Isolation, X-ray Structures, and Electronic Spectra of Reactive Intermediates in Friedel−Crafts Acylations

Reactive intermediates in the Friedel−Crafts acylation of aromatic donors are scrutinized upon their successful isolation and X-ray crystallography at very low temperatures. Detailed analyses of the X-ray parameters for the [1:1] complexes of different aliphatic and aromatic-acid chlorides with the Lewis acids antimony pentafluoride and pentachloride, gallium trichloride, titanium and zirconium tetrachlorides provide unexpected insight into the activation mechanism for the formation of the critical acylium carbocations. Likewise, the X-ray-structure examinations of aliphatic and aromatic acylium electrophiles also isolated as crystalline salts point to the origins of their electrophilic reactivity. Although the Wheland intermediates (as acylium adducts to arene donors) could not be isolated in crystalline form owing to their exceedingly short lifetimes, transient (UV−vis) spectra of benzenium adducts of acylium carbocations with hexamethylbenzene can be measured and directly related to Wheland intermediates with other cationic electrophiles that have been structurally established via X-ray studies

Interdisciplinary Research-Based Learning in Organic Chemistry and Microbiology Laboratories: Synthesis and Biological Testing of Novel Penicillin Derivatives

Interests in the mechanism that penicillin bestows on its target protein has driven the curiosity of its binding specificity towards the methicillin resistant strain of Staphylococcus areus, and its expression of a unique penicillin binding protein that has enabled its resistance. The ability of bacteria to gain antibiotic resistance has strengthened the ongoing need to synthesize and discover novel drugs to combat the diseases that follow infection. If it were not for the collaborations between scientific disciplines, the production of effective novel drugs such as penicillin would not be the same. To encourage undergraduate students to make real world connections across disciplines, the development of an interdisciplinary organic chemistry-microbiology laboratory experiment was developed. By utilizing discovery-based, authentic research to intentionally encourage student collaboration and improve retention of knowledge gained, a pedagogical experiment involving students from both organic chemistry and microbiology was designed to meet these goals. To implement this educational experiment into existing curriculum, an original experiment was designed and tested in the fall of 2014 to develop a synthetic experimental procedure and biological assay that could be used by organic chemistry and microbiology students in the following spring. The synthetic experimental portion had to be completed within a three-hour laboratory period, yet provide enough versatility for each set of students to synthesize different penicillin compounds by varying the acyl tails attached to the penicillin head group. Once the penicillin compounds were synthesized, the organic chemistry students prepared brief presentations to explain the chemistry behind their syntheses to the microbiology students, who aided in their biological testing, allowing students to visualize the antimicrobial efficacy of their antibiotic on bacterial strains. Microbiology students collaborated in the biological analysis by teaching the chemistry students how to perform a disc diffusion assay and interpret possible susceptibility that the antibiotics may have had on gram-negative and gram-positive bacterial strains. This experiment illustrated the benefits of performing open-ended research to create new possible antibiotics in a chemistry course and of testing the synthesized products in a biology course to visualize the antimicrobial efficacy of their antibiotic on bacterial strains. Overall, this experiment gave students in each course the chance to teach and share their newly learned expertise with their peers, to make scientific connections across disciplines and to address an authentic, open-ended research problem through cooperative learning

Synthesis and reactions of 1-amino-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-ones

1-Amino-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-ones, as previously unknown ring-annelated isoquinolines with a 3-aminoimidazolidin-4-one scaffold, were selectively prepared upon reacting 2-carbamoylmethyl- or 2-ethoxycarbonylmethyl-3,4-dihydroisoquinolinium salts with hydrazine hydrate. Acylation of the primary amino group with benzoyl chlorides, followed by reductive ring cleavage of the annelated 4-imidazolidinone ring and final cyclodehydration of the N,N'-diacylhydrazines resulted in the synthesis of 1-methyl-2(5-aryl-[1,3,4]oxadiazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolines which are of interest due to their potential use as bioisosteres of biologically active N-aryl-2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl) acetamides

Catch and release’ cascades: a resin-mediated three-component cascade approach to small molecules

The application of a ‘catch and release’ approach to palladium-catalysed multi-component cascade reactions leads to diverse libraries of pharmacologically interesting small molecules in high yield and with excellent purity

New Catalytic Reactions in Carbohydrate Chemistry

Carbohydrates or sugars are some of the most diverse and abundant biological molecules. They are involved in a multitude of processes in the body such as fertilization, cell-cell communication, and cancer metathesis. Because of these vital functions, the study of sugars is rapidly growing field. The field however is limited due to the complex nature of sugars which results in difficulties in obtaining large quantities for study. Protecting group manipulation is a large emphasis area in carbohydrate chemistry due to the need to selectively protect different functional groups of each molecule during synthesis. Catalytic and selective cleavage of protecting groups is a growing area in the field of carbohydrates as current methods are time-consuming and require large excess of reagents. Picoloyl ester is becoming a common protecting group due to its ability to provide a powerful stereodirecting effect in glycosylation reaction. Chapter 2 details the development of a new catalytic approach to remove the picoloyl group in a highly chemoselective manner. Protecting group manipulation is only one part of carbohydrate synthesis. New catalytic methods for glycosylation, a fundamental reaction for connecting two sugar units, are also needed. Chapter 3 describes our recent discovery that catalytic FeCl3 can efficiently activate glycosyl chloride to produce disaccharides in respectable yields in 30 min – 16 h. Chapter 4 further elaborates upon the topic of chemical glycosylation. Described herein is the application of a cooperative Ag2O and triflic acid catalysis to glycosidation of glycosyl chlorides. Fast reaction times and near quantitative yields are the main traits of this method. Lastly, Chapter 5 combines findings described in the previous chapters into development of a new superior platform for oligosaccharide synthesis. Currently used strategies for oligosaccharide synthesis are time consuming, inefficient, and may lead to low yields of oligosaccharides. By combining the catalytic picoloyl group cleavage and activation of glycosyl chlorides using FeCl3 we developed a reverse orthogonal synthetic strategy which combined protecting group cleavage and activation of glycosyl donors in one step. We then showcase how efficiently this concept works for the rapid assembly of oligosaccharide sequences

