Reactions of Alkenes

Alkenes generally react in an addition mechanism

(addition – two new species add to a molecule and none leave)

Have already observed using a H+ electrophile (HBr or H+/H2O) that a carbocation intermediate is generated which directs the regiochemistry

Whenever a free carbocation intermediate is generated there will not be a stereopreference due to the nucleophile being able to react on either lobe of the carbocation

(already observed this with SN1 and E1 reactions)

H+ H3C CH2CH3H Br

Br

Br

Obtain racemic mixture of this regioisomer

R

R

X Y X Y

R HH R

There are three questions to ask for any addition reaction

1)  What is being added?

(what is the electrophile?)

2)  What is the regiochemistry?

(do the reagents add with the X group to the left or right?)

3)  What is the stereochemistry?

(do both the X and Y groups add to the same side of the double bond or opposite sides?)

Reactions of Alkenes

All of these questions can be answered if the intermediate structure is known

R

R

X Y X Y

R HH R

Reactions of Alkenes

Dihalogen compounds can also react as electrophiles in reactions with alkenes

Br BrBr

Experimentally it is known, however, that rearrangements do nor occur with Br2 addition

-therefore free carbocations must not be present

Br Br Br Does not rearrange, therefore this carbocation must not be present

The large size and polarizability of the halogen can stabilize the unstable carbocation

Br

With an unsymmetrical alkene, however, both bonds to the bromine need not be equivalent

Br!+

!+ Br!+

!+More stable partial

positive charge

Called a “Bromonium” ion

-this structure will direct further reactions

or

Possible partial bond structures

Dihalogen Addition

The bromonium ion thus forms a partial bond to the carbon that can best stabilize

a positive charge which will then react with the bromide nucleophile

Br Br Br!+

!+ Br BrBr

Due to the 3-centered intermediate, dihalogen additions occur with an anti addition

H3CCH3 Br Br

Br

Br

H3C

HCH3

H Br

Br

H3C

CH3H

H

Obtained product

Not obtained

Formation of Halohydrins

When water is present when a dihalogen is added to a double bond,

then water can react as the nucleophile with the halonium (e.g. bromonium) ion

The halohydrin is named according to which halogen is present

(chlorohydrin, bromohydrin, iodohydrin)

Br Br Br!+

!+ BrH2O

While water is a weaker nucleophile than bromide,

because it is the solvent there is a much greater concentration present

BrOH

Favored product

The halonium ion thus directs both the regiochemistry (oxygen adds to the carbon that can best stabilize the partial positive charge) and the stereochemistry (due to the three membered

ring the oxygen must add anti to the the bromine already present)

Br Br CH3Br

!+!+

H2OCH3H

D DH

Br

DHOH

CH3

Halogenation of Alkynes

Dihalogen can be added to alkynes in addition to alkenes

The reaction is similar to alkenes with the main difference being the presence of two π bonds thus allowing reaction to occur twice for a total of 4 halogens adding to the compound

H3C CH3Br Br

Br CH3

BrH3C Br BrH3C

CH3Br Br

Br Br

With one addition, obtain trans vicinal dihalogen

Second addition is favored, hard to stop at alkene stage as alkene is more reactive

than alkyne

Due to difference in reactivity,

it is possible to selectively add to an alkene in the presence of an alkyne

Br Br1 equiv.

Br

Br

Oxymercuration

An alkene can also be hydrated using mercury salts (called oxymercuration)

HgOO

OO

Mercury diacetate [Hg(OAc)2] is a common reagent

which loses one acetate to generate an electrophilic source of mercury

HgO

O

The electrophilic mercury reacts with an alkene to form a mercurinium ion which is similar to bromonium ions in that a three membered ring is formed with a partial bond to the carbon

that can best handle the partial positive charge

Water can then react (which is typically the solvent for these reactions) in an anti addition

H2O NaBH4

The mercury can subsequently be removed with sodium borohydride to form the alcohol

CH3H

HCH3

Hg !+

HH

AcO !+

CH3Hg !+

HH

AcO !+AcOHg

H HOH

CH3 OH

Routes to Hydrate an Alkene

Different routes have been seen to hydrate an alkene,

each route though offers different advantages and often an entirely different product

