Post on 20-Oct-2020
Ch.11 Nucleophilic Substitutions and Eliminations
X
Cδ+
δ-
electrophilic site
XCNu- Nu C
- nucleophilic substitution and base-induced elimination of alkyl halides
Substitution
Ch.11 Nucleophilic Substitutions and Eliminations
H
C
X
C
B-
C C B-H + X-+
Elimination
Ch.11 Nucleophilic Substitutions and Eliminations
11.1 The Discovery of Walden Inversion
In 1896, Walden discovered pure enantiomeric (+)- and (-)-malic acids could be interconverted by a series of simple substitution reactions.
HOOCCOOH
OH
(-)-Malic acid
[α]D = -2.3o
PCl5 HOOCCOOH
Cl(+)-Chlorosuccinic acid
Ag2O, H2O
HOOCCOOH
OH
(+)-Malic acid
[α]D = +2.3o
PCl5HOOC
COOH
Cl(-)-Chlorosuccinic acid
Ag2O, H2O
Et2O
Et2O
Walden's cycle of reactions interconverting (+)- and (-)-malic acids
necleophilic substitution reactions
Ch.11 Nucleophilic Substitutions and Eliminations
11.2 Stereochemistry of Nucleophilic Substitution
In 1920s, Kenyon and Philips: mechanism of nucleophilic substitution reactions
YR
Substitution
Nu- NuR + Y-
Y = Cl, Br, I, OTs
Nu = nucleophile S CH3O
OO = OTs
Ch.11 Nucleophilic Substitutions and Eliminations
Interconverting (+)- and (-)-1-phenyl-2-propanol
OH H
(+)-1-Phenyl-2-propanol[α]D = +33.0
o
OH Ts
[α]D = +31.1o
TsCl
pyridine+ HCl
HO
[α]D = -7.06o
CH3COO-
+ -OTs
O CH3
OH
CH3O
HO
(-)-1-Phenyl-2-propanol[α]D = -33.2
o[α]D = -31.0
o
+HClTsCl
pyridine
CH3COO-
+-OTs
H2O, -OH
+ CH3COO-
H
HOTs
[α]D = +7.0o
Ch.11 Nucleophilic Substitutions and Eliminations
Inversion of stereochemistry in the nucleophilic substitution step
OH Ts
[α]D = +31.1o
HO
[α]D = -7.06o
CH3COO-
+ -OTs
O CH3Inversion of configuration
Ch.11 Nucleophilic Substitutions and Eliminations
11.3 Kinetics of Nucleophilic Substitution
Reaction rate: a useful tool in the mechanism studies
BrH3C OHH3C + Br-HO- +
Kinetics: measure the relationship between reaction rate and reactant concentrations
reaction rate = rate of disappearance of reactant
= k x [RX] x [-OH] k = a constant
Second-order reaction: the reaction rate is linearly dependent on the concentration of two species
Ch.11 Nucleophilic Substitutions and Eliminations
11.4 The SN2 Reaction
Nucleophilic substitution reactions:
1. Inversion of stereochemistry at the carbon center2. The reaction show second-order kinetics
Rate = k x [RX] x [Nu-]
SN2 reaction: substitution, nucleophilic, bimolecular; bimolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.
Ch.11 Nucleophilic Substitutions and Eliminations
BrC
H
H3CH3CH2C
HO C
H
CH3CH2CH3
BrC
A
BC
HOδ- δ-
HO-
In 1937, Hughes and Ingold; suggested a SN2 mechanism
- Inversion of stereochemistry: back-side attack of nucleophile from a direction 180o away from the leaving group
- Second-order kinetics: SN2 reaction occurs in a single step and two molecules are involved in the step
Ch.11 Nucleophilic Substitutions and Eliminations
Brno substitution reaction with -OH
• evidence for back-side SN2 displacement
Why ?
Ch.11 Nucleophilic Substitutions and Eliminations
11.5 Characteristics of the SN2 Reaction
The effects of changes in reactant and transition-state energy levels on reaction rate.
∆G
∆G∆G ∆G
A higher reactant energy level: faster reaction (smaller ∆G‡)
A higher transition state energy level: slower reaction (higher ∆G‡)
• reaction rate is determined by ∆G‡
• reactant and transition energy levels can affect the reaction rate
Ch.11 Nucleophilic Substitutions and Eliminations
A. The Substrate: Steric Effects in the SN2 Reaction
Since the SN2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, stericallyhindered alkyl halides are less reactive.
