Ambident ReactivityAOR No5 (2016.6.03)

Ambident Electrophiles

Ambident Nucleophiles

O

O

Me

O

O

Me

O

O

Me

OEt

Br

EtO

BrCvsO(C:soft,O:hard)

hard

soft

4.3 Ambident Nucleophiles

Nucleophiles which have two sites at which an electrophile may attack are called ambident.

hard electrophiles reacting at the harder nucleophilic site soft electrophiles reacting at the softer site

4.3.1 Thiocyanate lon, Cyanide lon and Nitrite lon (and the NitroniumCation)

isomerizationkinetic thermodynamic

Reaction issofastthattheselectivity isnotcontrolled.

-O N O

CH3I

OMe3+

MeOTf

H3C O N O H3C NO-

O+

30 70

50 50

59 41

HSAB

SN2

4.3.2 Enolate lonsWhy does an enolate ion react with some electrophiles at carbon andwith others at oxygen?

Effect of Leaving Groups

The harder the leaving group, the lower the proportion of C-alkylation The softer the leaving group, the lower will be the energy of the LUMO.

4.3.3 Allyl Anions

4.3.3.1 X-substituted Allyl Anions

α/γ selectivity

thermodynamicallystable

Li vs Zn

6-memberedtransitionstate

α

γ

α

C-Substituted Allyl Anions - Pentadienyl Anions

Both α attack and γ attack

Birchreduction

Z-Substituted Allyl Anions - Dienolate lons

α attack

sec-isoamyl

dienolate

13CNMR:chargedensity

Dienol etherγ carbonismorenucleophilicsitetowardssoftelectrophile

X,Z-substituted------- α vsγ

4.3.4 Aromatic Electrophilic Substitution

Wheland intermediate

4.3.4.1 Molecular orbitals of the lntermediates in Electrophilic Attack on Monosubstituted Benzenes

Origin of o,p-regioselectivity

Curly arrows illustrate the electron distribution in the frontier orbital, and for reaction kinetics it is the frontier orbital that is most important.

But, for the thermodynamic argument, we need to know the energy of all of the filled orbitals, and not just one of them.

Morestable

Model for an X-substituted Benzene Ring

ψ3 in 4.87 does not lower the energy level (0β) because there are no π-bonding interactions between any of the adjacent atoms-it is a nonbonding molecular orbital.

2x3.50β 2x3.45β 2x3.08β≈ >>

1.4.3 Longer Conjugated System

Model for an Z-substituted Benzene Ring

m-regioselectivity

(Ψ1 +ψ2) of 4.91 is greater than those of 4.89 and 4.96.

relatively slow rate of meta- substitutionsrelatively fast rate of the ortho- and para-substitutions

The endothermicity of 1.28β on the right is not much greater than that forbenzene (1. 27β); however, the presence of two positive charges in theintermediate on the right has not been all0wed for, and this willobviously raise the energy of this intermediate.

4.3.4.2 The Frontier Orbitals of Monosubstituted Benzenes

C-substituents

Benzene

Benzylsystem

(1) Place a zero on the smaller number of alternate atoms: node

(2) the sum of the coefficients on all the unmarked atoms joined to anyone of the marked atoms must be zero

Rule of Orbital Coefficients Estimation

ESR

C,X,Z

Fukui’s frontier electron population

WhereC3 andC2 arethecoefficientsatthatsiteinthetwohighest-energyπorbitalsψ3 andψ2,respectively,withtheonelabelledψ3 havingarbitrarilythehigherenergy,Δλ.isthedifferenceinenergybetweenψ3 andψ2,andDisaconstant(3isusedinfact)representingsomekindofmeasureofthecontributionofψ2 totheoveralleffect.

K. Fukui, J. Chem. Phys. 1954, 22, 1433

4.3.4.3 Halogenobenzenes

AmixtureofthepropertiesoftheZ- andX-substituted benzenes

Slowreactionwitho/p directing

Theo /p orientationismainlydependent onthecoefficientsandoverallchargesateachoftheatoms,andthereducedratecouldbelargelydeterminedbytheenergiesofthehigheroccupiedorbitals.

4.3.4.4 Frontier Orbitals of Polycyclic Aromatic Molecules. 4.3.4.5 ortho/para Ratios

3.50β 3.45βStericeffect

3.08β(3.05β) (2.93β)

Soft-soft interaction 4.3.4.6 Pyrrole, Furan and Thiophen

Morestable

4.3.4.7 Pyridine N-oxide Estimation by the Salem-Klopman Equation

G.Klopman,JACS 1968,90,223

HardestSO3:C3NO2

+:C4SoftestHgOAc+:C2

4.4 Electrophilicity

Characterised by having a low-energy LUMO and electron deficiency, either as a full positive charge or as a polarised bond with a partial positive charge at one or more sites

4.4.1 Trigonal Electrophile

Carbonyl groups

acid chlorides > aldehydes > ketones > esters > amides > carboxylate

strong weakelectrophilicity

Acid chlorides:

(i) the π stabilisation is small, because chlorine is electronegative, andconsequently the energy match is poor

(ii) the π stabilisation is offset by strong inductive electron withdrawalalong the C-Cl bond, raising the electrophilicity of the carbonyl group

(iii) anomeric stabilisation in the tetrahedral intermediate is greater-conjugation of the oxyanion with the C�Cl σ* orbital pulls down theenergy of the transition structure.

Stabilisation in the intermediate plays a larger role in determiningelectrophilicity than the differences in the energy of the startingmaterials

electrophilicity in alkyl halides in SNl , SN2, E1 and E2 reactions (I- > Br-> Cl->> F-)

X=FvsCl(I)600(3100)timesfaster

Oppositeorderinaromatichalides (F- > Cl-> Br-> I-)

Anomericeffect

2.2.3.3 The Anomeric Effect 4.4.2 Tetrahedral Electrophiles

electrophilicity of alkyl halides in SN2 reactions:methyl > ethyl > isopropyl > tert-butyl.

Steric effect andhyperconjugation which lowers the energy of the LUMO of the C�Br bondin tert-butyl bromide more than that in methyl bromide also reduces thecoefficient on, and at the same time lowers the overall energy of thestarting material.

8000:1

SN2

4edelocalization inallylicoverlap

ρ+ =-2.9

XacceleratesSN2

4.4.3 Hard and Soft Electrophiles

thehardestelectrophiles aresmall,chargedandhavearelativelyhigh-energyLUMO,andsoftelectrophiles arelarge,havelittlechargeandhaveaconspicuouslylow-energyLUMO.

RXvsC=O

SN2:exothermic----earlytransitionstructure—orbital interactionRX:softelectrophile

Addition:endothermic--- latetransitionstructureC=O:hardelectrophilewithlowLUMO

Evenwithinagroupofverysimilarelectrophiles, allsoftlikeprimaryalkylhalidesundergoingSN2displacement, thescaleofelectrophilicity isnotconstant.

4.5 Ambident Electrophile

LargeLUMOCoefficient

4.5.1 Aromatic Electrophiles

Pyridinium Cation

“H-”

hard

Soft

thermodynamicallystable

LUMO

Charge

4.5.1.2 ortho-and para-Halogenonitrobenzenes.

Linear-conjugated

faster

Cross-conjugated

Coulombic

4.5.2 Aliphatic Electrophiles

4.5.2.1 α,β-Unsaturated Carbonyl Compounds

α-fast

Thermodynamicallystable

+Li+:98:2

- Li+:23:77

softer 4.5.2.2 Allyl Hallides

InPolarsolvent SN1,SN1’

4.5.2.3 Unsymmetrical Anhydrides

LiAlH4 100:0(R=MeO)88:12(R=Me)

Elimination vs. Substitution

G.Biale,JACS 1971,93,4735

Singlet carbene Triplet carbene

concerted stepwise

Reactivity Carbene HOMO: high LUMO: low High ReactivityNucleophilic and electrophilic

Nucleophilic Carbenes Electrophilic Carbenes Cycloaddition,insertion intoC-H

Aromatic Carbene

nucleophilic

Cyclopentadienylidene

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Report No6 (6/03)

The dipole of pyrrole points in the direction 4.120. The explanation usuallyoffered is that the orbitals are polarised in the sense illustrated by thecanonical structures 4.121 and 4.122. This cannot be the reason, because thisis only one of the π orbitals, the HOMO. We can see on the drawing 4.104 thatthe total π charge, is higher on the nitrogen atom and lower on the carbon

atoms. The same must be true in the σ framework. Why then is the dipolepointing in the other direction?