Methanolysis (solvolysis) And Synthesis Of 4′'-substituted 4-benzyloxybenzyl Chlorides And Some Related Compounds: Comparisons With The Corresponding Benzoyl Compounds

The kinetics of methanolysis (solvolysis) in 97.4% MeOH-dioxan of a series of 4′-substituted 4-benzyloxybenzyl chlorides, and of 4-anisyl, 4-phenoxybenzyl, and benzyl chlorides have been studied and discussed, including comparisons with the data for the corresponding series of benzoyl chlorides, previously reported by us. The 4′-substituted precursor alcohols, chlorides, and product methyl ethers are all new compounds. 4-Anisyl chloride and the series of benzyloxybenzyl chlorides react by the SN1 mechanism, whereas benzyl chloride reacts by the SN2 mechanism. 4-Phenoxybenzyl chloride shows intermediate behaviour. A similar pattern was observed with the corresponding benzoyl compounds. In both series the reactivity order is CH3O > 4′-CH3C6H 4CH2O (-0.76) >C5H5CH 2O (-0.74) > 4′-ClC6H4CH2O (-0.69) > 4′-NO2C6H4CH2O (-0.60) > C6H5O > H (values in parentheses are new σ+ values). At 25° the overall range of rates is 4 290 in the benzyl series, compared with only 2.42 in the benzyl series. The Arrhenius parameters in the two series demonstrate, however, an underlying similarity with obvious differences superimposed. In both series, the introduction of 4-OR groups leads to a ΔS‡ increase of ca. 40 J mol-1 K -1. In the benzyl series this is accompanied by ΔE‡ decreases of ca. 6-10 kJ mol-1, whereas in the benzoyl series ΔE‡ values increase by ca. 10-15 kJ mol-1. The equation log k = log k0 + n[MeOH] in mixtures with increasing content of dioxan, was used to study the rate dependence on MeOH concentration. Values of n are ca. 5 between 97.4 and 8.3.% MeOH, and ca. 3 between 83.3 and 50.0% MeOH.110010

Reaction Kinetics of the Alcoholysis of Substituted Benzoyl Chlorides

The reaction kinetics of the alcoholysis of substituted benzoyl chlorides was studied. The mechanism of the alcoholysis reaction, which is most generally accepted (1), shows that the overall reaction should be second-order and that the reaction should be first-order with respect to the acid chloride and first-order with respect to the alcohol. This rate study was carried out using a large excess of alcohol as the solvent, thus obtaining pseudo-first order rate constants, first-order with respect to the acid chloride only

Substituent effects on the magnetic resonance spectra of 1, 4-disubstituted benzenes

The Nuclear Magnetic Resonance spectra of five complete series of para-substituted benzenes have been investigated: the benzoic acids, benzonitriles, benzoyl chlorides, methyl benzoates and nitrobenzenes. Precise values of aromatic proton chemical shifts and coupling constants were obtained from LAOCOON3 computer analyses of the spectra. Using the relative internal chemical shift technique of Beachell and Beistel, excellent linear correlations among all five series were found. All substituents gave proton shifts which lay on the least-squares line, so it is concluded that all substituents are well behaved. Using the correlation plots the chemical shifts of the aromatic ring protons can be predicted to 0.01 ppm. Highly resolved, first-order spectra were observed at 100 MHz for the 4-alkyl-nitrobenzenes. The group designations A₂B₂X, A₂B₂XX\u27 and A₂B₂XX\u27X were assigned to 4-nitro-cumene, 4-ethyl-nitrobenzene and 4-nitro-toluene respectively. Basic spin wave functions were constructed for both the A₂B₂X and A₂B₂XX\u27 systems and both diagonal and off-diagonal matrix elements were evaluted. No methyl-ring proton coupling was found for 4-t-butylnitrobenzene and ring proton spectrum was simply A₂B₂. The perturbed valence bond model of Beistel has been used to rationalize substituent effects on the p.m.r. spectra of the para-substituted benzenes. This model assumes that the hybridization of the skeletal atoms can be perturbed from sp² to (sp²+Δp) or (sp²-Δp), depending on the directive abilities of the substituent. The perturbation influences the proton shift upfield relative to benzene when the proton is bonded to a carbon hybridized (sp²+Δp), and downfield for a carbon hybridized (sp²-Δp). Available carbon-13 shift data has proved consistent with the proposed model. The directive abilities of the substituents decrease in the sequencer N(CH₃)₂, NH₂, OCH₃, OH, F, CH₃, C₂H₅ , H, C₃H₇, Cl, C₄H₉, Br, CN, COOCH₃, COCl, I and N0₂. That is according to the hybridization of the central atom, its relative nuclear charge and the principal quantum number of the valence electrons. The groups COH, CONH₂ and COCH₃ have not been included in the sequence since complete series were not studied. Files of spectral data and selected measurements suggest that these groups lie between CN and COOCH₃ in the order indicated --Abstract, pages iii-iv

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl) benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m- sulfamoylbenzamide analogues