CH3H3C CH3

CH3H3C CH3

CH3H3C CH3

H+/H2O

1) BH3•THF2) H2O2, NaOH

1) Hg(OAc)2, H2O2) NaBH4

H3C

CH3CH3

HO CH3

CH3H3C CH3

HO

CH3H3C CH3

OH

Markovnikov product

Generate free carbocation that

rearranges to more stable 3˚ cation

Anti-Markovnikov

Markovnikov product

Do not generate free carbocation

therefore no rearrangements occur

Epoxidation

To form an epoxide from an alkene, need to generate an electrophilic source of oxygen

Previously we have observed oxygen acting as a nucleophile

and reacting with carbocation sites

A peroxy acid (or peracid) is a source of electrophilic oxygen

H3C

O

OH H3C

O

O O H

!-

!-

!-

!-!+ !+

!+

Acetic acid

Peracetic acid

(called peracid or peroxy acid)

Due to the high electronegativity for oxygen, typically the oxygen atoms

in an organic compound have a partial negative charge (therefore nucleophilic)

In a peracid, however, the terminal oxygen is already

adjacent to an oxygen with a partial negative charge

The terminal oxygen thus has a partial positive charge and thus is electrophilic

Epoxidation

When an alkene reacts with a peracid, an electrophilic reaction occurs

where the π bond reacts with the electrophilic oxygen

CH3CH3

OH O

O CH3

CH3CH3

OO

OH CH3

The reaction forms an epoxide (oxirane) with a carboxylic acid leaving group

Due to the cyclic transition state for this reaction, the two new bonds to oxygen form SYN

CH3CH3 CH3

CH3O

RCO3H

CH3H3C RCO3H CH3

CH3O

Epoxides

Selectivity in Epoxide Formation

When synthesizing an epoxide from an alkene with peracid

the peracid is acting as a source of an electron deficient oxygen,

therefore the most electron rich double bond will react preferentially

RCO3H O

More alkyl substituents, therefore more electron rich

double bond

1 equivalent

If more equivalents are added, the remaining double bonds

can still react

Reaction of Epoxides

Unlike straight chain ethers, epoxides react readily with good nucleophiles

Reason is release of ring strain in 3-membered ring

(even with poor alkoxide leaving group)

Same reaction would never occur with straight chain ether

O O

OCH3O No reaction

CH3OO

Reaction of Epoxides

Most GOOD nucleophiles will react through a basic mechanism

where the nucleophile reacts in a SN2 reaction at the least hindered carbon of the epoxide

H3CO

H3CO

H3CO

CH3MgBr

NH3

LiAlH4

"LAH""H-"

Grignard reagents are a source of nucleophilic carbon based anions “R-”

Neutral amines also are good nucleophiles

Lithium aluminum hydride is a source of “H-” which also reacts in a SN2 type reaction

H3C

OHCH3

H3C

OHNH2

H3C

OHH

All products after work-up

Reaction of Epoxides

Epoxides will also react under acidic conditions

Can use weaker nucleophiles in this manner since we have a better leaving group

Common examples of nucleophiles include water or alcohols

The oxygen is first protonated which then allows the positive charge to be placed

selectively on the carbon that is most stable with a partial positive charge

similar to bromonium or mercurinium ions

H3CO H+

H3COH !+

H3CO!+ H H2O

H3COH

OH

Vicinal diol

(glycol)

Reaction of Epoxides

Differences in Regiochemistry

The base catalyzed opening of epoxides goes through a common SN2 mechanism,

therefore the nucleophile attacks the least hindered carbon of the epoxide

O

In the acid catalyzed opening of epoxides, the reaction first protonates the oxygen

This protonated oxygen can equilibrate to an open form that places more partial

positive charge on more substituted carbon,

therefore the more substituted carbon is the preferred reaction site for the nucleophile

HO OCH3

CH3MgBrO

O H+ OH

CH3OH

Reaction of Epoxides

Grignard and Organolithium compounds are good nucleophiles which can react with an epoxide in a basic mechanism

H3CO CH3MgBr

H3C

OHCH3

These reagents can sometimes cause problems due to their very strong base strength

-side reactions can occur and also they are very reactive and thus not selective

(they will react with any carbonyl present in the compound for example)

To overcome these drawbacks organocuprates can also deliver an R- source as a nucleophile

They will not react, however, with carbonyl compounds

H3CO (CH3)2Cu(CN)Li2

CH3Li CuCN

H3C

OHCH3

Asymmetric Epoxidation

Epoxides are thus a very versatile functional group that can react

with a variety of nucleophiles to allow synthesis of a wide selection of products

When an achiral alkene and an achiral peracid react, however,

the epoxide formed would not be chiral

Many targeted compounds are chiral and their chirality is critical for the properties

A tremendous advantage was obtained when a simple and convenient method

was developed to synthesize chiral epoxides

Sharpless epoxidation

R OH CO2EtEtO2C

OH

OH Ti[OCH(CH3)2]4(CH3)3CO3H R OH

O

Glycol Formation

We have observed glycols (vicinal diols) being formed by reacting epoxides

with either basic or acidic water

H3CO NaOH

H3COH

OH

This reaction generates an ANTI glycol

RCO3H O NaOHOH

OH

Would need another method to generate a SYN glycol

Glycol Formation

There are two common reagents for SYN dihydroxy addition to alkenes

Both involve transition metals that deliver both oxygens from the same face

CH3

H3COs

O

O

O

O OOsO

H3C

H3C O

OH2O2 HO OH

HO OH

Na2SO3H2O

or

CH3

H3CMn

O

O

O

O OMnO

H3C

H3C O

OH2ONaOH

Contrast this stereochemistry with glycols formed by reacting epoxides

CH3

H3C

1) RCO3H2) NaOH

HO OH

Carbonyl Compounds

R

O

R R

O

H R

O

OH R

O

ORR

O

NH2 R

O

Cl

Ketone

two R groups

Aldehyde

one R, one H

Amide

one R, one N

Acid

one R, one OH

Ester

one R, one OR

Acid chloride

one R, one Cl

A carbon-oxygen double bond is a common, and useful,

functional group in organic chemistry

Called a carbonyl group (the carbon is thus called the carbonyl carbon)

The type of carbonyl changes depending upon the substituents on the carbonyl carbon

Carbonyl compounds can also be synthesized from alkenes

Ozonolysis

Instead of reacting the alkene with transition metal reagents to synthesize glycols,

other 1,3-dipolar reagents can be used which generate a similar 5-membered ring intermediate

When ozone is used (O3) the reaction is called an “ozonolysis”

O O O OO O O O O

O O O

H3C

CH3

OO

O OO

O OOO Zn(CH3SCH3)(H2/Pd)

O

H

Mechanism of Ozonolysis

Molozonide

(primary ozonide)

Ozonide

Reductive

workup

Ozonolysis

With reductive workup, either ketones or aldehydes can be obtained

depending upon the substituents on the alkene starting material

H3C

CH3CH3

H

1) O32) CH3SCH3

H3C CH3

O

H3C

O

H

With oxidative workup, however, aldehydes are oxidized to carboxylic acids

but ketones are not reactive under these conditions

H3C

CH3CH3

HH3C CH3

O

H3C

O

OH

1) O32) H2O2

Hydrohalogenation of Alkynes

Similar to reactions with alkenes, when alkynes react with hydrohalic acid (e.g. HBr) the proton reacts with the π bond and the positively charged intermediate is reacted with the halide

Unlike alkene reactions, however, the addition of HBr to the first π bond

generates a high yield of the trans product

(not a mixture of cis and trans as would be expected with a free carbocation)

CH3H3CHBr

CH3H3CH!+

!+

Br H3C

Br

H

CH3

Since there is still a remaining π bond, additional equivalents of HBr

will react a second time to generate the geminal (on the same carbon) dihalogen

H3C

Br

H

CH3

HBr

H3CCH3

Br Br

Vinyl cations are very unstable

Hydration of Alkynes

To hydrate an alkyne a mercury catalyst is added

(in contrast to alkene reactions when acidic water alone is sufficient)

Similar to oxymercuration routes with alkenes

CH3H3CHg(OAc)2H2O

H3C

HO

HgOAc

CH3

H OH2

CH3

H3C

HO

HgOAcH

HO

H3C

CH3

H

Due to the positive charge developed after second π bond reacts with acid,

do not need to add a reducing agent (NaBH4) similar to the alkene oxymercuration

The last step is a KETO-ENOL equilibrium

(not resonance)

Ketone form is generally more stable

O CH3

H3C

Keto-Enol Equilbrium

Generally the ketone form is more stable than the enol form

(carbon-oxygen double bonds are relatively more stable)

