Investigation of Reactions Involving Pentacoordinate Intermediates: The Mechanism of the Wittig Reaction

245 Pages·2012·4.51 MB·English

by  Peter A. Byrne (auth.)

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Peter A. Byrne
Investigation
of Reactions Involving
Pentacoordinate
Intermediates
The Mechanism of the
Wittig Reaction
Doctoral Thesis accepted by
University College Dublin, Ireland
123
Author Supervisor
Dr. PeterA.Byrne Prof.Dr. DeclanGilheany
SchoolofChemistryandChemicalBiology SchoolofChemistryandChemicalBiology
UniversityCollege Dublin,Belfield UniversityCollege Dublin,Belfield
Dublin 4 Dublin 4
Ireland Ireland
ISSN 2190-5053 ISSN 2190-5061 (electronic)
ISBN 978-3-642-32044-6 ISBN 978-3-642-32045-3 (eBook)
DOI 10.1007/978-3-642-32045-3
SpringerHeidelbergNewYorkDordrechtLondon
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(cid:2)Springer-VerlagBerlinHeidelberg2012
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Parts of this thesis have been published in the following journal articles:
1. ‘‘Unequivocal experimental evidence for a unified Li salt-free Wittig reaction
mechanism for all phosphonium ylide types: Reactions with b-heteroatom
substitutedaldehydesareconsistentlyselectiveforcis-oxaphosphetanederived
products’’—P. A. Byrne, D. G. Gilheany, Journal of the American Chemical
Society, 2012, DOI: 10.1021/ja300943z
2. ‘‘A Convenient & Mild Chromatography-Free Method for the Purification of
the Products of Wittig and Appel Reactions’’—P. A. Byrne, K. V. Rajendran,
J. Muldoon, D. G. Gilheany, Organic and Biomolecular Chemistry, 2012, 10,
3531–3537. DOI: 10.1039/C2OB07074J
3. ‘‘erythro b-Hydroxyphosphonium Salts’’—P. A. Byrne, H. Müller-Bunz,
D. G. Gilheany, in preparation, to be submitted to Phosphorus, Sulfur, Silicon
Relat. Elem.
4. ‘‘Anomalous Z-selectivity in the reactions of keto-stabilised phosphonium
ylides with ortho-heteroatom substituted benzaldehydes’’—P. A. Byrne,
L. J. Higham, P. McGovern, D. G. Gilheany, in preparation, accepted for
publication in Tetrahedron Lett., manuscript ID TETL-D-12-01594 Tetrahe-
dron Letters.
5. ‘‘Observation of Wittig reaction products, intermediates, and their quench
products by variable temperature NMR’’—P. A. Byrne, Y. Ortin, J. Muldoon,
D. G. Gilheany, in preparation to be submitted to Eur. J. Org. Chem.
6. ‘‘The modern mechanistic interpretation of the mechanism of the Wittig
reaction’’—review paper to be submitted to Acc. Chem. Res.
Supervisor’s Foreword
The Wittig reaction involves the formation of an alkene and a phosphine oxide
fromaphosphoniumylideandanaldehydeorketone.Itisperhapsthemostwidely
usedC=Cbondformingreactioninchemistry.1,2Ingeneral,theselectivityforEor
Zalkenedependsonthenatureofthephosphoniumylide.3‘‘Reactive’’ylides(R
2
= alkyl) consistently reacts with all types of aldehyde to give predominantly the
thermodynamically disfavoured Z-alkene, while ‘‘stabilised’’ ylides (e.g. R2 =
CO Me) consistently gives mostly E-alkene in its reactions. ‘‘Semi-stabilised’’
2
(e.g. R2 = phenyl) ylides gives mixtures containing similar proportions of Z and
Ealkene,withtherelativequantityofeachdependingontheexactstructureofthe
ylide and the reaction conditions.
R P O
3
Betaine
R
R2 R1
Ylide R P R2
R
R P O -R PO
O 3 3
Aldehyde Z-alkene
R1 R2
R1 H R2 R1
[2+2]
cycloaddition
OPA R3P O -R3PO R1 R2 E-alkene
R2 R1
1 MaryanoffBE,ReitzAB(1989)ChemRev89:863.
2 VedejsE,PetersonMJ(1994)In:ElielEL,WilenSH(eds)Topicsinstereochemistry,vol21.
Wiley,NewYork,p1.
3 JohnsonAW(1993)Ylidesandiminesofphosphorus.NewYork,Wiley,pp221–305(Chaps.
8and9).
vii
viii Supervisor’sForeword
Since the discovery of the Wittig reaction in 1953, its reaction mechanism has
never been definitively settled, with many different variants proposed and
disproved. The initially favoured mechanism that involved initial formation of a
betaine followed by ring closure to oxaphosphetane (OPA) and subsequent OPA
cycloreversiontogivetheproductshassincefallenintodisfavour.Initsplacehas
risen the [2+2] cycloaddition mechanism, whereby OPA is formed directly and
irreversibly from ylide + aldehyde, with the stereochemistry of the alkene being
decided in the OPA-forming step.4 Several of the developments that led to this
consensusonthemechanismoccurredmanyyearsapartfromeachother.Thisfact,
alongwiththepoorlyunderstoodeffectsoflithiumcationonthereaction,andthe
differingselectivitiesobservedinthereactionsofdifferenttypesofylidehaveled
toconfusionontheissueinthewiderworldofchemistry,whichisreflectedinthe
contentofmanyundergraduatetextbooksandlecturesontheWittigreaction.The
viewpoint persists that different mechanisms operate in different Wittig reactions,
with some involving reversible formation of OPA or even involving betaine.
Peter’sthesisdescribesthediscoveryofaneffectthatoperatesinrepresentative
examplesofalltypesofphosphoniumylideunderLisalt-freeconditions.Reactions
of both aromatic and aliphatic aldehydes bearing a heteroatom substituent in the
b-position (two carbons away) relative to the carbonyl group uniformly show
dramaticallyincreasedselectivityforZ-alkeneoritsprecursor,cis-OPA,compared
with analogous aldehydes lacking such a substituent. An example of this remark-
ableswinginselectivityisshownbelow.Ylide(A)reactswithbenzaldehyde(B)to
give alkene with Z/E ratio of 7:93, whereas its reaction with the b-heteroatom
substituted2-chlorobenzaldehyde(C)givesanalkeneZ/Eratioof94:6!Theorigin
oftheeffectliesintheexistenceofabondinginteractionbetweenthephosphorus
and the b-heteroatom in the cycloaddition transition state leading to the OPA
intermediate.
-78° C Ph -78° C
THF THF Cl
Ph P
CHO CHO
Me Me Me Me
A
Z/E = 7:93 B C Cl Z/E = 94:6
This is the first time that an effect that is common to all Wittig reactions has
beendiscovered.Sinceitisconsistentacrossalltypesofylideandaldehyde,there
must be a single mechanism in operation in these and therefore all other Li salt-
freeWittigreactions.Theeffectcanonlyberationalisedinthecontextofthedirect
cycloadditionmechanism,andsotheworkinthisthesisshowsunequivocally,and
for the first time, that all Wittig reactions occur by the same [2+2] cycloaddition
mechanismunderLisalt-freeconditions.Theissueofthemechanismofoneofthe
most important reactions in organic chemistry is thus settled.
4 VedejsE,MarthCF(1988)JAmChemSoc110:3948.
Supervisor’sForeword ix
As a remarkable added bonus, the thesis also describes the development of a
new chromatography-free method for the removal of phosphine oxide from the
alkene product of the Wittig reaction, thus addressing the main operational diffi-
culty facing an experimentalist employing this reaction. The technique involves
theconversionofphosphineoxidetochlorophosphoniumsaltbyadditionofoxalyl
chloridetothecrudeproduct.Cyclohexaneisthenadded,andthealkeneproductis
isolated by filtration of the solution to remove phosphorus and subjected to
aqueouswork-up.Thistechniquecanalsobeappliedtotheremovalofphosphine
oxide from the products of many other reactions.
Dublin, August 2012 Prof. Dr. Declan Gilheany
Contents
1 Introduction to the Wittig Reaction and Discussion
of the Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 The Wittig Reaction: Introduction, Utility
and Recent Developments. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Classification and Reactivity Trends of Phosphonium Ylides . . . 4
1.3 Proposed Mechanisms: Description and Evaluation
in the Light of Experimental Evidence. . . . . . . . . . . . . . . . . . . 6
1.3.1 The Betaine Mechanism . . . . . . . . . . . . . . . . . . . . . . . 6
1.3.2 Bergelson’s ‘‘C–P–O–C’’ Betaine Mechanism . . . . . . . . 10
1.3.3 Schweizer Mechanism. . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.4 Olah’s Single Electron Transfer Mechanism. . . . . . . . . . 12
1.3.5 Bestmann’s ‘‘P–O–C–C’’ Betaine Mechanism. . . . . . . . . 14
1.3.6 McEwen’s Spin-Paired Diradical Mechanism. . . . . . . . . 15
1.3.7 Schlosser Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.3.8 Vedejs Cycloaddition Mechanism. . . . . . . . . . . . . . . . . 17
1.4 Modern Mechanistic Interpretation of the Wittig Reaction . . . . . 19
1.4.1 The Operation of Kinetic Control
in the Wittig Reaction. . . . . . . . . . . . . . . . . . . . . . . . . 19
1.4.2 The Nature of the First Formed Intermediate
in the Wittig Reaction. . . . . . . . . . . . . . . . . . . . . . . . . 31
1.4.3 Oxaphosphetane Structure and Pseudorotation . . . . . . . . 32
1.4.4 How Does the Observed Selectivity for Z or E
Alkene Arise? An Explanation of the Currently
Accepted Mechanism and Source of Stereoselectivity . . . 35
1.5 Aldehydes Bearing Remote Heteroatoms: Influence
of These Substituents on Selectivity in the Wittig Reaction . . . . 46
1.5.1 Wittig Reactions of Benzylidenetriphenylphosphoranes
with ortho-Heteroatom Substituted Benzaldehydes . . . . . 47
1.5.2 Wittig Reactions of Aliphatic Aldehydes Bearing a
b-Heteroatom Substituent. . . . . . . . . . . . . . . . . . . . . . . 51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
xi