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Home , Carbocation, Epoxide, Halohydrin, Halonium ion, Peroxy acid

Reactions of

Alkenes generally react in an addition mechanism (addition – two new species add to a and none leave)

R X Y X Y H R R R H

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

Whenever a free carbocation intermediate is generated there will not be a stereopreference due to the being able to react on either lobe of the carbocation (already observed this with SN1 and E1 reactions)

Br

Br H+ H H3C Br CH2CH3

Obtain racemic mixture of this regioisomer Reactions of Alkenes

There are three questions to ask for any addition reaction

R X Y X Y H R R R H

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 or opposite sides?)

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

Dihalogen compounds can also react as in reactions with alkenes Possible partial bond structures + !+ Br Br ! Br Br Br !+ or Br !+ More stable partial positive charge

Experimentally it is known, however, that rearrangements do nor occur with Br2 addition -therefore free must not be present The large size and polarizability of the can stabilize the unstable carbocation

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

Called a “Bromonium” -this structure will direct further reactions

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

The bromonium ion thus forms a partial bond to the that can best stabilize a positive charge which will then react with the bromide nucleophile

!+ Br Br Br Br Br !+ Br

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

H Br H Br H3C H3C CH Br Br H C 3 CH3 H 3 Br H Br CH3

Obtained product Not obtained Formation of

When 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

!+ Br Br OH Br !+ Br Br H2O Favored product

While water is a weaker nucleophile than bromide, because it is the solvent there is a much greater concentration present The thus directs both the regiochemistry ( 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) + ! CH3 Br + H ! Br CH Br Br H2O OH 3 H CH3 D D H D The is named according to which halogen is present (chlorohydrin, bromohydrin, iodohydrin) of

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 adding to the compound

H C Br Br Br Br Br 3 Br Br H3C CH3 CH3 H3C Br CH3 Br Br With one addition, obtain Second addition is favored, trans vicinal dihalogen hard to stop at alkene stage as alkene is more reactive than Due to difference in reactivity, it is possible to selectively add to an alkene in the presence of an alkyne

Br Br Br 1 equiv. Br Oxymercuration

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

Mercury diacetate [Hg(OAc)2] is a common reagent which loses one acetate to generate an electrophilic source of mercury H CH3 !+ O O O AcO Hg H !+ O O O H CH3 Hg Hg H

The electrophilic mercury reacts with an alkene to form a mercurinium ion which is similar to bromonium 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

!+ AcO CH3 Hg !+ H O NaBH OH 2 AcOHg 4 H CH3 OH H H H

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

CH 3 Markovnikov product CH3 H+/H2O CH3 H3C Generate free carbocation that H3C CH3 HO CH3 rearranges to more stable 3˚ cation

1) BH3•THF CH3 HO CH3 2) H2O2, NaOH Anti-Markovnikov H3C CH3 H3C CH3

OH 1) Hg(OAc) , H O CH 2 2 CH Markovnikov product 3 2) NaBH 3 4 Do not generate free carbocation H3C CH3 H3C CH3 therefore no rearrangements occur Epoxidation

To form an 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 (or peracid) is a source of electrophilic oxygen

- - ! O ! O !+ !- O H3C !+OH H3C !+O H !- (called peracid or ) Due to the high electronegativity for oxygen, typically the oxygen in an 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

O CH O CH 3 H 3 H O O O O

CH3 CH3 CH3 CH3

The reaction forms an epoxide (oxirane) with a

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

O RCO H CH3 3 CH3 CH3 CH3

O CH RCO3H 3 H3C CH3 CH3

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

O RCO3H 1 equivalent

More substituents, If more equivalents are added, therefore more electron rich the remaining double bonds double bond can still react Reaction of Epoxides

Unlike straight chain , epoxides react readily with good Reason is release of ring strain in 3-membered ring (even with poor leaving group)

O O CH3O O

Same reaction would never occur with straight chain

CH3O O No reaction 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

OH O All products CH3MgBr CH3 H3C H3C after work-up

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

OH O NH3 NH2 H3C H3C Neutral also are good nucleophiles

OH O LiAlH 4 H H C H C 3 "LAH" 3 "H-"

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

Epoxides will also react under acidic conditions

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

H !+ OH O H+ O !+ O H H2O H C H C H C OH 3 3 3 H3C Vicinal (glycol)

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

Common examples of nucleophiles include water or 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 O CH3MgBr

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

H O H+ O HO CH3OH OCH3 Reaction of Epoxides

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

OH O CH3MgBr CH3 H3C H3C

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

CH3Li CuCN

OH O (CH3)2Cu(CN)Li2 CH3 H3C H3C Asymmetric Epoxidation

Epoxides are thus a very versatile 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

