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Chapter 9: Elimination Reactions of Alkyl Halides:
Competition between Substitutions and
Eliminations
GoalsAfter this chapter, you should be able to:
Predict products of E2 and E1 reactionsDetermine stereochemistry of E2/E1 ProductsDetermine whether SN2, SN1, E1 or E2 will occur
What is an SN2 Reaction?SN2 mechanism; S for substitution, N for nucleophilic and 2 because two molecules collide at the critical point in the reaction.
Review: An SN2 Reaction
Stereochemistry of Inversion
If the nucleophile and the leaving group are both high in the R/S priority order, this means that an R alkyl halide gives an S product, and vice-versa
Energy of Inversion
Energy of Inversion
With SN2, Size of Substituent Groups
Matters
Relative Reactivity Toward SN2tertiary < secondary < primary < methyl
Kinetics of Nucleophilic Substitution
Rate = k[RBr][Nu-]Second order kinetics
Effect of Bond Strength of the Leaving Group on SN2
ReactivitySince the carbon-halogen bond strength increases up the periodic table the relative SN2 reactivity of the alkyl halide is:
RF < RCl < RBr < RITosO- is a better leaving group than
I-
OH-, NH2-, and RO- are worse than F-
Nucleophilicity:
CH3CO2 (-) < Cl(-) < Br(-) < N3
(-) < CH3O(-) < CN(-) < I(-) < SCN(-) < CH3S
(-)
NucleophilicityParallels basicity
H2O < C2H3O2- < OH-
Increases down the periodic tableI- < Cl- < F-
Anions are more nucleophilic than neutral compoundsThe solvent matters!
Solvent EffectsConsider KBr as a nucleophile sourceProtic solvents with –OH, -NH slow SN2 rxn
These solvents cluster around the nucleophile lowering the effective nucleophilicity
Polar aprotic solvents speed SN2
These solvents cluster around the metal ion of the salt freeing the nucleophile to be nucleophilic.
Characteristics of SN2 Reactions
Single Step MechanismInversion of configuration SN2 reactions are generally reliable only when the alkyl halide is primaryHalogen is generally Cl or Br since
C-F bond is too strongC-I bond is weak and compounds are unstable
An SN2 Reaction
SN1 ReactionsSN1 reactions proceed by a two step mechanism
First: Leaving group leaves giving a carbocation
Second: Nucleophile attacks carbocation
R
C
R
BrR
R
C
R
+ Br-R
R
C
R
R + H2O
R
C
R
R OH + H+
Review: An SN1 Reaction
SN1 Reactions
H
C
H
BrH
R
C
H
BrH
R
C
R
BrH
R
C
R
BrR< < <
Relative Reactivity Toward SN1
Leaving GroupsOH- < NH2
-<RO- F - < Cl - < Br - < I < TosO-
Susceptibility to leaving
Evidence for SN1 KineticsThe reaction rate is only dependent upon the concentration of the substance with the leaving group
R-X R+ + X- is a slow = rate determining
Racemic mixtures are usualCarbocation formation
Rate = k[R-X] where X is leaving group
SN1 Reaction RatesDepend on stability of the carbocation
More stable carbocation=faster reaction
-CH3 < 1° < 2° < 3°
Relative Stability of Carbocation
H2C CCH2
HCH2
The Nucleophile and SN1
NO EFFECT!
R
C
R
BrR
R
C
R
RFAST
R
C
R
R
R
C
R
R OH + H+
+ Br-
+ H2O
SLOW
Energy for SN1
Solvent Effects on SN1Polar solvents stabilize the intermediate carbocation.
R
C
R
R O
H
H
OH
HO
H
H
OH
H
Summary SN1Fastest with
Compounds that form stable carbocationGood leaving groupNucleophiles that are not basic to prevent competing elimination reactionsPolar solvents
An SN1 Reaction
Elimination ReactionsZaitsev’s Rule:
Base induced elimination reactions generally give the more highly substituted double bond alkene product
H3C C
H
H3C Br
CH3
H
H3C C
H
H3C
CH2
H
H3CC
H3C
CH3
H
An E2 Reactions
E2 ReactionsSingle step attack of nucleophile on hydrogen on carbon adjacent to the carbon containing the leaving group.
