proposed suggesting an electrophilic addition of the reagent to the aldehyde groups, a mechanism that was also supported by iodide ion release studies.

Living Anionic Polymerization of 1‐Adamantyl 4‐vinylphenyl ketone

The anionic polymerization of 1‐adamantyl 4‐vinylphenyl ketone (1), a styrene derivative carrying an electrophilic carbonyl group, is carried out in tetrahydrofuran (THF). Although no polymerization of 1 occurs with sec‐BuLi at −78 °C for 48 h, a polymeric product of 1 is obtained with diphenylmethyllithium in 10% yield under similar conditions. The resulting poly(1) has a very broad molar‐mass dispersity (Đ M = M w/M n = 1.72) and a molecular weight higher than the calculated value based on the molar ratio of the monomer and initiator and the conversion. On the other hand, the polymerization of 1 with diphenylmethylpotassium or diphenylmethylcesium quantitatively proceeds in THF at −78 °C within 48 h to form the polymers with predicted molecular weights and narrow molecular weight distributions (M w/M n < 1.1). The stability of the propagating carbanion derived from 1 is demonstrated by the quantitative efficiency of the postpolymerization (sequential monomer addition). The reaction of the adamantyl ketone moieties of poly(1) with methylmagnesium iodide quantitatively proceeds in THF/diethyl ether at room temperature, indicating the high electrophilicity of ketone groups. The resulting poly(1) has a high glass transition temperature at 193 °C, indicating the effect of the bulky adamantyl substituent. image

REDUCTION OF 5-(INDOL-3-YL)PYRROLIDIN-2-ONES

The reduction of activated 5-(indol-3-yl)pyrrolidin-2-ones leading to a mixture of the respective indolyl pyrrolidines and their borane complexes, as well as several other transformations indicate that the electrophilicity of carbonyl group in 5-indolylpyrrolidin-2-ones is significantly decreased. How to Cite Sadovoy, A. V.; Nikitina, V. N.; Rybakov, V. B.; Kochetkov, K. A.; Sviridova, L. A. Chem. Heterocycl. Compd. 2016 , 52 , 21. [ Khim. Geterotsikl. Soedin. 2016 , 52 , 21.] For this article in the English edition see DOI 10.1007/s10593-016-1832-8

Reduction of 5-(indol-3-yl)pyrrolidin-2-ones

The reduction of activated 5-(indol-3-yl)pyrrolidin-2-ones leading to a mixture of the respective indolyl pyrrolidines and their borane complexes, as well as several other transformations indicate that the electrophilicity of carbonyl group in 5-indolylpyrrolidin-2-ones is significantly decreased.

Substituted 2-(Dimethylamino)biphenyl-2'-carboxaldehydes as Substrates for Studying n→π* Interactions and as a Promising Framework for Tracing the Bürgi-Dunitz Trajectory.

The Bürgi-Dunitz trajectory traces points along the pathway of bond formation between a nucleophile and electrophile. Previous X-ray crystallographic studies of some molecules containing a nucleophilic nitrogen atom and electrophilic carbonyl group provided some initial evidence for various degrees of bond formation via initial n→π* interactions. Observation of a complete set of points along the trajectory, however, has not yet been attained. In this paper, we present a DFT computational study investigating substituted 2-(dimethylamino)biphenyl-2'-carboxaldehydes as substrates for further examination of n→π* interactions and as a potential framework for more complete tracing of the Bürgi-Dunitz trajectory. These compounds are particulary suitable for study because of the rotational freedom granted by the C-C bond connecting the two aromatic rings allowing the molecule to choose the degree of interaction between the two complementary groups. The extent of interaction is measured by interatomic distance, NBO second-order perturbative analysis energies, volume of transferred electron density as provided by ETS-NOCV analysis, and differences in energies between models that allow for n→π* interactions and those that do not. A series of substituted biphenyls are ultimately identified as future synthetic targets that have maximum potential for providing improved tracing of the Bürgi-Dunitz trajectory.

Twisted amide electrophiles enable cyclic peptide sequencing.

There is an ever-increasing interest in synthetic methods that not only enable peptide macrocyclization, but also facilitate downstream application of the synthesized molecules. We have found that aziridine amides are stereoelectronically attenuated in a macrocyclic environment such that non-specific interactions with biological nucleophiles are reduced or even shut down. The electrophilic reactivity, revealed at high pH, enables peptide sequencing by mass spectrometry, which will further broaden the utility of aziridine amide-containing libraries of macrocycles.

