REACTION MECHANISMS OVERVIEW

I. Alkenes Reaction Mechanisms (Addition Reactions):

- Makovnikovs Rule (Rich gets richer): In the addition of HX: The H atom bonds to the carbon that has more H atoms to begin with, to
form the more stable, more substituted carbocation. In X
2
/H
2
O (halohydrin reaction) X
+
(like H
+
) is added to the C with the most Hs.
1. Hydrohalogenation: (Addition of hydrogen halides; X= Cl, Br)
Mechanism:
2 steps reaction
Rate Determining Step (R.D.S) forms a carbocation.
Rearrangements can occur.
Follow Makovnikovs Rule.
Stereochemistry: Syn and anti addition of H and X occurs.
Example:



2. Hydration: (Addition of H
2
O or ROH)
Mechanism:
3 steps reaction
Rate Determining Step (R.D.S) forms a carbocation.
Rearrangements can occur.
Follow Makovnikovs Rule.
Stereochemistry: Syn and anti addition of H and OH occurs.
Example:




3. Halogenation:
Mechanism:
2 steps reaction
Rate Determining Step (R.D.S) forms a bridged halonium ion.
NO rearrangements can occur. Produced vicinal dihalide.
Stereochemistry: ONLY ANTI ADDITION.
Example:





4. Halohydrin:
Mechanism:
3 steps reaction
Rate Determining Step (R.D.S) forms a bridged halonium ion.
NO rearrangements can occur.
Follow Makovnikovs Rule (The electrophile X
+
bonds to the carbon with the most Hs to begin with)
Stereochemistry: ONLY ANTI ADDITION OCCURS
Example:


5. Hydroboration Oxidation:
Mechanism:
1step reaction: The addition of H and BH
2
occurs all at once.
NO rearrangements can occur.
ANTI Makovnikovs Rule.
Stereochemistry: ONLY SYN ADDTITION. BH
2
bonds to the carbon with the most Hs. OH replaces BH
2
no change in arrangement.
Example:


II. Alkynes Reaction Mechanism (Addition Reactions):
- Tautomers: constitutional isomers that differ in the location of a double bon and a H atom. Two tautomers are at equilibrium with each
other.
An enol tautomer has an OH group bonded to a C=C.
A keto tautomer has a C=O and additional C-H bond.
Tautomerization: the process of converting one tautomer into another.
1. Hydroboration Oxidation:
Mechanism:
ANTI Makovnikovs Rule.
Stereochemistry: The unstable enol first formed after oxidation rearranges to a carbonyl group (Alcohol => aldehyde)
Example:



2. Hydration (Addition of H
2
O)
Mechanism:
Follow Makovnikovs Rule.
Stereochemistry: An unstable enol is first formed which rearranges to a carbonyl group (Alcohol => Ketone).
Example:


3. Hydrohalogenation (addition of hydrogen halides H-X with X= Cl, Br, I):
Mechanism:
Follow Makovnikovs Rule.
Stereochemistry: Both H atoms bond to the same carbon.
Example:




4. Halogenation (Addition of X
2
with X= Cl, Br, I):
Mechanism:
Bridged halonium ions are formed as intermediates (2times)
Follow Makovnikovs Rule.
Stereochemistry: ANTI addition of X
2
occurs.
Example:




III. Substitution and Elimination Reactions:

S
N
2
(Substitution Nucleophilic
Bimolecular)
E2
S
N
1
(Substitution Nucleophilic
Unimolecular)
E1
Kinetics
- 1 step reaction.
- Rate = k[substrate][nuc
-
]
- 2
nd
order reaction





- 1 step reaction.
- Rate = k[substrate][base
-
]
- 2
nd
order reaction

- 2 steps reaction, forming carbocation intermediate.
- Rate = k[substrate]
- 1
st
order reaction

Substrate
Structure
CH
3
X > RCH
2
X

>> R
2
CHX >>>
R
3
CX
In the transition stage, there are 5
things around the carbon => want
the least hindered substrate.
R
3
CX >

R
2
CHX >> RCH
2
X >>>
CH
3
X
Need to make double bond
R
3
CX >

R
2
CHX >> RCH
2
X >>> CH
3
X
Make carbocation intermediate in the R.D.S.
(make double bond)
Nucleophile/
Base
Strong nuc
-
= strong base.
Best nuc
-
has a full (-) charge.
Larger = better.
Less electronegative = better
(Size > electronegativity)



Favor strong base. There are good
nuc
-
that are not strong base to go
E2, e.g.: Cl
-
, Br
-
,I
-
,
-
CN,
-
N
3
,
If a good nuc is also a strong base
=> make the nuc bulky to go E2
E.g.: LDA, KO
t
Bu
The strength of the Nucleophile does not matter since it doesnt
involve in the R.D.S.

