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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)
R
X Y
X
H
R
R
Y
H
R
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)
Br
H+
H3 C
H
CH2CH3
Br
Br
Obtain racemic mixture
of this regioisomer
Reactions of Alkenes
There are three questions to ask for any addition reaction
R
R
X
X Y
H
R
Y
H
R
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?)
All of these questions can be answered if the intermediate structure is known
Reactions of Alkenes
Dihalogen compounds can also react as electrophiles 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 carbocations must not be present
The large size and polarizability of the halogen can stabilize the unstable carbocation
With an unsymmetrical alkene, however, both bonds to the bromine need not be equivalent
Called a “Bromonium” ion -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 carbon 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
H3C
CH3
Br Br
H3C
H
Br
Br
H
CH3
Obtained product
H3C
H
Br
Br
H
CH3
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
!+
Br
Br Br
!+
OH
Br
Br
H2 O
Favored product
While water is a weaker nucleophile than bromide, because it is the solvent there is a much greater concentration present
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
H
CH3
D
Br Br
H
D
!+
CH3
CH3
H2O
Br
OH
HD
The halohydrin is named according to which halogen is present
(chlorohydrin, bromohydrin, iodohydrin)
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
CH3
Br Br
H3C
Br
Br
Br Br
Br Br
H3 C
CH3
CH3
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
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
O
O
O
O
O
Hg
CH3
H
O
Hg
!+
AcO Hg !+
CH3
H
H
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
!+
AcO Hg !+
CH3
H
H
H2O
CH3
AcOHg
NaBH4
OH
OH
H H
The mercury can subsequently be removed with sodium borohydride to form the alcohol
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
CH3
CH3
H+/H2O
H3C
HO CH3
H3C CH3
CH3
1) BH3•THF
2) H2O2, NaOH
H3C CH3
CH3
H3C CH3
CH3
HO
CH3
Markovnikov product
Generate free carbocation that
rearranges to more stable 3˚ cation
Anti-Markovnikov
H3C CH3
1) Hg(OAc)2, H2O
2) NaBH4
OH
CH3
H3C CH3
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
!-
O
!!+
H3 C
OH
Acetic acid
!-
O
!+
O
H
H3C !+ O
!-
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 O
H
O
CH3
H
O
CH3
O
O
O
CH3
CH3
CH3
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
O
CH3
RCO3H
CH3
CH3
CH3
O
H3C
CH3
RCO3H
CH3
CH3
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
O
RCO3H
1 equivalent
More alkyl substituents,
therefore more electron rich
double bond
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)
CH3O
O
O
O
Same reaction would never occur with straight chain ether
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
O
OH
CH3MgBr
H3C
CH3
H3C
All products
after work-up
Grignard reagents are a source of nucleophilic carbon based anions “R-”
O
OH
NH3
NH2
H3 C
H3C
Neutral amines also are good nucleophiles
O
H3C
OH
LiAlH4
"LAH"
"H-"
H3 C
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
O
H3C
!+
!+ O H
O
H+
H3C
H3C
OH
H2O
H3C
OH
Vicinal diol
(glycol)
Can use weaker nucleophiles in this manner since we have a better leaving group
Common examples of nucleophiles include water or alcohols
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
O
H+
H
O
CH3OH
HO
OCH3
Reaction of Epoxides
Grignard and Organolithium compounds are good nucleophiles which can react with an
epoxide in a basic mechanism
O
OH
CH3MgBr
H3C
CH3
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
O
H3C
CuCN
OH
(CH3)2Cu(CN)Li2
H3C
CH3
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
OH
R
OH
EtO2C
CO2Et
OH
Ti[OCH(CH3)2]4
(CH3)3CO3H
O
R
OH
Glycol Formation
We have observed glycols (vicinal diols) being formed by reacting epoxides with either basic or acidic water
O
OH
NaOH
H3 C
H3C
OH
This reaction generates an ANTI glycol
RCO3H
O
NaOH
OH
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
H3 C
H3C
O O
Os
O O
H3C
O O
Os
O O
H2O2
HO
OH
HO
OH
or
Na2SO3
H2O
CH3
H3 C
H3 C
O O
Mn
O O
H3 C
O O
Mn
O O
H2O
NaOH
Contrast this stereochemistry with glycols formed by reacting epoxides
CH3
H3 C
1) RCO3H
2) NaOH
HO
OH
Carbonyl Compounds
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
O
R
O
O
R
R
H
Ketone
two R groups
R
O
NH2
Amide
one R, one N
Aldehyde
one R, one H
R
O
R
OH
O
OR
R
Cl
Ester
one R, one OR
Acid
one R, one OH
Carbonyl compounds can also be synthesized from alkenes
Acid chloride
one R, one Cl
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
O
O
O
O
O
O
Mechanism of Ozonolysis
O
O
O
O
H3C
O
O
O
O
O
CH3
Molozonide
(primary ozonide)
O
Zn
O
O (CH3SCH3)
Ozonide
(H2/Pd)
Reductive
workup
O
H
Ozonolysis
With reductive workup, either ketones or aldehydes can be obtained depending upon the substituents on the alkene starting material
CH3
CH3
H3 C
1) O3
2) CH3SCH3
O
H3 C
H
O
CH3
H
H3C
With oxidative workup, however, aldehydes are oxidized to carboxylic acids but ketones are not reactive under these conditions
CH3
CH3
H3 C
H
1) O3
2) H2O2
O
H3 C
O
CH3
H3C
OH
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)
H3C
HBr
CH3
!+
H
H3C !+
Br
CH3
H3 C
Br
H
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
H3 C
Br
H
CH3
HBr
Br Br
H3 C
CH3
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
H3C
CH3
Hg(OAc)2
H3C
H2O
HO
The last step is a KETO-ENOL equilibrium (not resonance)
Ketone form is generally more stable
HgOAc
H OH2
CH3
HO
H3C
H3 C
O
H3 C
CH3
HO
HgOAc
H
CH3
H
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
H3 C
O
R
H
H O
H
HO
CH3
H
R
HH
H O
H
-H
H
CH3
R
HH
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
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)
B H
R
R
H
H
BR2
H
(Sia)2BH
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
H
BR2
NaOH
H
OH
R
H
H
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 alkane
H2
catalyst
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 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
R
R
H2, Pt
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
R
R
H2
H
H
Lindlar’s catalyst
(Pd/CaCO3/Pb)
R
R
*Obtain cis reduction, because the alkyne must approach the metal surface
from one direction, hence both hydrogens 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
R
R
Na
R
H
NH3(l)
H
R
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
The mechanism for dissolving metal reductions involve the formation of a solvated electron
Na
NH3(l)
NH3(l)•
Na
This solvated electron can add to the LUMO of the alkyne to generate a radical/anion
R
R
R
NH3(l)•
R
H NH2
R
H
R
H
1) NH3(l)•
2) NH3
R
R
H
R
R
H
R
With radical/anion want to
sterically place R groups apart
R
An acid base reaction
generates a vinyl radical
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)
H
C
H
Highly reactive
This compound will react quickly with alkenes to form a cyclopropane
H3 C
H3 C
CH3
CH3
H
C
H
H3C
H3C
CH3
CH3
Common method to generate cyclopropane structures
Carbenes
There are a number of ways to generate a carbene
H2C N N
Br
Br
Br
OC(CH3)3
H
Loss of diazo leaving group
CH2
Br
CBr2
Br
Br
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
H2 C 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,
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
CH3
H
H
CH3
H3 C
CH3
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)