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Electrophilic Addition to Alkenes Introduction to this Lecture Set: http://youtu.be/-uBozL9WSxc
Key Conceptsi Lecture 1: Overview of Electrophilic Addition http://youtu.be/jEyDxZQVUg4 ! The standard electrophilic addition reaction mechanism is a two-step sequence. The
electrophile is attracted to the electrons of the pi bond, which is relatively weak and therefore more readily broken that a sigma bond. The first step creates a carbocation intermediate, which attracts the unshared electron pair of a nucleophile, forming a second sigma bond in this step.
C C C CR C CR
NuEE
NuE
! The electrophile can add to either of the two alkene carbons. When those two
carbons have different substituents attached, the reaction is regioselective: the electrophile adds to the carbon that makes the more stable carbocation intermediate.
! Because tetrahedral carbons are being formed in this addition reaction, the potential for creating one or two new stereogenic centers exists. When only one stereogenic center is created, a racemic mixture (50:50 mixture of R & S) results. When two stereogenic centers are created, either two or four stereoisomers are created, depending on the details of the reaction mechanism.
! With respect to the energetics of the alkene substrate, this 1,2-addition is favorable: A rather weak pi bond is broken and two sigma bonds are formed. This is illustrated in the typical energy diagram for electrophilic addition, as shown below, which has a negative value for ΔH.
reaction
EactEact
H
ΔH
! The energy diagram also reflects the fact that the first step is the rate-determining
step: The activation energy for formation of the unstable carbocation intermediate is much greater than for the reaction of that carbocation with a nucleophile to form a stable product.
Electrophilic Addition to Alkenes Lecture 2: Addition of Hydrogen Halides HCl, HBr and HI http://youtu.be/ZY4tjm7t9JY
! Electrophilic addition of hydrogen halides (HX) to an alkene follows the mechanism shown above. A proton donated by HX, which is the electrophile. This first step forms a halide anion, X-, which is the nucleophile in the second step.
H
X
HH X
X
! When there are more alkyl groups attached to one carbon than the other, the proton
adds to the carbon that places the positive charge on the more substituted carbon – because alkyl substitution makes carbocations more stable. Addition of the proton to the other carbon would make a less substituted, less stable carbocation intermediate. This observation is known as Markovnikov’s rule, which he stated in terms of the location of the addition of the hydrogen: “The hydrogen adds to the double bond carbon that has more hydrogens attached to it.”
H X
H
! This regioselectivity is readily understood by looking at the energy diagrams for
addition of the proton to the two alternative carbons. The transition state leading to the less stable 2o carbocation is less stable (in accord with Hammond’s postulate), resulting in a greater activation energy and therefore slower reaction.
2o carbocationslower reaction
reaction
Eact
Eact
H
3o carbocationfaster reaction
T.S.
Electrophilic Addition to Alkenes
! When the more substituted alkene carbon has two different alkyl groups, a stereogenic center is created when the nucleophile adds. Because the nucleophile can add just as well to either lobe of the empty p orbital, this creates a racemic (50:50) mixture of enantiomers. Therefore, this reaction is not stereospecific, because the stereochemistry (E or Z) does not affect the stereochemistry of the product.
H HH X
X
H
+X X
C CMe
EtHH
X
X
Et
Electrophilic Addition to Alkenes Lecture 3: Addition of Water Using an Acid Catalyst http://youtu.be/rKPY-eRST6k
! The acid-catalyzed addition of water to an alkene is accomplished using water together with a strong acid, usually sulfuric acid, H2SO4. This combination creates H3O+, which is the electrophile that initiates 1,2 electrophilic addition.
! The reaction mechanism parallels that described above for addition of hydrogen halides, with a significant departure: because the nucleophile, H2O, is uncharged, the initial product must lose a proton in a final step.
H HH OH2H
+OH HO
C CMe
EtHH
OH2
OH2
OH2
H H
H2O H2O
H H
+OH HO
conc. H2SO4H2O
Et
! The initial step of this reaction is protonation, like the addition of HX, and therefore, for the same reasons, acid-catalyzed addition of water (1) is regiospecific, following Makovnikov’s rule (the OH adds to the more substituted carbon) and (2) is not stereospecific: a racemic mixture of enantiomers is formed regardless of the stereochemistry (E or Z) of the reacting alkene when there are two different alkyl groups attached to the more substituted carbon.
Electrophilic Addition to Alkenes Lecture 4: Addition of Bromine and Chlorine http://youtu.be/C35aD87srn0
! When bromine (or chlorine) approaches the electrons of a pi bond, it is polarized sufficiently to create an electrophile through the partial positive charge on the near bromine atom. The resulting intermediate is a cyclic bromonium ion, which adds a nucleophile (Br-, formed in the first step) – the typical second step of electrophilic addition.