SN2 variables
BrC
H3C
H3C
H3CBrC
H3C
H3C
HBrC
H
H3C
H
Ch.11 Nucleophilic Substitutions and Eliminations
The Substrate: Steric Effects in the SN2 Reaction
SN2 reactions can occur only at relatively unhindered sites: methyl halides, 1o halides, a few simple 2o halides
CH
HH3CC
H
CH3H3CC
CH3
CH3H3C
primarysecondarytertiary
reactivity
CH
HH
methyl
more reactiveless reactive
BrBrBrBr CCH3
CH3H3C
neopentyl
CH2 Br
40,000500
Ch.11 Nucleophilic Substitutions and Eliminations
sp2 hybrid carbons: vinylic, aryl halides are unreactive toward SN2 reaction
• the approach from the back side in the C=C double bond plane is inaccessible
C CR R
R Cl
Nu-X Cl
Nu-
X
Ch.11 Nucleophilic Substitutions and Eliminations
B. The Attacking Nucleophile
Nucleophiles: have an unshared pair of electrons (Lewis base); neutral or negatively charged
Nu:- + R Y +R Nu Y:-
Negatively charged Nu:-
neutral
Nu: + R Y +R Nu Y:-
Neutral Nu:-
positively charged
Ch.11 Nucleophilic Substitutions and Eliminations
H3C Br+Nu:- Nu CH3 + Br-
CH3S
HS
N C
N N N
I
CH3O
HO
Cl
H3N
CH3CO2(CH3)3N
H
Methanethiolate
Hydrosulfide
Cyanide
Azide
Iodide
Methoxide
Hydroxide
Chloride
Ammonia
Acetate
trimethyl amine
Hydride
CH3S
HS
N C
N N N
I
CH3O
HO
Cl
H3N
CH3CO2(CH3)3N
H
CH3CH3
CH3
CH3CH3
CH3
CH3
CH3
CH3CH3
CH3
CH3
Br-
Br-
Nucleophiles
Ch.11 Nucleophilic Substitutions and Eliminations
Nucleophilicity: depends on the substrate, the solvent, the reactant concentration...
nucleophilicity
H3C Br+Nu:- Nu CH3 + Br-
HSN CICH3OHOClH3NCH3CO2H2O
1 500 700 1,000 16,000 25,000 100,000 125,000 125,000
nucleophilicityless
nucleophilicmore
nucleophilic
Trends in nucleophilicity: complete explanations aren't known
Ch.11 Nucleophilic Substitutions and Eliminations
• Nucleophilicity roughly parallels basicity:because "nucleophilicity" measures the affinity of a Lewis base for a carbon atom in the SN2 reaction, and "basicity" measures the affinity of a base for a proton
CH3O HO CH3CO2 H2ONucleophileRate of SN2 reaction with CH3BrpKa of conjugate acid
25
15.5
16 0.5 0.001
15.7 4.7 -1.7
Correlation of Basicity and Nucleophilicity
Ch.11 Nucleophilic Substitutions and Eliminations
• Nucleophilicity usually increases going down a column of the periodic table: due to increased polarizability
HS- > HO-I- > Br- > Cl-
• Negatively charged nucleophiles are usually more reactive than neutral ones.; As a result, SN2 reactions are often carried out under basic conditions rather than neutral or acidic conditions.
HO- > H2O
Ch.11 Nucleophilic Substitutions and Eliminations
C. The Leaving Group
Good leaving groups:- well-stabilized negative charge; stable anions- weaker base: the stability of an anion is inversely related to the basicity
leaving group ability
OH-, OR-
Ch.11 Nucleophilic Substitutions and Eliminations
Poor leaving groups: F-, OH-, OR-, NR2- are not displaced by nucleophiles
R F R OH R OR' R NH2
YC Nu CYCNuδ- δ-
Nu:- + Y:-
Transition State(Negative charge is delocalized
over both Nu- and Y
The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction
Ch.11 Nucleophilic Substitutions and Eliminations
D. The Solvent
Protic solvents; those contain -OH or -NH groups- are generally the worst solvent
protic solvents: CH3OH, EtOH
X:-H
H HH
OR
OR
OR
ROA solvated anion
(reduce nucleophilicity due to enhanced ground-state stability)
Solvation: solvent molecules hydrogen bond to the nucleophile, orienting themselves into a "cage" around it and thereby lowering its reactivity
Ch.11 Nucleophilic Substitutions and Eliminations
n-Bu-Br + N3- n-Bu-N3 + Br
-
solvent CH3OH H2O DMSO DMF CH3CN HMPA
relativereactivity 1 7 1,300 2,800 5,000 200,000
solvent reactivitymore
reactiveless
reactive
Polar aprotic solvents; have strong dipoles but no -OH or -NH groups are the best for SN2 reaction- CH3CN, DMF (Me2NCHO), DMSO (Me2SO), HMPA [((Me2N)3PO]- increased solubility of salts- solvate metal cations rather than nucleophiles→ the bare unsolvatedanions have greater nucleophilicity
Ch.11 Nucleophilic Substitutions and Eliminations
A Summary of SN2 Reaction Characteristics
Substrates Steric hindrance raises the energy of the transition state, thus increasing ∆G‡ and decreasing the reaction rate. As a result, SN2 reactions are best for methyl and primary substrates.
