Lecture 9: Addition Reactions

Synthesis of Halohydrins

Water is the solvent.
Anti addition of HO and Br
Example:
- Cyclohexene + $Br<em>2$ in $H</em>2O$ yields trans-2-Bromocyclohexanol (a bromohydrin)
Anti addition of HO and Cl
Example:
- (E)-But-2-ene + $Cl<em>2$ in $H</em>2O$ yields (2S,3R)- and (2R,3S)-3-Chlorobutan-2-ol (a chlorohydrin)

Halohydrin Formation Mechanism

Even though $Br^-$ is present, $H<em>2O$ is the dominant nucleophile because, being the solvent, $H</em>2O$ is much more abundant.

Halohydrins and Regiochemistry

Regiochemistry becomes an issue with halohydrin formation if the alkene reactant is unsymmetrical.
With distinct alkene carbon atoms, two possible constitutional isomers can be produced.

Mechanistic Explanation for Regioselective Halohydrin Formation

Mechanism for the formation of a bromohydrin, including regiochemistry:
1. Electrophilic addition: $Br^+$ attacks the alkene. The side of the ring that acquires more positive charge from Br than the other side of the ring because one C atom is benzylic.
2. $SN<em>2$ : $H</em>2O$ attacks the side of the ring that acquires the greater amount of positive charge.
3. Proton transfer.

Formation of Epoxides by Nucleophilic Substitution

A halohydrin can be converted to an epoxide.
Example:
- A halohydrin + NaOH in Diethyl ether, 24 h yields an epoxide (96% yield)
Mechanism for the formation of an epoxide from a halohydrin:
1. Proton transfer: Hydroxide deprotonates the alcohol.
2. $SN_2$ : Attack from the side opposite the leaving group. The leaving group is $Cl^-$ .

Epoxides as Substrates

Neutral conditions:
- Epoxide + $H_2O$ yields 2-Chloroethanol
Basic conditions:
- Epoxide + $NaOCH_3$ yields 2-Methoxyethanol
- Reaction conditions: DMSO, 80 °C, 8 h

Epoxide Mechanism

Mechanism for epoxide ring opening by a strong nucleophile under basic conditions
Ring opening relieves ring strain
Poorly stabilized leaving group
1. $SN_2$ : Nucleophile attacks the epoxide.
2. Proton transfer
Epoxides can undergo $SN_2$ reactions due to the relief of ring strain.

Regiochemistry of Epoxide Ring Opening Under Neutral or Basic Conditions

Under neutral or basic conditions, a nucleophile attacks an epoxide at the less highly alkyl-substituted C atom of the ring, from the side opposite the O atom.

Mechanism for Attack on the Epoxide Under Basic Conditions

Attack occurs at least substituted site.
Less steric hindrance
Backside attack leads to Walden inversion

Reactions of Epoxides under Acidic Conditions

The regiochemistry is different from that observed under neutral or basic conditions.
Under acidic conditions, a nucleophile attacks an epoxide at the more highly alkyl-substituted C atom.

Mechanism for the Reaction of an Epoxide under Acidic Conditions

Mechanism for epoxide ring opening under acidic conditions
1. Proton transfer: Oxygen of epoxide is protonated
2. $SN_2$ : Nucleophile attacks protonated epoxide at the more substituted carbon.
Weaker bond to O on more substituted carbon
Larger $\delta +$ on more substituted carbon

Effect of Protonation on Epoxide Bond Lengths

Larger partial positive charge on more substituted carbon
Longer bond length = weaker bond

Oxymercuration–Reduction: Addition of Water

An alternate method to add water across a double bond is oxymercuration-reduction (also called oxymercuration–demercuration).
Recall that $H_2O$ can add across a C=C double bond in the presence of a strong Brønsted acid catalyst.

Oxymercuration-Reduction Mechanism

Mechanism for the oxymercuration-reduction of an alkene
1. Electrophilic addition: Mercuric acetate adds to the alkene to form a mercurinium ion intermediate
2. $SN_2$ : Water attacks the more substituted carbon.
3. Proton transfer.
4. Add $NaBH_4$ : Sodium borohydride reduces the C atom, replacing the Hg group with an H atom.
This side of the ring bears the larger positive charge.

Syn and Anti Addition

Even though oxymercuration takes place with anti addition, any stereochemistry set up by oxymercuration is scrambled during the reduction step, giving a mixture of both syn and anti addition of water.

Organic Synthesis: Catalytic Hydrogenation of Alkenes

In the presence of a solid metal catalyst such as palladium, platinum, or nickel, $H_2$ gas readily adds to the C=C double bond of an alkene, converting it to a single bond.

Hydrogenation Mechanism

$H_2$ molecule (gas)
Alkene dissolved in solution
$H$ atoms adsorbed onto metal surface
Alkene adsorbed onto metal surface
First $C-H$ bond formed, releasing one $C$ atom
Second $C-H$ bond formed, releasing the second $C$ atom

Hydrogenation of Alkenes

Reaction is thermodynamically favorable
However, large activation energy means no reaction occurs under standard conditions
Requires the use of a catalyst
Hydrogen can be added across alkenes to form alkanes
Heterogeneous catalyst: Palladium on charcoal is an insoluble
Homogeneous catalyst: Wilkinson’s Catalyst $(Rh(PPh_3)Cl)$ is a soluble
Summary: Hydrogenation of alkenes
- $Pd/C (10%) + H_2$ yields alkane
- $Rh(PPh<em>3)Cl (cat.) + H</em>2$ yields alkane

Catalytic Hydrogenation of Alkynes: Poisoned Catalysts

Catalytic hydrogenation of an alkyne can be stopped at the alkene stage by using a stoichiometric amount of $H_2$ and a poisoned catalyst.

Poisoned Catalyst

A poisoned catalyst is simply a metal catalyst that has been specially treated to decrease its catalytic ability, thus making possible a slower and more controlled reaction (allowing a stereospecific hydrogenation).
One example is Lindlar’s catalyst - palladium deposited on calcium carbonate $(CaCO_3)$ and treated with a small amount of quinoline and a lead salt.

Stereospecific Hydrogenation of Alkynes

The reduction of alkynes can be stopped at the alkene using a poisoned palladium catalyst
- Reduces the activity of the palladium
- Slows down the rate of the second reduction to allow the alkene to be isolated
Hydrogenation is a syn-addition, leading to the (Z)-alkene
Lindlar’s catalyst is a common palladium catalyst poisoned with lead $(Pd, CaCO<em>3, Pb(OAc)</em>2$ , and quinoline)
$Alkyne + H_2$ and Lindlar's Catalyst yields Z-Alkene