1 42 3
Br Brδ δ
14
2 3
Br1
4
2
3
Br
Br 1
4
2
3
Br
Br
+
+ Br
BrBr ! The nucleophile may add to either carbon, which therefore forms two different
products when “1” and “2” are different from “3” and “4” (see drawing). In either case, Br- must approach from the side away from the bromine atom of the intermediate.
! The intermediate bromonium ion maintains the spatial relationships of “1”, “2”, “3” and “4” in the reacting alkene, and those relationships carry through to the product. Therefore, electrophilic addition of bromine to an alkene is stereospecific. (The stereochemistry of the reactant dictates the stereochemistry of the products.) For this reason, when two different stereogenic centers are created, only two of the possible four stereoisomers are formed.
! Addition of the two bromine atoms occurs with what is termed “anti” addition, because the nucleophile must approach the intermediate from the “back side” – the side away from the bromine atom. This anti addition is responsible for dictating which two of the four possible stereoisomers are formed. In the example shown below, the Z alkene makes a pair of enantiomers: R,R and S,S and the E alkene makes the other pair of enantiomers: S,R and R,S.
Et MeH H
Et
Me
H
H
Br
Br Et
Me
H
H
Br
Br
+
H MeEt H
H
Me
Et
H
Br
Br H
Me
Et
H
Br
Br
+
ZR R S S
SRRSE
Electrophilic Addition to Alkenes Lecture 5: Making Halohydrins by Addition of BrOH and ClOH http://youtu.be/C35aD87srn0
! The reaction mechanism to make bromohydrins (and chlorohydrins) from alkenes parallels addition of bromine to make dibromides. When bromine (or chlorine) approaches the electrons of a pi bond, it is polarized sufficiently to create an electrophile through the partial positive charge on the near bromine atom. The resulting intermediate is a cyclic bromonium ion, which adds a nucleophile – the typical second step of electrophilic addition. Because water is the nucleophile, a final step to remove a proton from oxygen is required.
1 42 3
Br Brδ δ
14
2 3
Br1
4
2
3
Br
OH 1
4
2
3
OH
Br
+
+ Br
OH2H2OHH
H2O H2O
1
4
2
3
Br
OH 1
4
2
3
OH
Br
+
! This reaction is regioselective: Water adds to the carbon that has more alkyl
groups. The transition state during water addition has partial positive charge on the carbon, which, like carbocations, is stabilized by alkyl groups.
Br2
H2O
OH
BrMe
EtMe H
Br
MeEt
Me H
Br
OH2 OH2
δ δ
δ δ
charge stabilizedby 3 alkyl groups
(more stable)
charge stabilizedby 2 alkyl groups
(less stable)
! The nucleophile must approach the intermediate from the side away from the
bromine atom intermediate, resulting in overall anti addition of Br and OH. ! The intermediate bromonium ion maintains the spatial relationships of “1”, “2”, “3”
and “4” in the reacting alkene, and those relationships carry through to the product. Therefore, formation of halohydrins from alkenes is stereospecific. (The stereochemistry of the reactant dictates the stereochemistry of the products.) For this reason, when two different stereogenic centers are created, only two of the possible four stereoisomers are formed.
Electrophilic Addition to Alkenes ! Addition of bromine and hydroxyl group occurs with what is termed “anti” addition,
because the water molecule must approach the intermediate from the “back side” – the side away from the bromine atom. This anti addition is responsible for dictating which two of the four possible stereoisomers are formed. In the example shown below, the Z alkene makes a pair of enantiomers: R,R and S,S and the E alkene makes the other pair of enantiomers: S,R and R,S.
Z
Et MeMe H
Et
Me
Me
H
Br
OH Et
Me
Me
H
Br
OH
+
Me MeEt H
Me
Me
Et
H
Br
OH Me
Me
Et
H
Br
OH
+
R R S S
ES R R S
Electrophilic Addition to Alkenes Lecture 6: Addition of Water Using Oxymercuration http://youtu.be/SX8xw-w3k2w
! The reaction mechanism to add H2O to alkenes using mercuric acetate parallels the formation of halohydrins. In an initial ionization, mercuric acetate forms an electrophile, which then adds to the double bond. The intermediate is a cyclic cation, like the bromonium ion. This cyclic intermediate directs addition of the water molecule from the opposite side (anti addition). Because water is the nucleophile, a final step to remove a proton from oxygen is required. The product must be treated with a reducing agent in a subsequent reaction: The Hg-C bond is replace by C-H.
