Chemistry of C-C π-bonds Lectures 1-4: Alkenes, Alkynes and Conjugation doc

Conjugate addition reactions: catalysed by acid or by base Kinetic and thermodynamic 1,2 va 1,4 addition Reactions controlled by charge Reactions controlled by orbitals The effect of the

Chemistry of C-C π-bonds Lectures 1-4: Alkenes, Alkynes and Conjugation

Handout 1

Handouts will be available at:

http://msmith.chem.ox.ac.uk/teaching.html

Dr Martin Smith Office: CRL 1st floor 30.087 Telephone: (2) 85103

Email: martin.smith@chem.ox.ac.uk

“When an unsymmetrical alkene combines with a hydrohalic acid, the halogen adds on to the carbon atom containing the fewer hydrogen atoms, that is the carbon that

is more under the influence of other carbons

I cannot here enter into a detailed examination of the various facts that permit us

to establish such a law.”*

*Markovnikov, V V Ann 1870, 153, 228.

Alkene and Alkyne chemistry I

 Alkene chemistry

Structures and influence of orbitals on reactivity: How do alkenes react and why? Typical reactions of alkenes: Nucleophilic reactions

Electrophilic reactions Pericyclic reactions Recap of methods for alkene generation

Recap of frontier molecular orbitals for simple reactions

Diels-Alder OsO4 (iii) free radical additions allylic bromination (comparison with ionic)

(iv) catalytic hydrogenation reduction to alkanes

 Conjugation and delocalization in non-aromatic systems

Effects of π-bond on structure and reactivity

Structures of conjugated alkenes and alkynes

MO approach to conjugated systems: the allylic cation, allylic radical and butadiene Allylic bromination

Modifications to reactivity as a result of conjugation

Conjugate addition reactions: catalysed by acid or by base

Kinetic and thermodynamic (1,2 va 1,4 addition)

Reactions controlled by charge

Reactions controlled by orbitals

The effect of the nucleophile: hard and soft nucleophiles and electrophiles

The effect of the electrophile

Books

“Organic Chemistry”, Clayden, Greeves, Wothers and Warren, OUP, 2000

Comments, questions and queries welcome

The Chemistry of C-C π-Bonds - 3 -

 The most important feature of alkenes is the π bond

Alkenes possess !-bonds and "-bonds

 A π-bond is made up of two 2p orbitals

A !-orbital results from a combination of two 2p orbitals of two carbon atoms

 Alkenes may be made by elimination reactions (Prof Dixon’s course)

1 The E2 elimination: concerted and can be stereospecific

ylid carbonyl

The Chemistry of C-C π-Bonds - 5 -

 Typical modes of reaction of alkenes [1] Nucleophilic

Alkenes can be electron-rich and are therefore nucleophilic

O

O

H

 Interactions between molecules: HOMO and LUMO – a recap

HOMO = highest occupied molecular orbital

LUMO = lowest unoccupied molecular orbital

filled orbital

of molecule 1

vacant orbital

on molecule 2

When two orbitals are brought together they can interact

to form new molecular orbitals

In order for these two orbitals to interact they must:

If these requirements are met, then the two electrons will prefer to occupy the new bonding orbital (as it is lower in energy) and the result is a covalent bond

 For alkene modes of reactivity:

E + R

For electron-poor alkene

O

OEt

O OEt

The Chemistry of C-C π-Bonds - 7 -

 Reactions of electron rich alkenes: electrophilic addition reactions

Br

Br - lone pair

"# C-Br

Br Br

dibromide product

S N 2 inversion

The bromonium ion is an intermediate - this means it can be observed, and in special cases, isolated Note this is distinct from a transition state (which is a hypothetical state

in between bond-breaking and bond-forming)

Overall: anti- addition of Br2 across the double bond

 Bromination of alkenes is stereospecific

Book Definition: “A reaction is termed stereospecific if starting materials differing only

in their configuration are converted into stereoisomeric products”

This is useful if we relate it to mechanism and hence a pragmatic working definition is:

bromonium cation

Br

Br Br

dibromide product

S N 2 inversion

Bromination of cyclohexene gives only the anti- diastereoisomer – stereospecific?

[but we cannot make the trans-cyclohexene]

To check for stereospecificity we need to see if alkene geometry is reproduced in the

products – examine both cis- and trans- but-2-ene:

S N 2 inversion

Br

H Me

Br

H Me

attack at most hindered end (why?)

(i)

(ii)

The Chemistry of C-C π-Bonds - 9 -

 Development of charge in the transition state can affect regioselectivity

development of charge stabilized by phenyl group (more heavily substituted)

Br

HO H

[see epoxide opening from Prof Dixon’s Course for a similar situation]

 A similar reaction can be performed with mercury(II) acetate ‘acyloxymercuration’

! on alkene

Ph

Hg OAc

Overall: Addition of water across the double bond (compare with hydroboration)

 4 Reaction with HBr: Regioselectivity

Relate to mechanism of the reaction - initial protonation to give the most stable cation:

H

The Chemistry of C-C π-Bonds - 11 -

We break weak bonds and make strong bonds in the propagation step

Br

H Br

Regiochemistry is dictated by addition of the bromine radical

to generate the most stable radical

 5 Reaction With Peracids: Stereospecific Epoxidation

LUMO

 6 Hydroboration: stereospecific syn-addition of the B-H bond across an alkene

Mechanism of hydroboration:

B H

HOMO

LUMO

HOMO

The alkene reacts with the electron

deficient boron leading to development of positive charge on the

more subsituted carbon

and at about the same time the developing cation on the more substituted carbon attacks the hydride, which is thus delivered syn.

Application of hydroboration to a useful reaction: addition of H 2 O across an alkene

H B

H

B H

H H

H

H repeat x 2

The Chemistry of C-C π-Bonds - 13 -

B

H B

H

H

R R

OH H

We can oxidize the borane to an alcohol whilst maintaining the stereochemistry of the hydroboration

Mechanism:

B

H

R R

B H

HO O

-H

B O

OR OR

-OH OH

H

Overall: syn addition of water across the double bond (compare with

acyoxymercuration/reduction)

 Pericyclic reactions involving alkenes

 6 Pericyclic reactions: Reaction with Ozone and subsequent reduction

(a useful method for the cleavage of C=C bonds)

R

O O O

HOMO

LUMO

O O O

O

O O

R

O O

O

redraw

R

O O O

The Chemistry of C-C π-Bonds - 15 -

 7 Pericyclic reactions: Reaction with Osmium tetroxide

O O

H 2 O

R 1

R 2

OH OH

OH

Os HO

O O

N

O

O reoxidant:

because the reaction demands a specific stereochemical outcome (a consequence of the concerted 1,3-dipolar cycloaddition)

 8 Pericyclic reactions: The Diels-Alder reaction

A great way to make complex six membered rings

H

H O

redraw

Tip: draw reaction product in the same orientation as the transition state

This reaction is effective because: (1)

(2)

The Chemistry of C-C π-Bonds - 17 -

 9 Reduction: alkene can be reduced to alkanes by hydrogenation

H H

redraw

This means we get overall cis reduction of the alkene

(1): cis selective reduction of alkynes

Key point: The alkyne is more susceptible to hydrogenation than the alkene

Both hydrogens are added to the alkyne simultaneously

and hence the cis alkene is produced

The Chemistry of C-C π-Bonds - 19 -

 Trans- selective reduction

H H

H

H H

H

H H

H

The significantly increased acidity of alkynes is synthetically useful

for functionalization of alkynes:

 Application of alkyne alkylation to the synthesis of billion dollar anti AIDS medicine:

N H

O Cl

Li H

Cl

Cl Br

Cl

H

Strong base (pKa approx 45)

The Chemistry of C-C π-Bonds - 21 -

 Hydration of alkynes with Mercury (II) acetate (compare with alkenes)

H R

! on alkyne

Hg

OAc AcO

R

Hg OAc

O

R H

H

O R

H

OR

 Conjugation and has effects on reactivity and reaction outcome

OH

Br Br

OH

Kinetic product

distribution Thermodynamic product distribution

The same ratio of products is obtained regardless

of which allylic alcohol we start with – why?

The allyl cation can be represented in several different ways:

The allyl cation is a delocalized system with the charge shared between the two

carbons at the end of the system

How can we consider this in terms of molecular orbitals?

The Chemistry of C-C π-Bonds - 23 -

 Molecular orbital picture of the allyl cation

We can consider this as an extension of the simple picture covered on p3:

!-orbital

combine 'in phase'

2 electrons

in a ! bond p-orbital vacant

The easiest way to do this is to look at a combination of THREE p-orbitals,

which will lead to THREE molecular orbitals The picture is very similar to the picture for the formation of a π-bond outlined on p3

three degenerate p-orbitals

SAME energy

NONBONDING

HOMO LUMO

increasing energy

Once we place the electrons in the orbitals in increasing energy, we can examine the

picture and relate it to the reactivity we observe

LUMO

This orbital picture is consistent with what we observe - attack on the two 'ends' of the cation

 A summary of the allyl cation:

1 The two bonding electrons in the π-system are spread out over all three atoms

‘delocalized’ (with most electron density on the central carbon)

O

Br

N O

O

O

O Br H

Br

NH O

O

Br NH

O

O

The Chemistry of C-C π-Bonds - 25 -

Step 2: Hydrogen abstraction to give the most stable radical (compare with the other

radical process we’ve covered on p 10).

three degenerate p-orbitals

SAME energy

NONBONDING

increasing energy

bonding

interaction

antibonding

interaction

 We can use an extended version to look at two alkenes in conjugation – butadiene

Consider butadiene as a combination of two ethene MOs:

increasing energy

antibonding interaction

Combine two MOs of ethene

What does all this tell us about the chemistry of a conjugated alkene – butadiene – when

we compare it to a non-conjugated alkene such as ethane?

1

2

3 The cationic intermediate in the bromination reaction is delocalized (cf the allyl

cation)

The Chemistry of C-C π-Bonds - 27 -

 We can now also now rationalize the behaviour of ‘electron rich’ alkenes such as

those we outlined on page 5

The model is essentially same as we used for the allyl cation system, but this time

with FOUR electrons (two from the π-bond and two from the lone pair)

good

overlap

poor overlap

three orbitals

p-SAME energy

NONBONDING

HOMO

increasing energy

have drawn them to be) but the overall conclusion is the same regardless

Conjugate Addition: alkenes conjugated with electron withdrawing groups

HO Nu Attack at the carbonyl:

Attack at the alkene

Conjugate addition requires the presence of an electron-withdrawing group on the alkene

(that leads to a lowering in energy of all the orbitals – covered in more detail in next lecture)

The Chemistry of C-C π-Bonds - 29 -

Spectroscopic evidence for conjugation II

O Spectroscopic evidence from 13 C NMR (ppm)

 Examples of Conjugate Addition

 Acid catalysed:

HCl O

 Base catalysed process:

H

O

O O

H

O O

H O O

The Chemistry of C-C π-Bonds - 31 -

 Why does conjugation with an electron withdrawing group facilitate 1,4 addition?

Direct Addition versus Conjugate Addition –

 For some nucleophiles conjugate addition is the major pathway, though for other

nucleophiles direct addition is the major pathway



 Slight variation in conditions can alter the course of the reaction

 Amines:

OEt O

N H

OEt

O +

 ……but in the presence of copper(I) undergo conjugate addition

The Chemistry of C-C π-Bonds - 33 -

 Cyanide additions: both 1,2 and 1,4-manifolds are accessible:

NaCN, HCN 80˚C

Effectively irreversible reaction at this temperature

Reversible reaction

at this temperature

 Kinetic versus Thermodynamic Control

1 The conjugate addition product is generally the

2 A rough comparison of the bonds broken and formed predicts that the conjugate addition product is indeed the thermodynamically more stable product

Overall: the conjugate addition product is 100 kJmol -1 more stable

The conjugate addition product is the thermodynamically most stable product as it retains

the strong carbonyl double bond – this is general for most α,β-unsaturated systems

In this specific example: (1) the direct addition product is the

(2) This means it is the product formed by the pathway with

the

O O O

The carbonyl carbon carries the largest partial positive charge

as it is nearest the electronegative oxygen atom

Why is direct addition the kinetic product in this case?

 Kinetic versus Thermodynamic Control

NC

O

O NC

O

kinetic control thermodynamic control

energy

extent of reaction

kinetic product

thermodynamic

product

NaCN + HCN

 At 80 °C cyanohydrin formation is reversible

 At 0 °C cyanohydrin formation is irreversible

The Chemistry of C-C π-Bonds - 35 -

At 80 °C cyanohydrin formation is reversible

At 0 °C cyanohydrin formation is irreversible

0˚C

80˚C fast

-Thermodynamically controlled reaction

Final product is the most stable

Charged nucleophiles usually do direct addition

H

 Revisit earlier examples: 2 Additions of amines

Not all products arising from conjugate addition are the result of initial reversible direct

addition For certain nucleophile-electrophile partners conjugate addition is the kinetically

most favoured pathway

OEt O

OEt O

N H

N H

N O

Some nucleophiles inherently prefer conjugate addition over direct addition

 Orbital Controlled Reactions

The Chemistry of C-C π-Bonds - 37 -

 Hard and Soft nucleophiles and electrophiles

Ph OEt

O

N H

O

Conjugate addition is the major pathway in the above example

The reaction is under orbital control

 General comments:

1 Generally 2nd row elements (e.g P, S) favour conjugate addition as they have high-energy 3s/3p lone pairs that are a good energy match for the LUMO of the substrate

2 If the nucleophile is uncharged then conjugate addition often results

Nucleophiles (and electrophiles) may be loosely categorized as HARD or SOFT

Experimentally it was noted that reactions of soft nucleophiles with soft electrophiles are favoured as are the reactions of hard nucleophiles with hard electrophiles





 Hard-Hard interactions mean that a reaction is predominately charge controlled (and

therefore generally favours 1,2-addition)

 Soft-Soft interactions mean a reaction that is predominately orbital controlled (and

therefore generally favours 1,4-addition)

Examples of addition of HARD and SOFT nucleophiles:

 Addition of thiolate anion:

PhSH, base

Nucleophile is PhS [PhSH pKa is 6.6]

O Bu OH BuMgBr is effectively "Bu - "

Charged nucleophile ('Hard') BuMgBr

 Copper-catalysed Grignard reagents

BuMgBr 1% CuCl

3d orbital on Cu is high in energy Probably forms "Bu-Cu" reagent (exact structure complex)

The Chemistry of C-C π-Bonds - 39 -

 The Conjugate Acceptor makes a difference too

Make R large

O

O MeMgBr

Summary





 Less reactive nucleophiles prefer conjugate addition

 Less reactive electrophiles prefer conjugate addition

i.e thermodynamically most stable product is formed