Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal

Lisa Marie Mohr; Christina H. McCulley; Jakob Blom; Johannes N. Lamhauge; Karl Anker Jørgensen

doi:10.1002/chem.202103376

Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal

Lisa Marie Mohr, Christina H. McCulley, Jakob Blom, Johannes N. Lamhauge, Karl Anker Jørgensen^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)- and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.

Original language	English
Journal	Chemistry - A European Journal
Volume	27
Issue	69
Pages (from-to)	17465-17475
ISSN	0947-6539
DOIs	https://doi.org/10.1002/chem.202103376
Publication status	Published - Dec 2021

Keywords

chlorination
computational investigations
mechanism
organocatalysis
α-branched aldehydes

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10.1002/chem.202103376

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title = "Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal",

abstract = "Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)- and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.",

keywords = "chlorination, computational investigations, mechanism, organocatalysis, α-branched aldehydes",

author = "Mohr, {Lisa Marie} and McCulley, {Christina H.} and Jakob Blom and Lamhauge, {Johannes N.} and {Anker J{\o}rgensen}, Karl",

note = "Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

year = "2021",

month = dec,

doi = "10.1002/chem.202103376",

language = "English",

volume = "27",

pages = "17465--17475",

journal = "Chemistry - A European Journal",

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publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",

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TY - JOUR

T1 - Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal

AU - Mohr, Lisa Marie

AU - McCulley, Christina H.

AU - Blom, Jakob

AU - Lamhauge, Johannes N.

AU - Anker Jørgensen, Karl

PY - 2021/12

Y1 - 2021/12

N2 - Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)- and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.

AB - Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)- and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.

KW - chlorination

KW - computational investigations

KW - mechanism

KW - organocatalysis

KW - α-branched aldehydes

U2 - 10.1002/chem.202103376

DO - 10.1002/chem.202103376

M3 - Journal article

C2 - 34622997

AN - SCOPUS:85117402118

SN - 0947-6539

VL - 27

SP - 17465

EP - 17475

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 69

ER -

Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal

Abstract

Keywords

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