Enol form is thus not the stable form,

if an enol is generated in a reaction convert the structure to the keto form

O CH3

H3C

HO

H3C

CH3

H

R

O

H

HH

H R

O HH

HH -H R

O H

HH

Hydroboration of Alkynes

Hydroboration of alkynes can also occur

*need bulky reagent to prevent side reactions due to second π bond

(Sia is an acronym for sec-isoamyl)

Notice hydroboration still occurs with syn addition and the

regiochemistry is dictated by the stability of the initial carbocation intermediate

R H

B H

R H

H BR2(Sia)2BH

Oxidation of borane product

The borane can be oxidatively removed

(analogous to alkene reactions)

*if a terminal alkyne is used the product of this reaction sequence

is an aldehyde after keto-enol equilibrium

Hydroboration of Alkynes

R H

H BR2

H2O2

NaOH

R H

H OH

R H

OHH

Hydrogenation of π Bonds

An alkene can also be reduced to an alkane

A catalyst is required for this process

(hydrogen gas alone will not reduce alkenes)

Heterogeneous catalyst reaction occurs on the metal surface of the catalyst (Pt, Pd, Ni, Pd/C)

and thus results in SYN reduction

N NH H(diimide)

A nonmetallic reducing agent can also be used,

diimide is a common choice and also results in SYN reduction

H2catalyst

Hydrogenation of π Bonds

Reduction of alkynes

With two π bonds important to realize a variety of structures can be obtained

depending upon the reducing conditions used

If use hydrogen gas with a variety of metal catalysts (Pt, Pd, Ni, Pd/C are common choices)

it is hard to stop at the alkene, the alkyne will be fully reduced to the alkane

In order to stop at the alkene stage, a weaker catalyst is needed

R RH2, Pt R

R

Hydrogenation of π Bonds

Alkyne to Alkene

One approach is to use a “poisoned” catalyst (Lindlar’s catalyst)

the catalyst has impurities added which lower the effectiveness of the metal surface

*Obtain cis reduction, because the alkyne must approach the metal surface

from one direction, hence both hydrogens are added from the same side

(Pd/CaCO3/Pb)

R RH2

R R

H H

Lindlar’s catalyst

Alkyne to trans-Alkene

To obtain a trans alkene from reduction of alkyne a different mechanism is required

Dissolving metal reduction yields the trans product

Reaction is run at low temperature so that the ammonia is a liquid

(acts as solvent)

Mechanism involves dissolved electrons reducing the alkyne

Hydrogenation of π Bonds

R RNa

NH3(l) H R

R H

Hydrogenation of π Bonds

The mechanism for dissolving metal reductions involve the formation of a solvated electron

Na NH3(l) Na NH3(l)•

This solvated electron can add to the LUMO of the alkyne to generate a radical/anion

R R NH3(l)•R

RWith radical/anion want to

sterically place R groups apart

RR H NH2 R

R

H

An acid base reaction generates a vinyl radical

RR

H

1) NH3(l)•2) NH3

RR

H

H The vinyl radical repeats the two steps to add the second

hydrogen TRANS

Other Reactions of Alkenes

Carbenes

A carbene refers to a carbon atom containing only 6 electrons in the outer shell

(two covalent bonds and an extra two electrons – unlike a carbocation)

This compound will react quickly with alkenes to form a cyclopropane

Common method to generate cyclopropane structures

CH

HHighly reactive

H3C

H3C

CH3

CH3

CH

HH3C CH3

H3C CH3

Carbenes

There are a number of ways to generate a carbene

H2C N N CH2

Br

HBrBr

OC(CH3)3 Br

BrBr CBr2

Loss of diazo leaving group

Dihalo carbenes (typically dichloro or dibromocarbene)

are generated by reacting haloforms with strong base

Either of these methods of carbene generation will react with alkenes

H2C N N

Carbenes

Since with carbenes we have 6 electrons in the outer shell, it depends upon

which orbitals the electrons are placed to determine the “flavor” of the carbene

HH

HH

Both electrons in same orbital, must be spin paired and thus this is called a “singlet” state

Electrons in different orbitals, electrons will have the same spin and thus called a “triplet” state

Both states of carbenes can react, but the singlet state is generally more reactive

The singlet can react in a concerted manner (both new C-C bonds of cyclopropane are formed at same time) and thus the reaction must be SYN

The triple cannot form both bonds at the same time and thus the cyclopropane

formed can be either SYN or ANTI in addition

(experimentally these reactions are used to differentiate which state is reacting)

HH

CH3

CH3 H3C CH3