Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions
The present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide ion using silver salts with weakly coor...
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Veröffentlicht in: | European journal of organic chemistry 2021-11, Vol.2021 (44), p.5905-5913 |
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creator | Helbing, Tim Georg, Mats Stöhr, Fabian Carraro, Caterina Becker, Jonathan Gatto, Barbara Göttlich, Richard |
description | The present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide ion using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem‐methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3‐chloropiperidines. Therefore, the underlying Thorpe‐Ingold effect might be considered as another option to adjust the alkylation activity of these compounds.
In this research, we analyzed the alkylation mechanism of 3‐chloropiperidnes by isolation of the proposed intermediate aziridinium ions and NMR kinetic investigations. The bicyclic structure of these predicted intermediates was confirmed by single crystal XRD, while the kinetic analysis revealed remarkable reactivity differences between the gem‐methylated compounds and their corresponding non‐methylated analogues. |
doi_str_mv | 10.1002/ejoc.202101072 |
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In this research, we analyzed the alkylation mechanism of 3‐chloropiperidnes by isolation of the proposed intermediate aziridinium ions and NMR kinetic investigations. The bicyclic structure of these predicted intermediates was confirmed by single crystal XRD, while the kinetic analysis revealed remarkable reactivity differences between the gem‐methylated compounds and their corresponding non‐methylated analogues.</description><identifier>ISSN: 1434-193X</identifier><identifier>EISSN: 1099-0690</identifier><identifier>DOI: 10.1002/ejoc.202101072</identifier><language>eng</language><publisher>Weinheim: Wiley Subscription Services, Inc</publisher><subject>Alkylation ; Antitumor agents ; Aqueous solutions ; Aziridinium ions ; Crystal structure ; Kinetics ; Mustard ; NMR ; Nuclear magnetic resonance ; Nucleophiles ; Single crystals ; Structure-Activity relationship</subject><ispartof>European journal of organic chemistry, 2021-11, Vol.2021 (44), p.5905-5913</ispartof><rights>2021 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3572-c2ba256e8b981a99d7bd73a0adc537be4ae11fec154005fbdf7e7b734ad72e843</citedby><cites>FETCH-LOGICAL-c3572-c2ba256e8b981a99d7bd73a0adc537be4ae11fec154005fbdf7e7b734ad72e843</cites><orcidid>0000-0002-6708-8604 ; 0000-0002-1424-3084 ; 0000-0002-1284-3254 ; 0000-0001-9465-6913</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fejoc.202101072$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fejoc.202101072$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Helbing, Tim</creatorcontrib><creatorcontrib>Georg, Mats</creatorcontrib><creatorcontrib>Stöhr, Fabian</creatorcontrib><creatorcontrib>Carraro, Caterina</creatorcontrib><creatorcontrib>Becker, Jonathan</creatorcontrib><creatorcontrib>Gatto, Barbara</creatorcontrib><creatorcontrib>Göttlich, Richard</creatorcontrib><title>Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions</title><title>European journal of organic chemistry</title><description>The present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide ion using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem‐methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3‐chloropiperidines. Therefore, the underlying Thorpe‐Ingold effect might be considered as another option to adjust the alkylation activity of these compounds.
In this research, we analyzed the alkylation mechanism of 3‐chloropiperidnes by isolation of the proposed intermediate aziridinium ions and NMR kinetic investigations. 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In this research, we analyzed the alkylation mechanism of 3‐chloropiperidnes by isolation of the proposed intermediate aziridinium ions and NMR kinetic investigations. The bicyclic structure of these predicted intermediates was confirmed by single crystal XRD, while the kinetic analysis revealed remarkable reactivity differences between the gem‐methylated compounds and their corresponding non‐methylated analogues.</abstract><cop>Weinheim</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1002/ejoc.202101072</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-6708-8604</orcidid><orcidid>https://orcid.org/0000-0002-1424-3084</orcidid><orcidid>https://orcid.org/0000-0002-1284-3254</orcidid><orcidid>https://orcid.org/0000-0001-9465-6913</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Alkylation Antitumor agents Aqueous solutions Aziridinium ions Crystal structure Kinetics Mustard NMR Nuclear magnetic resonance Nucleophiles Single crystals Structure-Activity relationship |
title | Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions |
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