H3C C
H
H3C Br
CH3
H
H3C C
H
H3C
CH2
H
H3CC
H3C
CH3
H
E2 KineticsThe rate of the reaction is dependent upon the concentration of the compound containing the leaving group and the nucleophile base.Rate = k[RX][Base]
Geometry of E2All atoms involved are in same planeThe hydrogen and leaving group are anti
H3C C C
H
H3C Br
CH3
H
Cycloalkane E2: What do you expect?
Br
H
RKOH
BrHR
KOH
E2 ReactionBr
H
RKOH
BrHR
KOH
R
No Reaction
An E2 Reactions
Zaitsev’s Rule LimitationsDon’t use for conjugated double bonds.You can trick the reaction into favoring the least substituted alkene by using a Bulky base.
C
Br
CH2
C H3
C H3
CH3C
C H3
O–
CH3
C H3
+
Zaitsev’s Rule LimitationsDon’t use for conjugated double bonds.You can trick the reaction into favoring the least substituted alkene by using a Bulky base.
CH
C H3C
C H3
CH3
CH2
C H3C
C H3
CH2
C
Br
CH2
C H3
C H3
CH3C
C H3
O–
CH3
C H3
+
E1 ReactionsFirst step is identical to SN1 – Elimination of the leaving group giving a carbocationFirst step is slow and rate determiningSecond step is the attack of a hydrogen on a carbon adjacent to the carbocationRacemic mixtures are usual
The E1 Reaction
E1 KineticsRate = k[R-X]
CH3
C
CH3
H3C BrCH3
C
CH3
H3C + Br-
CH3
C
CH3
H3C Br
CH3
C
CH2
H3C
H
HO
H
CH3
C
CH2
H3C
E
Nucleophile Anionic Nucleophiles(Weak Bases)(RS-, SCN-, I-, Br-, N3
-, CN- etc.)
Anionic Nucleophiles(Strong Bases: HO-, RO-)
Neutral Nucleophiles(H2O, ROH, RSH, R3N)
Alkyl Group
Primary
RCH2-
Rapid SN2 substitution. The rate may be reduced by substitution of -carbons, as in the case of neopentyl.
Rapid SN2 substitution. E2 elimination may also occur.e.g. ClCH2CH2Cl + KOH ___> CH2=CHCl
SN2 substitution. (N S >>O)
Secondary
R2CH-
SN2 substitution plus E2 elimination (depends on basicity of the nucleophile). The rate of substitution may be reduced by branching at the -carbons, and this will increase elimination.
E2 elimination will dominate. SN2 substitution. (N S >>O)In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be formed slowly.
Tertiary
R3C-
E2 elimination will dominate with most nucleophiles (even if they are weak bases). No SN2 substitution due to steric hindrance. In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be expected.
E2 elimination will dominate. No SN2 substitution will occur. In high dielectric ionizing solvents SN1 and E1 products may be formed.
E2 elimination with nitrogen nucleophiles (they are bases). No SN2 substitution. In high dielectric ionizing solvents SN1 and E1 products may be formed.
Allyl
H2C=CHCH2-
Rapid SN2 substitution for 1° and 2°-halides. For 3°-halides a very slow SN2 substitution or, if the nucleophile is moderately basic, E2 elimination. In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be observed.
Rapid SN2 substitution for 1° halides (note there are no hydrogens. E2 elimination will compete with substitution in 2°-halides, and dominate in the case of 3°-halides. In high dielectric ionizing solvents SN1 and E1 products may be formed.
Nitrogen and sulfur nucleophiles will give SN2 substitution in the case of1° and 2°-halides. 3°-halides will probably give E2 elimination with nitrogen nucleophiles (they are bases). In high dielectric ionizing solvents SN1 and E1 products may be formed. Water hydrolysis will be favorable for 2° & 3°-halides.
Benzyl
C6H5CH2-
Rapid SN2 substitution for 1° and 2°-halides. For 3°-halides a very slow SN2 substitution or, if the nucleophile is moderately basic, E2 elimination. In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be observed.
Rapid SN2 substitution for 1° halides (note there are no hydrogens. E2 elimination will compete with substitution in 2°-halides, and dominate in the case of 3°-halides. In high dielectric ionizing solvents SN1 and E1 products may be formed.
Nitrogen and sulfur nucleophiles will give SN2 substitution in the case of1° and 2°-halides. 3°-halides will probably give E2 elimination with nitrogen nucleophiles (they are bases). In high dielectric ionizing solvents SN1 and E1 products may be formed. Water hydrolysis will be favorable for 2° & 3°-halides.
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