S
N
2 E2 S
N
1 E1
Leaving Group
- Best leaving group is weak base (more resonance in better)
- Larger is better
- More electronegative is better. (Size > electronegativity)
(rearrangement can occur in S
N
1 and E1)
Solvent
Polar Aprotic solvent (no H-bonding) works best
E.g.: DMSO, DMF
Polar aprotic solvent solvated the metal cation => give free nuc.
Sometimes, if a polar protic solvent is required tn the reaction that
makes the nuc, E2 and S
N
2 can still happen.
Polar Protic solvent (solvent that has H-bonding) works best.
E.g.: H
2
O, R-OH, acetone
Polar protic solvent stabilizes the LG.
Stereochemistry
The nuc comes in the opposide
side of the LG => invert the
stereochemistry (make the other
enantiomer)
Make double bond. Follow Zaitsev
rule: The major product in
elimination is more substituted.
Favor anti periplanar (H and X
atoms are on opposide sides of the
molecule)
If use a bulky base => some time
only the least hindered H can be
removed => Make Hoffmann
orientation product.
The nuc can come from both side
of the LG => Make racemic
mixture (racemize at the carbon)
Make double bond. Follow
Zaitsev rule: The major product
in elimination is more
substituted.

Other notes
To determine which reaction will occur, look at: SUBSTRATE NUCLEOPHILE (E1 and S
N
1 tent to have neutral nuc while E2 and S
N
2
have (-) charge nuc/base) SOLVENT. Between E2 and S
N
1/E1, there are possibilities of competition when using R
3
CX => look at the
charge nuc to determine which reaction will occur: If (-) = all steps have to be (-) or neutral; If (+) = all steps have to be (+) or neutral. If
neutral nuc = every thing is fair game => look at other thing (e.g.: solvent) to determine.

Examples:
S
N
1:


S
N
2:


E1:


E2:




NOTE: If see a ring (cyclohexane) => draw the chair conformation with the LG in the axial position. Elimination can only occur if there are H
nearby that is also in axial position. If not, substitution reaction will occur.



IV. Alcohols (R-OH), Ethers (R-O-R), and Epoxides:
A. Synthesis reactions:
1. Synthesis of alcohol S
N
2 reaction - works best for CH
3
X and 1
o
RX





2. Williamson Ether Synthesis - works best for CH
3
X and 1
o
RX





3. Intramolecular S
N
2 reaction preparation of eposides




B. Substitutions:
1. Reaction with H-X to form R-X or reaction with H+ and strong base:
Mechanism:
Order of reactivity: R
3
COH > R
2
CHOH > RCH
2
OH
The mechanism for 2
o
and 3
o
ROH is S
N
1 carbocation are intermediates and rearrangements can occur
The mechanism for 1
o
and CH
3
OH is S
N
2
Example:



2. Reaction with other reagents to form RX AVOID MAKING CARBOCATION:
Mechanism:
S
N
2 reaction = DO NOT WORK ON 3
o
alcohol.
If using SOCl
2
=> get R-Cl
If using PBr
3
=> get R-Br
Stereochemistry: S
N
2 - Always add is the opposite side of the LG
Example:


3. Reaction with tosyl chloride (TsCl) to form alkyl tosylates (R-OTs) and reactions of alkyl tosylates:
Mechanism:
Reaction that makes R-OTs: The C-O bond is not broken, so the configuration at a stereogenic center is retained.
Reaction of R-OTs: Substitution with strong nuc => S
N
2 mechanism; Elimination with strong base => E2 mechanism
Example:




4. Reaction of ether: ETHER ONLY GOES DECOMPOSITION WITH STRONG ACID:
Mechanism:
The mechanism for 2
o
and 3
o
ROH is S
N
1 carbocation are intermediates and rearrangements can occur
The mechanism for 1
o
and CH
3
OH is S
N
2
React with 1 equiv H-X = make R-X and R-OH; React with 2 equiv H-X = make R-X and R-X (X= Br or I)
Example:



C. Eliminations (Dehydration to form alkenes):
1. Using strong acid:
Mechanism:
Order of reactivity: R
3
COH > R
2
CHOH > RCH
2
OH
The mechanism for 2
o
and 3
o
ROH is E1 carbocation are intermediates and rearrangements can occur
The mechanism for 1
o
ROH is E2
Follow Zaitsev Rule
Example:




2. Using POCl
3
and pyridine:
Mechanism:
The mechanism is E2 NO CARBOCATION REARRANGEMENTS OCCUR.
Example:



D. Epoxides:
1. Using nuc:
Mechanism:
S
N
2 reaction nuc comes in the least crowded side.
The reaction occurs with backside attack, resulting in TRANS or ANTI products
Example:





2. Using nuc with acid: From intermediate of HO
+
- analogous of halonium bridge:
Mechanism:
With H
+
, the mechanism is between S
N
1 and S
N
2 and Nuc add to the most substituted carbon.
Example:





V. Oxidations and Reductions:
- Oxidation: Loss of es (increased bonds to oxygen or halogen)
- Reduction: Gain of es (increasing bonds to hydrogen)
A. Reductions:
1. Reduction of alkene/alkyne by adding H
2
/Pt: ALWAYS ADD SYN!


2. Reduction of alkynes:
i. Producing cis alkene using Lindlars catalyst:


ii. Producing trans alkene using Na
o
and NH
3
:


3. Hydride reactions:
i. Reduce of halogens:


ii. Reduce of epoxides:

B. Oxidations:
1. Epoxidation of an alkene:


2. Hydroxylation of a alkene (Dihydroxylation):
i. Trans addition: (Using mCPBA to make epoxide and then 1.NaOH/2.H
3
O
+
to make trans alcohols)


ii. Cis addition: (Using OsO
4
and then 1.NaHSO
3
/2.H
2
O to make cis alcohols)


3. Oxidative cleavage: (Using 1.O
3
/2.CH
3
SCH
3
or KMnO
4
,H
2
O and H
+
)
i. Alkynes: Make ketones and/or aldehyde

ii. Alkynes:
a. Internal alkyne: Make carboxylic acids


b. Terminal alkyne: Make carboxylic acid and CO
2


4. Oxidation of Alcohols (Using K
2
Cr
2
O
7
, or NaCr
2
O
7,
or CrO
3
/H
+
, or KMnO
4
, or PCC)
i. 3
o
alcohols: NO REACTION!!! No H atoms on the carbon with the OH group!!!!
ii. 2
o
alcohols: Make ketone


iii. 1
o
alcohols:
a. With K
2
Cr
2
O
7
, or NaCr
2
O
7,
or CrO
3
/H
+
, or KMnO
4
=> Make carboxylic acid


b. With PCC => Make aldehyde


VI. Radical Reactions:
- A radical: a reactive intermediate with a single unpaired electron.
- Acarbon radical: sp
2
hybridized and trigonal planar.
- Stability (based on hyperconjugation): Allylic (best with stabilized resonance) > 3
o
> 2
o
> 1
o
> CH
3
.


- The compound with the lowest bond dissociation energies will form the most stable radical!


1. Halogenation of alkanes:
Mechanism:
Follow a radical chain mechanism with initiation, propagation, and termination
The weaker the C-H bond, the more readily the H is replaced by X.
Chlorination is faster and less selective then bromination. (More detail in Hammond Postulate section)
Stereochemistry: Radical substitution at a stereogenic center results in racemization.
Example:
Chlorination











Bromination
- Hammond Postulate: In any given reaction steps, the transition state looks most like the highest energy species.
Exothermic reactions
The transition state is not much radical character. Therefore, 3
o
, 2
o
, or
1
o
doesnt matter much!




Endothermic Reaction
The transition state has lots of radical character. Therefore, endothermic
reactions are more specific and strongly favor the most stable intermediate.

2. Radical addition of HBr to an alkene:
Mechanism:
A radical addition mechanism is followed.
Br bonds to the less substituted carbon atom to form the more substituted, more stable radical.
Example:






3. Radical polymerization of alkenes:
Mechanism: Follow a radical addition mechanism
Example: