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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
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