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Controlling (E/Z)-stereoselectivity of −NHC=O chlorination: mechanism principles for wide scope applications

Controlling (E/Z)-stereoselectivity of −NHC=O chlorination: mechanism principles for wide scope applications
Controlling (E/Z)-stereoselectivity of −NHC=O chlorination: mechanism principles for wide scope applications

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

DFT, Halogen, Hydrazonoyl halide, Protein modification, Reaction kinetics, Reaction mechanism, Stereoselectivity, X-ray structure
0947-6539
Maklad, Raed M.
697d38a8-bed0-41b2-8a48-b27e10e20c37
Moustafa, Gamal A.I.
1a452cdc-4856-4243-9864-b391fb115f07
Aoyama, Hiroshi
e1cc97e2-a1d4-4125-9ada-858a412e8097
Elgazar, Abdullah A.
164e9d1a-82f9-47d1-b3ae-7468e2c946b4
Maklad, Raed M.
697d38a8-bed0-41b2-8a48-b27e10e20c37
Moustafa, Gamal A.I.
1a452cdc-4856-4243-9864-b391fb115f07
Aoyama, Hiroshi
e1cc97e2-a1d4-4125-9ada-858a412e8097
Elgazar, Abdullah A.
164e9d1a-82f9-47d1-b3ae-7468e2c946b4

Maklad, Raed M., Moustafa, Gamal A.I., Aoyama, Hiroshi and Elgazar, Abdullah A. (2024) Controlling (E/Z)-stereoselectivity of −NHC=O chlorination: mechanism principles for wide scope applications. Chemistry - A European Journal, 30 (60), [e202400785]. (doi:10.1002/chem.202400785).

Record type: Article

Abstract

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

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Chemistry A European J - 2024 - Maklad - Controlling E Z ‐Stereoselectivity of NHC O Chlorination Mechanism Principles - Version of Record
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Accepted/In Press date: 3 July 2024
e-pub ahead of print date: 16 October 2024
Published date: 28 October 2024
Keywords: DFT, Halogen, Hydrazonoyl halide, Protein modification, Reaction kinetics, Reaction mechanism, Stereoselectivity, X-ray structure

Identifiers

Local EPrints ID: 495925
URI: http://eprints.soton.ac.uk/id/eprint/495925
ISSN: 0947-6539
PURE UUID: 4bcbddf3-8f6d-44e4-aa8f-d93543ea6436
ORCID for Gamal A.I. Moustafa: ORCID iD orcid.org/0000-0002-9940-0033

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Date deposited: 27 Nov 2024 17:51
Last modified: 28 Nov 2024 02:56

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Contributors

Author: Raed M. Maklad
Author: Hiroshi Aoyama
Author: Abdullah A. Elgazar

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