OH Ti[OCH(CH3)2]4 O EtO2C (CH3)3CO3H R OH CO2Et R OH OH Glycol Formation

We have observed glycols (vicinal ) being formed by reacting epoxides with either basic or acidic water

OH O NaOH OH H3C H3C

This reaction generates an ANTI glycol

OH RCO3H NaOH O 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 from the same face

CH3 O O H3C O O H2O2 HO OH Os Os O O O O or H3C H3C Na2SO3

H2O

CH3 H3C O O O O H O HO OH Mn Mn 2 O O H3C O O H3C NaOH

Contrast this stereochemistry with glycols formed by reacting epoxides

CH3 1) RCO3H HO OH 2) NaOH

H3C Carbonyl Compounds

A carbon-oxygen double bond is a common, and useful, functional group in organic chemistry

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

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

O O O O O O

R R R H R NH2 R OH R OR R Cl

Ketone two R groups one R, one N one R, one OR Acid Acid chloride one R, one H one R, one OH one R, one Cl

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

O O O O O O O O O

Mechanism of Ozonolysis

O O O O Zn O H C O O O O O 3 O O O (CH3SCH3) H CH3 (H2/Pd) Molozonide Ozonide (primary ozonide) Reductive workup Ozonolysis

With reductive workup, either or can be obtained depending upon the substituents on the alkene starting material

1) O3 CH3 2) CH3SCH3 O O CH3 H3C H3C CH3 H3C H H

With oxidative workup, however, aldehydes are oxidized to carboxylic but ketones are not reactive under these conditions

CH 3 1) O3 O O CH3 2) H2O2 H3C H3C CH3 H3C OH H 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)

!+ HBr H Br H3C H H3C CH3 H3C !+ CH3 Br CH3 Vinyl cations are very unstable

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

H C H 3 HBr Br Br CH3 Br CH3 H3C 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

Hg(OAc) H3C HgOAc H3C HgOAc 2 H OH2 H3C CH3 H H2O HO CH3 HO CH3

The last step is a KETO-ENOL equilibrium H3C H3C H (not ) form is generally more stable O CH3 HO CH3

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 Keto-Enol Equilbrium

Generally the ketone form is more stable than the enol form (carbon-oxygen double bonds are relatively more stable)

H3C H3C H

O CH3 HO CH3

H R H H R H -H R H H

H O H H O H O H

Enol form is thus not the stable form, if an enol is generated in a reaction convert the structure to the keto form 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)

B H

R H R H

(Sia)2BH H BR2

Notice hydroboration still occurs with syn addition and the regiochemistry is dictated by the stability of the initial carbocation intermediate Hydroboration of Alkynes

Oxidation of borane product

The borane can be oxidatively removed (analogous to alkene reactions)

R H H2O2 R H R H H H BR2 NaOH H OH H O

*if a terminal alkyne is used the product of this reaction sequence is an aldehyde after keto-enol equilibrium Hydrogenation of π Bonds

An alkene can also be reduced to an

H2 catalyst

A catalyst is required for this process ( 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 N H H (diimide)

A nonmetallic reducing agent can also be used, diimide is a common choice and also results in SYN reduction 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

H2, Pt R R R R

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 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

H H H2 R R Lindlar’s catalyst R R

(Pd/CaCO3/Pb)

*Obtain cis reduction, because the alkyne must approach the metal surface from one direction, hence both are added from the same side Hydrogenation of π Bonds

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

Na R H R R NH3(l) H R

Reaction is run at low temperature so that the is a liquid (acts as solvent)

Mechanism involves dissolved electrons reducing the alkyne 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 With radical/anion want to R R NH3(l)• R sterically place R groups apart

R An acid base reaction R H NH R R 2 generates a vinyl radical H

1) NH (l)• 3 H 2) NH3 The vinyl radical repeats the R R R R two steps to add the second H H hydrogen TRANS Other Reactions of Alkenes

Carbenes A refers to a carbon containing only 6 electrons in the outer shell (two covalent bonds and an extra two electrons – unlike a carbocation)

H C H Highly reactive

This compound will react quickly with alkenes to form a cyclopropane

H C H3C CH3 H H3C CH3 H C CH H3C CH3 3 3

Common method to generate cyclopropane structures

There are a number of ways to generate a carbene

H2C N N CH2 Loss of diazo leaving group

Dihalo carbenes (typically Br OC(CH3)3 Br dichloro or dibromocarbene) CBr Br Br 2 are generated by reacting Br H Br 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

H H H H

Both electrons in same orbital, Electrons in different orbitals, must be spin paired and thus electrons will have the same spin this is called a “singlet” state 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

CH3 H H H C CH CH3 3 3 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)