Alkene ozonolysis

doi:10.1016/j.tet.2017.03.039

Tetrahedron

Volume 73, Issue 30, 27 July 2017, Pages 4233-4258

https://doi.org/10.1016/j.tet.2017.03.039 Get rights and content

Abstract

The synthetic application of alkene ozonolysis is reviewed. Emphasis is placed on the scope of potential transformations, traditional and emerging reaction protocols and technologies, comparisons with other oxidations, and safety.

Section snippets

Introduction and overview

The reaction of ozone with alkenes, first reported in 1840,1, 2, 3, 4, 5 remains a popular synthetic method,⁶ combining operational simplicity with the ability to access a range of products through choice of substrate and conditions. Scheme 1 summarizes the most common synthetic transformations.

Substrates and selectivity

As illustrated in Scheme 1, Scheme 2, most alkenes undergo cleavage to generate new C=O groups; alternate pathways are discussed in Section 4. The following section discusses characteristics associated with ozonolysis of individual classes of alkenes.

Reaction workups

The range of products available from alkene ozonolysis (Scheme 1) reflects in major part the range of chemistries possible for the intermediate ozonides or hydroperoxyacetals. The first portion of this section describes the common work-up procedures involving reduction or fragmentation to form carbonyls or alcohols (Scheme 6). Oxidative workups, and those based upon radical and heterolytic fragmentations and rearrangements are described in subsequent sections.

Anomalous ozonolyses

Several classes of alkenes frequently undergo ozonolysis via pathways other than simple C=C scission.

Scale

Delivery of 1–2 mmol/min of ozone is possible with inexpensive generators.³¹⁰ Large-scale applications are typically conducted in specialized facilities capable of generating O₃ on a scale of hundreds of kg/day.¹³ Batch-scale ozonolysis reactions have been reported,26, 29 including the reactions illustrated in equation (65) (2.3 kg scale) and equation (66) (17 kg scale).192, 201 Both examples employ generation and reduction of hydroperoxyacetals as an alternative to working with ozonides. The

Novel reaction conditions

Oxidation of substrates absorbed on polymers or dry silica has been used to prepare ozonides not easily available via solution reactions.17, 39, 40, 322, 323, 324 Interestingly reaction on hydrated silica affords carbonyls and acids in a process probably related to reductive ozonolyses in the presence of solubilized water (see section 3.2). Ozonolysis of resin-bound alkenes generates products analogous to those observed in solution,³²⁵ and cleavage of alkenes has been achieved at the surfaces

Novel applications

Ozonolysis has been used to dissociate twin-chain gemini surfactants via scission of an alkene linker.³³¹ Elimination of beta leaving groups from ozone-generated ketones has been used to release enones from a solid-phase support332, 333; an analogous release of a fluorophore has been used as a chemical dosimeter for solution ozone.¹¹⁴ Ozonolysis of unsaturated peptides offers a convenient route to peptide aldehydes.³³⁴ An ozonide derived from an N-allyl amide was shown to inhibit the cysteine

Oxidation or reduction

Ozonolysis products have been directly applied as starting materials for hydrogenations,7, 203 Clemmensen reduction,³³⁶ hydride reductions (see section 3.1), and reductive aminations (section 3.3). Isolation of an unstable ozonide-derived aldehyde has been accomplished using in-situ oxime formation.³³⁷ Oxidation of ozonides with Cr(VI) generates carboxylic acids under surprisingly mild conditions (equation (68)),338, 339 and reductive ozonolysis using solvated water (see section 3.2) has been

Cleavage to aldehydes and ketones

An introduction to this area can be found in recent reviews and encyclopedia listings,341, 349, 350, 351, 352 including a perspective based upon syntheses of nopinone.¹⁷⁷ The Lemieux oxidation, which combines OsO₄-promoted dihydroxylation with periodate cleavage of the resulting diol, is the major alternative to ozonolysis³⁵³; variations include OsO₄/Pb(OAc)₄ (compatible with thioethers)³⁵⁴ and OsO₄/PhI(OAc)₂.³⁵⁵ A few generalizations can be made regarding choice of OsO₄ or O₃.356, 357, 358, 359

Safety issues and hazard minimization

A hazard analysis for alkene ozonolysis must consider the reagent, the reaction, and the products.42, 367, 368 An online safety resource targeting academic labs is available.³⁶⁹

Acknowledgments

We thank Dr. Christopher Schwartz for useful discussions and the NSF (CHE-1057982 and -146914) for financial support.

Pat Dussault (b. 1960) did his undergraduate work at UC Irvine (B.S. 1982), where he was introduced to research in the labs of Richard Chamberlin, and then moved onto Cal Tech (Ph.D. 1987) for graduate studies in organic synthesis with the late Robert Ireland. Following a National Cancer Institute postdoctoral fellowship with Ned Porter at Duke University, Dussault joined the University of Nebraska-Lincoln, where he is currently Charles Bessey Professor of Chemistry. Dussault has advised

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Tom Fisher received his B.S. in Chemistry from Bowling Green State University in 2007 and his PhD in Organic Chemistry from the University of Nebraska–Lincoln with Prof. Patrick H. Dussault in 2012. Following a Postdoctoral appointment with Prof. Anita E. Mattson at The Ohio State University, he joined The Goodyear Tire & Rubber Company in 2015 as a Tire Compounder in the Racing Division.

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Tetrahedron report 1143Alkene ozonolysis

Abstract

Section snippets

Introduction and overview

Substrates and selectivity

Reaction workups

Anomalous ozonolyses

Scale

Novel reaction conditions

Novel applications

Oxidation or reduction

Cleavage to aldehydes and ketones

Safety issues and hazard minimization

Acknowledgments

Chem Health Saf

J Chem Soc Perkin Trans

Ind Eng Chem Res

J Org Chem

Ann N Y Acad Sci

C R Hebd Seances Acad Sci

Ann Phys Chem

Bull Hist Chem

Liebigs Ann Chem

Ozonation in Organic Chemistry, Volume 1: Olefinic Compounds

Russ Chem Rev

Ozone and its Reactions with Organic Compounds

Ozonolysis

"Ozone" e-EROS Encyclopedia of Reagents for Organic Synthesis

Ozone

Hoboken

Chim Oggi Chem Today

Controlled ozonolysis of alkenes

Chem Sustain Dev

Helv Chim Acta

Helv Chim Acta

Helv Chim Acta

Quim Nova

Catal Rev Sci Eng

J Phys Chem Ref Data

Russ J Org Chem

Russ Chem Rev

Russ J Org Chem

Eur J Org Chem

Russ Chem Rev

Chem Rev

Ozonolysis in the production of chiral fine chemicals

Chim Oggi (Chem Today)

D H B Chem Rev

Angew Chem Int Ed Engl

Chem Listy

J Org Chem

Russ Chem Rev

Chem Rev

Chem Soc Rev

Sci Synth

Chim Oggi (Chem Today)

Chim Oggi (Chem Today)

“Ozone-Silica Gel” e-EROS Encyclopedia of Reagents for Organic Synthesis

Sci Synthesis

Phys Chem Chem Phys

J Am Chem Soc

J Chem Ed

Tetrahedron report 1143
Alkene ozonolysis