Abasic and Oxidized Abasic Site Reactivity in DNA: Enzyme Inhibition, Cross-Linking, and Nucleosome Catalyzed Reactions

Abasic lesions are a family of DNA modifications that lack Watson-Crick bases. The parent member of this family, the apurinic/apyrimidinic lesion (AP), occurs as an intermediate during DNA repair, following nucleobase alkylation, and from random hydrolysis of native nucleotides. In a given day, each cell produces between 10000 and 50000 AP lesions. A variety of oxidants including γ-radiolysis produce oxidized abasic sites, such as C4-AP, from the deoxyribose backbone. A number of potent, cytotoxic antitumor agents, such as bleomycin and the enediynes (e.g., calicheamicin, esperamicin, and neocarzinostatin) also lead to oxidized abasic sites in DNA. The absence of Watson-Crick bases prevents DNA polymerases from properly determining which nucleotide to incorporate opposite abasic lesions. Consequently, several studies have revealed that (oxidized) abasic sites are highly mutagenic. Abasic lesions are also chemically unstable, are prone to strand scission, and possess electrophilic carbonyl groups. However, researchers have only uncovered the consequences of the inherent reactivity of these electrophiles within the past decade. The development of solid phase synthesis methods for oligonucleotides that both place abasic sites in defined positions and circumvent their inherent alkaline lability has facilitated this research. Chemically synthesized oligonucleotides containing abasic lesions provide substrates that have allowed researchers to discover a range of interesting chemical properties of potential biological importance. For instance, abasic lesions form DNA-DNA interstrand cross-links, a particularly important family of DNA damage because they block replication and transcription absolutely. In addition, bacterial repair enzymes can convert an interstrand cross-link derived from C4-AP into a double-strand break, the most deleterious form of DNA damage. Oxidized abasic lesions can also inhibit DNA repair enzymes that remove damaged nucleotides. DNA polymerase β, an enzyme that is irreversibly inactivated, is vitally important in base excision repair and is overproduced in some tumor cells. Nucleosome core particles, the monomeric components that make up chromatin, accentuate the chemical instability of abasic lesions. In experiments using synthetic nucleosome core particles containing abasic sites, the histone proteins catalyze strand cleavage at the sites that incorporate these lesions. Furthermore, in the presence of the C4-AP lesion, strand scission is accompanied by modification of the histone protein. The reactivity of (oxidized) abasic lesions illustrates how seemingly simple nucleic acid modifications can have significant biochemical effects and may provide a chemical basis for the cytotoxicity of the chemotherapeutic agents that produce them.

Antimyeloma In Vitro Activity Of 15-Deoxy-D12,14-Prostaglandin J2 Is Associated With Endoplasmic Reticulum Stress In a Reactive Oxygen Species-Dependent Fashion

