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Metal-free C–H insertion via flow photolysis of aryldiazoacetates 3–5 with increased reaction efficiency in the presence of 4,4′-dimethoxybenzophenone.

A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC

This study highlights the impact of relative stereochemistry in epimer compounds on their mechanical properties; the crystals of one series of esters are ductile and deform plastically upon bending, whereas the other series are all brittle. Nanoindentation studies show that the hardness, H, and elastic moduli, E, of the brittle crystals are substantially larger than those of the ductile ones. For the brittle crystals, the H values range from 153(10) to 293(37) MPa and E from 2.85(0.33) to 9.10(0.51) GPa, whereas for the ductile crystals, the H values range from 76(2) to 125(11) MPa and E from 1.40(0.36) and 2.75(0.06) GPa. These are rationalized by recourse to the distinct crystal structural features, especially in terms of interdigitation in the molecular planes in the brittle crystals and slip planes in the ductile crystals. The indentation fracture toughness, Kc, values of the (2′S) crystals are higher than those typically reported for molecular crystals, due to the corrugated nature of their crystal packing which enhances the crack tortuosity. The Kc values are in the range 0.215 (0.08) to 0.278 (0.06) MPa m½ and the brittleness index values are in the range 711(19) to 1053(50) m−½.

Localized partitioning of amorphous enantioenriched aryl benzyl sulfoxides in the solid state can lead to substantial variation in enantiopurities, even for sulfoxides which do not show detectable levels of self-disproportionation of enantiomers (SDE) during chromatography on an achiral stationary phase. The importance of preparation of representative samples of enantioenriched sulfoxides for chiral HPLC to enable reproducible results is clear.

Over the past 20 years reports of sulfonyl migrations have appeared, frequently described as ‘unusual’ and ‘unexpected’. This comprehensive review compiles, for the first time, sulfonyl migrations reported over the last 20 years including formal 1,2-, 1,3-, 1,4-, 1,5-, 1,6- and 1,7-sulfonyl shifts, occurring through either radical or polar processes, either inter- or intramolecularly. Discussion of the sulfonyl migrations is structured according to reaction type, i.e. nitrogen–carbon, nitrogen–oxygen, nitrogen–nitrogen, oxygen–carbon (including anionic and non-anionic thia-Fries rearrangements), oxygen–oxygen and carbon–carbon migrations. Discussion of the underlying mechanisms for the migrations is included, with particular attention afforded to the principal techniques utilised for their elucidation, namely isotopic-labelling, crossover experiments, density functional theory calculations and electron paramagnetic resonance spectroscopy amongst others.

Generation of tosyl azide 12 in acetonitrile in flow under water-free conditions using an azide resin and its use in diazo transfer to a series of aryl acetates are described. Successful telescoping with a rhodium acetate-catalyzed O–H insertion has been achieved, thereby transforming the aryl acetate 8 to α-hydroxy ester 10, a key intermediate in the synthesis of clopidogrel 11, without requiring isolation or handling of either tosyl azide 12 or α-aryl-α-diazoacetate 9, or indeed having significant amounts of either present at any point. Significantly, the solution of α-diazo ester 9 was sufficiently clean to progress directly to the rhodium acetate-catalyzed step without any detrimental impact on the efficiency of the O–H insertion. In addition, the rhodium acetate-catalyzed O–H insertion process is cleaner in flow than under traditional batch conditions. Use of the azide resin offers clear safety advantages and, in addition, this approach complements earlier protocols for the generation of tosyl azide 12 in flow; this protocol is especially useful with less acidic substrates.

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C-H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Herein, we report the preparation and use of m-carboxybenzenesulfonyl azide as a diazo transfer reagent. This compound is an inexpensive and potentially scalable alternative to many of the diazo transfer reagents currently available, most of which have hazards associated with their use. Its usefulness and suitability as a diazo transfer reagent was assessed on the basis of cost, safety and its effectiveness in diazo transfer to a variety of different substrates.

The synthesis of a range of novel α-sulfenyl-β-chloroenones from the corresponding α-sulfenylketones, via a NCS mediated chlorination cascade, is described. The scope of the reaction has been investigated and compounds bearing alkyl- and arylthio substituents have been synthesised. In most instances, the Z α-sulfenyl-β-chloroenones were formed as the major products, while variation of the substituent at the β-carbon position led to an alteration in stereoselectivity. Stille cross-coupling with the Z α-sulfenyl-β-chloroenones led to selective formation of Z sulfenyl chalcones, while the E α-sulfenyl-β-chloroenones did not react under the same conditions. Oxidation of the Z α-sulfenyl-β-chloroenones was followed by isomerisation, leading to the E α-sulfinyl-β-chloroenones. Stille cross-coupling with the E α-sulfinyl-β-chloroenones produced the E sulfinyl chalcones. Either the E or Z sulfinyl chalcones can be obtained by altering the sequence of oxidation and Stille cross-coupling.

The marine transaminase, P-ω-TA, can be employed for the transamination from 1-aminotetralins and 1-aminoindanes with differentiation of stereochemistry at both the site of reaction and at a remote stereocentre resulting in formation of ketone products with up to 93% ee. While 4-substituents are tolerated on the tetralin core, the presence of 3- or 8-substituents is not tolerated by the transaminase. In general P-ω-TA shows capacity for remote diastereoselectivity, although both the stereoselectivity and efficiency are dependent on the specific substrate structure. Optimum efficiency and selectivity are seen with 4-haloaryl-1-aminotetralins and 3-haloaryl-1-aminoindanes, which may be associated with the marine origin of this enzyme.

Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline work-up and end-of-line crystallization in batch leading to isolation of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfer in flow. During the development of a continuous flow strategy for the production of appreciable quantities of the α-thio-β-chloroacrylamides, difficulties surrounding a labour and resource intensive work-up followed by final product isolation were addressed. A greener solvent choice was applied to the chemical synthesis which enabled inline purification and separation, resulting in the crystallization of pure product directly from the reaction mixture. This process was readily scalable and demonstrated control over impurity formation and removal, which is key in an industrial setting.

The synthesis of guanine α-carboxy nucleoside phosphonate (G-α-CNP) is described. Two routes provide access to racemic G-α-CNP 9, one via base construction and the other utilizing Tsuji-Trost allylic substitution. The latter methodology was also applied to the enantiopure synthesis of both antipodes of G-α-CNP, each of which showing interesting antiviral DNA polymerase activity. Additionally, we report an improved multigram scale preparation of the cyclopentene building block 10, starting material for the preferred Tsuji-Trost route to 9.

Cocrystallization studies on Naringenin with 27 coformers have led to the formation of five new solid forms: a piperazinium salt (PIP+-NR-) and four cocrystals with the coformers flavone (FLV), 4-hydroxypyridine (4-HP), anthranilamide (ATA), and 4,4′-bipyridine (Bipy). Structural characterization reveals that the hydrogen bonded head to tail dimer motif in naringenin is maintained only in the cocrystal with flavone (NR-FLV). All four neutral cocrystals maintain the S(6) OH···O=C intramolecular hydrogen bond seen in naringenin with this carbonyl oxygen atom bifurcated. The piperazinium salt is the only structure in which the ether oxygen is involved in hydrogen bonding. Some of the structures display disorder in the chiral center of naringenin, making them anomalous racemic solid solutions. The solubility study revealed that the salt formation has significantly enhanced the solubility of naringenin, for example the piperazinium salt has enhanced solubility of >3,000 times that of the neutral parent compound.

Irish Research Council (Project Numbers GOIPG/2013/1064 and GOIPG/2013/225); Science Foundation Ireland (Grant Number 02/PICA/B802/EC07)

In the solid state (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon evaporation from the melt, a rarely reported phenomenon. An additional racemic polymorph, Form III, has been characterized, and the thermodynamic relationship between the three forms established by a variety of computational and experimental methods including grinding, slurry crystallization and seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more stable conglomerate, Form I. Density Functional Theory calculations of the different polymorphs of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms.

α-Thio-β-chloroacrylamides are of considerable synthetic utility due to their versatile reactivity profile enabling a diverse range of useful transformations. Availability of accurate and extensive solubility data and models is a prerequisite for advanced process optimization of such valuable pure synthetic intermediate compounds, in particular facilitating their isolation with a high degree of efficiency and control. As an illustrative example the solubility of one such derivative, N-(4-methylphenyl-Z-3-chloro-2-(phenylthio)propenamide (Z-1), is described in the present work. Solubility data is reported in 12 pure solvents specifically selected for their potential utility in synthesis and isolation at scale. Solubility data are determined using the gravimetric method across a range of temperatures T= (278.15 to 318.15) K under pressure of 0.1 MPa. On a molar basis, the solubility of Z-1 at temperature T = 298.15 K was observed to follow the order: tetrahydrofuran > 1,2-dichloroethane > 2-methyltetrahydro...

A marriage made in Ireland! The Synthesis and Solid-State Pharmaceutical Centre (SSPC) transcends company and academic boundaries and is one of the largest research collaborations of its type globally. Trust, a culture of inclusivity and commitment to mutual benefit are just some of the factors that have led to the success of the SSPC. Fostering these ideals within its industry-academia, and inter-company collaborations remains crucial to further development.

Rhodium-catalysed S–H insertion of α-diazo-γ-butyrolactams has been successfully telescoped using continuous processing with in situ generated triflyl azide in flow and deacylative diazo transfer, incorporating real-time reaction monitoring of the final process outflow by IR spectroscopy. Significantly, the α-diazo-γ-butyrolactam reaction stream was sufficiently pure to progress to the rhodium-catalysed S–H insertion step without detrimental impact on the rhodium catalyst or the reaction efficiency.

The hazardous diazo transfer reagent mesyl azide, has been safely generated and used in situ for continuous diazo transfer as part of an integrated synthetic process with an embedded safety quench. Diazo transfer to β-ketoesters and a β-ketosulfone was successful. In-line phase separation, by means of a continuous liquid-liquid separator, enabled direct telescoping with a thermal Wolff rearrangement.

By tuning the steric properties of the acyl group to control the efficiency and selectivity of the resolution, 2-phenyl-1-propanol 1a was prepared by lipase-catalysed hydrolysis using a short-chain acyl group, with E-values of up to 66 (ee up to 95%). 2-Phenylbutan-1-ol 1b was similarly resolved (up to 86% ee) using the optimised conditions, while the ester of the more sterically demanding 3-methyl-2-phenylbutan-1-ol 1c proved resistant to enzymatic hydrolysis under these conditions.

Hydrolase-catalysed dynamic kinetic resolutions of chroman-2-ol and 3-methyl chroman-2-ol can be effected with up to 88% conversion and 92% ee through the use of organic solvents. Extension to the resolution of the tolterodine precursor 1 proved more challenging. The presence of the remote phenyl substituent had a significant impact on the resolution and it was not possible to achieve high enantioselectivity together with efficient conversion from the focussed panel of enzymes screened.

Intramolecular C–H insertion reactions of α-diazocarbonyl compounds typically proceed with preferential five-membered ring formation. However, the presence of a heteroatom such as nitrogen can activate an adjacent C–H site towards insertion resulting in regiocontrol issues. In the case of α-diazoacetamide derivatives, both β- and γ-lactam products are possible owing to this activating effect. Both β- and γ-lactam products are powerful synthetic building blocks in the area of organic synthesis, as well as a common scaffold in a range of natural and pharmaceutical products and therefore C–H insertion reactions to form such compounds are attractive processes.

A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 °C, 75% relative humidity or exposure to light. The effect of γ-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography–mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities., Graphical abstract fx1, Highlights • Method developed for extraction and analysis of an antimicrobial coated orthopedic device. • Evaluated the effect of light, humidity, oxygen and heat on the storage stability of drug coatings. • Also evaluated the influence of γ-ray sterilization on the chemical composition of drug coatings.

Highly regioselective synthetic methodology leading to densely functionalised C(3), C(4) and C(5) substituted pyrazoles 10a–q, 14a‐i and 16a–g via thermal [3+2]‐dipolar cycloaddition, of α‐diazoacetates and α‐thio‐β‐chloroacrylamides, at the sulfide, sulfoxide and sulfone levels of oxidation, is described. This method allows access to C(4)‐sulfenyl or sulfonyl pyrazoles, through migration of the sulfur substituent at the sulfide and sulfone oxidation levels, while elimination of the sulfinyl group leading to 3,5‐disubstituted pyrazoles, is observed. While the sulfide migration is readily rationalised, the carbon to carbon 1,2‐sulfonyl migration is unprecedented and mechanistically intriguing. The synthetically versatile generation of densely functionalised pyrazoles containing substituents amenable to further modification offers advantages over alternative synthetic routes. Isolation of the N‐alkylated pyrazoles 11a and 12a as by‐products from the cycloaddition through further reaction of the pyrazoles 10 with excess α‐diazoacetate, proved useful in rationalising the tautomeric behaviour evident in the NMR spectra of the pyrazoles, with the position of tautomeric equilibrium influenced by solvent and substituents.

peer-reviewed The influence of dairy cow feeding regime was investigated using H-1 nuclear magnetic resonance (NMR). Two different NMR analytical systems were deployed: high field H-1 NMR to investigate the influence on milk metabolomics and low field NMR to characterise proton relaxation linked to changes in the state of mozzarella cheese moisture during ripening. The metabolomics results showed that grass-based feeding increased the concentration of a biological marker that signifies near-organic milk production conditions. On the other hand, the investigation of cheese moisture distribution showed that grass-based diets reached final moisture partitioning in a shorter time, which implied the formation of a more compact protein structure in the cheese matrix. These results indicate that pasture-based dairying may be differentiated in terms of the provenance of milk produced along with the accrual of additional benefits during ripening of the resulting mozzarella cheeses. (C) 2018 Elsevier Ltd. All rights reserved. ACCEPTED peer-reviewed

Evaluation of an esterase annotated as 26D isolated from a marine metagenomic library is described. Esterase 26D was found to have a unique substrate scope, including synthetic transformations which could not be readily effected in a synthetically useful manner using commercially available enzymes. Esterase 26D was more selective towards substrates which had larger, more sterically demanding substituents (i.e. iso‐propyl or tert‐butyl groups) on the β‐carbon, which is in contrast to previously tested commercially available enzymes which displayed a preference for substrates with sterically less demanding substituents (i.e. methyl group) at the β‐carbon.

Correction for ‘Enantioselective copper catalysed intramolecular C–H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent’ by Amy E. Shiely et al., Org. Biomol. Chem., 2017, 15, 2609–2628.

Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2′-deoxynucleotide 5′-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.

Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel ω-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this ‘first in class’ selectivity at a remote chiral centre.

peer-reviewed Effective desymmetrization in copper-catalyzed intramolecular C–H insertion reactions of α-diazo-β-oxosulfones in the formation of fused thiopyran dioxides is described for the first time. The use of a copper–bis(oxazoline)–NaBARF catalyst complex system leads to formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee. The effect of varying the bis(oxazoline) ligand, copper salt, and site of C–H insertion on both diastereo- and enantioselectivities of these intramolecular C–H insertion reactions has been investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to date in a copper-mediated desymmetrization through C–H insertion.

Synthetic methodology for the generation of novel 1,2,5-oxathiazole-S-oxides from cycloaddition of nitrile oxide dipoles with α-oxo sulfines generated in situ via the α-sulfinyl carbenes derived from α-diazosulfoxides is described. Experimental evidence and mechanistic rationale for the unanticipated interconversion of the diastereomeric 1,2,5-oxathiazole-S-oxide cycloadducts are discussed. Notably, using rhodium acetate as a catalyst at 0 °C under traditional batch conditions led to the selective formation and isolation of the kinetic isomers, while, in contrast, using continuous flow thermolysis, optimal conditions for the synthesis and isolation of the thermodynamic isomers were established.

This review focuses on the synthesis and reactivity of thioketone S-oxides (sulfines). Sulfines have been long established as being reactive intermediates of high interest and with potential for wide application in organic synthesis. The review will cover many aspects of sulfines: the first section looks at the different routes to the synthesis of these compounds with a detailed look at more recently developed routes; the second section details the scope of reactivity of these types of compounds and how they are useful in synthetic organic chemistry with a particular look at cycloaddition and nucleophilic addition reactions.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including beta-ketoesters, beta-ketoamides, malonate esters and beta-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an alpha-diazocarbonyl in > 98% purity without any column chromatography.

A strategy combining a ditopic hydrogen-bond donor with two different hydrogen-bond acceptor molecules is proposed for the assembly of simple trimeric building blocks used in the construction of ternary cocrystals. The crystallization of each of three different low symmetry carboxyphenols (3-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, and ferulic acid) with acridine and 2-amino-4,6-dimethylpyrimidine yielded ternary cocrystals where the three components are joined by phenol-pyridine and carboxylic acid-amidine synthons. The use of pKa values, beta values, and synthon histories in the selection of the acceptor compounds is discussed. Significant challenges to the growth of the desired ternary products from solution were presented by competing crystalline phases, including the individual components, a variety of binary phases, salts, and hydrates. Molecular electrostatic potentials were used to analyze the donating and accepting abilities of the competing synthons.

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper–bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity.

Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼ 100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.

Cocrystallization utilizing halogen bonding involving the thiocarbonyl functional group of a series of primary aromatic thioamides has been investigated. The well-known organoiodide 1,4-diiodotetrafluorobenzene was utilized as the halogen bond donor and the C═S···I halogen bond was established as a robust supramolecular synthon in these systems. Weak N–H···S hydrogen bonding involving the thioamides influences the overall supramolecular architectures, meaning that there is a diverse range of structural motifs and cocrystal stoichiometries observed. The majority (60%) of the cocrystals obtained have a 2:1 ratio of thioamide/organiodide with the latter present over an inversion center. The higher ratio of organoiodide seen in the other cocrystals is achieved by additional I···I and I···π halogen bonding. The C═S···I halogen bond is replaced by N···I halogen bonding in the one cocrystal containing a pyridyl-substituted thioamide. The ability of the thioamides to form cocrystals and the strength of the haloge...