Et MeMe H
EtMe
Me H
Hg + OAc
H2O
Et
Me
Me
H
HgOAc
OH
HgOAcOAc
NaBH4
Et
Me
Me
H
H
OH
overall additionof H2O
Et
Me
Me
H
HgOAc
OHH
H2O
! This reaction is regioselective: Water adds to the carbon that has more alkyl groups. The transition state during water addition has partial positive charge on the carbon, which is stabilized by alkyl groups (like carbocations). This is the same rationale used to explain the regioselectivity in the formation of bromohydrins (see transition state structure shown in lecture 5). This regioselectivity follows Markovnikov’s rule: The hydrogen adds to the carbon that has more hydrogens.
Electrophilic Addition to Alkenes
! Because the reaction mechanism of this alkene hydration reaction avoids carbocation intermediates, this reaction can offer an advantage in the synthesis of alcohols. In particular, because the cyclic mercurinium ion intermediates don’t rearrange, alcohols can be made that cannot be made in good yield using acid-catalyzed hydration, as illustrated below.
1. Hg(OAc)2, H2O
2. NaBH4OH
H2SO4, H2O OH
H
H OSO3H
OH2
loss of H+
majorproduct
Electrophilic Addition to Alkenes Lecture 7: Addition of Water Using Hydroboration http://youtu.be/pMj7_sjytaA ! During hydroboration, both the electrophile – borane – and the nucleophile – hydride
donated by the borane – add at the same time. The result is syn addition of the boron and the hydrogen.
Et MeMe H Et
MeMe H
overall additionof H2O
Et MeMe H
BBH3H B
δ
δ
H
(BHR2)
Et MeMe H
OHHH2O2, HO-
! This addition of water by hydroboration is regioselective. Because the transition state has a partial positive charge on one of the carbons, the boron bonds to the less substituted carbon, placing that positive charge on the carbon that has more alkyl groups. (Alkyl groups stabilize positive charge on carbon atoms.) Overall, then, after boron is replaced by hydroxyl in the second step, this addition has anti-Markovnikov regioselectivity: the hydrogen adds to the more substituted carbon, and the hydroxyl adds to the less substituted carbon.
! Because hydroboration proceeds by syn addition, the reaction makes only one pair of enantiomers, not two pair. Therefore, hydroboration is stereospecific: the stereochemistry of the reacting alkene dictates the stereochemistry of the products. The Z alkene makes one pair of enantiomers, and the E alkene makes the other pair of enantiomers.
Et MeMe H Et Me
Me H
OHH
Me MeEt H Me Me
Et H
OHH
+
+ enantiomer (R,S)
enantiomer (S,S)
R R
RS
Z
E
Electrophilic Addition to Alkenes Lecture 8: Using Electrophilic Addition in Synthesis http://youtu.be/Z2XOUckwcF8
! Application of electrophilic addition reactions to organic synthesis permits exploitation of their key characteristics: ! creation of functional groups. ! regioselectivity: control regarding the transformation of each alkene carbon. ! stereoselectivity: control regarding the stereochemistry at new stereogenic centers. ! stereospecificity: control of stereochemistry in the product(s) by exploiting the E/Z
stereochemistry of the starting alkene. ! Examples are shown below.
target
H2SO4, H2O
or
1. Hg(OAc)2, H2O2. NaBH4
OH
OH
OHtarget
1. BH3
2. H2O2, HO- OH
Electrophilic Addition to Alkenes
OH
target
fromBr
OH
Br
or
not reasonablymade from
starting bomide
Br
OH
1. BH3
2. H2O2, HO-
KOEt
target
from an alkene
or
cannot controlregiochemistry
HBr
SCH3
SCH3 Br
Br SCH3NaSCH3
Electrophilic Addition to Alkenes
Key Reactionsi
Typical Examples
Addition of Water
C CH
C CH
C CH
conc. H2SO4, H2O
1. Hg(OAc)2, H2O
C CH
HHO
C COH
HH
C CH
HHO
2. NaBH4
1. BH3 or BHR2
2. H2O2, HO-
> Markovnikov regiochemistry> intermediate carbocation may rearrange
> Markovnikov regiochemistry> avoids rearrangement
> anti-Markovnikov regiochemistry> syn addition
conc. H2SO4, H2O
OH
1. Hg(OAc)2, H2O
2. NaBH4
OH
1. BHR2
2. H2O2, HO-H
OH
Typical Example
Addition of Hydrogen Halides
C CH
C CH
HX
> Markovnikov regiochemistryHX
X= Cl, Br or I
HClCl
Electrophilic Addition to Alkenes
Typical Examples
Addition Involving Cl2 and Br2
C C C C
X
H
X
> anti additon
C CH X2, H2O > X adds to C with more Hs
> anti addition
X2
X= Cl or Br
X= Cl or Br
C CX
HHO
Cl2Cl
Cl
Br2, H2O
Br
HO
H