Multiple myeloma (MM) is an incurable malignancy characterized by the accumulation of terminally differentiated plasma cells in the bone marrow, usually accompanied by continuous monoclonal immunoglobulin production. This production requires proper folding and assembly of immunoglobulin chains, conducted by disulfide bonds formation in the endoplasmic reticulum (ER). Disulfide bonds are formed via electron transfer from thiol groups in a protein relay system, from protein disulfide isomerase (PDI) to ER oxidoreductase1 (ERO1) and finally to molecular oxygen, generating one molecule of hydrogen peroxide (H2O2) as secondary product for each disulfide bond formed. The high ER protein-folding demand usually placed on MM cells predisposes them to accumulation of unfolded proteins, which results in ER stress and also oxidative stress, both capable to induce cell death. Cellular defense systems for these specific forms of stress, known as the unfolded protein response (UPR) and oxidative stress response, have been explored as therapeutic targets for MM.15-Deoxy-D12,14-prostaglandin J2 (15d-PGJ2) is a member of J2 series of PGs, characterized by the presence of an electrophilic carbonyl group in the cyclopentenone ring, which confers them biological properties that are different from those of other components of the PG family. These include anti-inflammatory, anti-proliferative and pro-apoptotic activities, depending on the concentration and cell type. Starting from the observation that15d-PGJ2 is emerging as the most potent antineoplastic agent of the J2 series of PGs, in the present study we investigated its effect on MM cells.We found that 15d-PGJ2 displayed superior cytotoxicity than dexamethasone in MM cell lines. Using flow cytometry, we demonstrated intracellular reactive oxygen species (ROS) formation in these cells after 15d-PGJ2 treatment, which was associated with an augmented ratio of oxidized to reduced glutathione (GSH), indicating that the cells were under oxidative stress. Due to its electrophilic property, it has been suggested that 15d-PGJ2 may directly react with GSH and/or other thiol compounds. Such reactions would deplete essential cellular antioxidants thereby leading to oxidative stress in MM cells. Resultsfrom qPCR analysis showed that 15d-PGJ2 induces transcription of UPR genes, including GRP78, GRP94, EDEM1 and also PRDX4. GRP78/BiP and GRP94 are ER-resident chaperones, members of the heat shock protein (HSP) 70 family and HSP 90 family, respectively. These chaperones were described to bind to immunoglobulin chains assisting their assembly. The ER degradation-enhancer mannosidase-like protein 1 (Edem1) is involved in the degradation of misfolded proteins to prevent their aggregation and cytotoxicity. PRDX4 encodes the ER-localized peroxiredoxin (Prx) IV, an enzyme not yet recognized as an UPR component, but recently demonstrated to use the H2O2 produced by ERO1 during disulfide bond formation to generate another pair of disulfide, with the additional benefit of reducing H2O2 to water. Increased transcription of these genes indicates an attempt to preserve ER-processing function and MM cells survival in response to accumulated misfolded proteins. In this regard, 15d-PGJ2-induced oxidative stress, by provoking oxidative modification of proteins, could have intensified the formation of misfolded proteins, thereby activating UPR signaling. In agreement with 15d-PGJ2-mediated accumulation of misfolded proteins, which are prevented from progressing further along the secretory pathway, our results from ELISA have shown a massive decrease in the concentration of light chain immunoglobulin secreted by MM cells in the presence of 15d-PGJ2, but not dexamethasone.These data suggest that 15d-PGJ2 favors ROS accumulation and protein misfolding, especially threatening the survival of cells that have a high protein-folding load and/or are susceptible to oxidative stress. In this sense, multiple myeloma and related disorders may benefit from 15d-PGJ2 therapy. Disclosures:Demasi:FAPESP: Research Funding. Napimoga:FAPESP: Research Funding.

Speeding-up enzyme-catalyzed synthesis of polyamides using ω-amino-α-alkoxy-acetate as monomer

The design of ω-amino-α-alkoxy-acetate as monomer enables to dramatically speed up the formation of polyamides catalyzed by the supported lipase B of Candida antarctica. Only 30 min are needed to reach 93% conversion whereas 240 h are necessary to observe the same level of conversion with a monomer devoided of an oxygen atom in position β relative to the electrophilic carbonyl group. Yields, Mn, Mw, DPn and PDI reach very good values for an enzymatic synthesis of polyamides.

Interdigitated Hydrogen Bonds: Electrophile Activation for Covalent Capture and Fluorescence Turn-On Detection of Cyanide

Hydrogen-bonding promoted covalent modifications are finding useful applications in small-molecule chemical synthesis and detection. We have designed a xanthene-based fluorescent probe 1, in which tightly held acylguanidine and aldehyde groups engage in multiple intramolecular hydrogen bonds within the concave side of the molecule. Such an interdigitated hydrogen bond donor-acceptor (HBD-HBA) array imposes significant energy barriers (ΔG(‡) = 10-16 kcal mol(-1)) for internal bond rotations to assist structural preorganization and effectively polarizes the electrophilic carbonyl group toward a nucleophilic attack by CN(-) in aqueous environment. This covalent modification redirects the de-excitation pathways of the cyanohydrin adduct 2 to elicit a large (>7-fold) enhancement in the fluorescence intensity at λmax = 440 nm. A remarkably faster (> 60-fold) response kinetics of 1, relative to its N-substituted (and therefore "loosely held") analogue 9, provided compelling experimental evidence for the functional role of HBD-HBA interactions in the "remote" control of chemical reactivity, the electronic and steric origins of which were investigated by DFT computational and X-ray crystallographic studies.