Nucleophile More reactive nucleophiles are less stable and have a higher ground-state energy, thereby decreasing ∆G‡ and increasing the reaction rate. Basic, negatively charged nucleophiles are more reactive than neutral ones.
Ch.11 Nucleophilic Substitutions and Eliminations
A Summary of SN2 Reaction Characteristics
Leaving group
Good leaving groups (more stable anions) lower the energy of the transition state, thus decreasing ∆G‡and increasing the reaction rate.
Solvents Protic solvents solvate the nucleophile, thereby lowering its ground-state energy, increasing ∆G‡, and decreasing the reaction rate. Polar aprotic solvents surround the accompanying cation but not the nucleophilic anion, thereby raising the ground-state energy of the nucleophile, decreasing ∆G‡, and increasing the reaction rate.
Ch.11 Nucleophilic Substitutions and Eliminations
Reaction energy diagram;- substrate and leaving group affect the transition states- nucleophile and solvent affect the reactant ground states
hinderedsubstrate
unhinderedsubstrate
poor leavinggroup
good leavinggroup
Ch.11 Nucleophilic Substitutions and Eliminations
Reaction energy diagram;- substrate and leaving group affect the transition states- nucleophile and solvent affect the reactant ground states
goodnucleophile
poornucleophile
polar aproticsolvent
proticsolvent
Ch.11 Nucleophilic Substitutions and Eliminations
11.6 The SN1 Reaction
CH
HH3C C
H
CH3H3C C
CH3
CH3H3C
primary secondary tertiary
reactivity
CH
HH
methyl
more reactiveless reactive
Br Br Br Br
121
Ch.11 Nucleophilic Substitutions and Eliminations
11.7 Kinetics of the SN1 Reaction
reaction rate = rate of disappearance of alkyl halide
= k x [RX] k = a constant
First-order reaction: the reaction rate is linearly dependent on the concentration of only one species; the concentration of the nucleophiledoes not appear in the rate expression
Rate-determining step (rate-limiting step): the slowest step in a successive steps of a multi-step reaction- no reaction can proceed faster than its rate-determining step- the overall reaction rate measured in kinetic experiments is determined by the height of the highest energy barrier
Ch.11 Nucleophilic Substitutions and Eliminations
∆G
1st step is RDS
∆G1
2nd step is RDS
Ch.11 Nucleophilic Substitutions and Eliminations
C
CH3
CH3
H3C Br
mechanism of SN1 reaction
C
CH3
CH3
H3C
+ Br-
OH2RDS
fastC
CH3
CH3
H3C OH
H
C
CH3
CH3
H3C O H
OH2
+ H3O+
• spontaneous dissociation of the leaving group occurs in a slow, rate-limiting step to generate a carbocation intermediate
Ch.11 Nucleophilic Substitutions and Eliminations
∆G
RX + Nu:-
R+ + X-
RNu+ X:-
• spontaneous dissociation of the leaving group occurs in a slow, rate-limiting step to generate a carbocation intermediate
Ch.11 Nucleophilic Substitutions and Eliminations
11.8 Stereochemistry of the SN1 Reaction
X
A
CB
A
CB
Nu- Nu-
Nu
A
CBNu
A
C B
planar, achiral50% inversion of configuration
50% retention ofconfiguration
carbocation intermediate: sp2-hybridized, planar, achiral
Ch.11 Nucleophilic Substitutions and Eliminations
CH3Cl H2O
EtOH
CH3HO OHH3C+
40% R(retention)
(R) 60% S(inversion)
- 80% racemized- 20% inverted
Only few SN1 reactions occur with complete racemization.Most give a minor (0-20%) excess of inversion.
Generally, SN1 reaction of enantiomerically pure substrates lead to racemicproducts.
Ch.11 Nucleophilic Substitutions and Eliminations
Ion pair (proposed by Saul Winstein): dissociation of the substrate occurs to give a structure in which the two ions are still loosely associated and in which the carbocation is effectively shielded from nucleophilicattack on one side by the departing anion.
X
A
CB
A
CB
Nu- Nu
A
C B
ion pair
X
shieldedopen
more inversion product
Ch.11 Nucleophilic Substitutions and Eliminations
11.9 Characteristics of the SN1 Reaction
• factors that lower ∆G‡, either by lowering the energy level of the transition state or by raising the energy level of the ground state, favor SN1 reactions
A. The Substrate
Hammond postulate: any factor that stabilizes a high-energy intermediate should stabilize the transition state leading that intermediate.; the rate-limiting step in the SN1 reaction is carbocation-formation step; The more stable the carbocation intermediate, the faster the SN1 reaction.
Ch.11 Nucleophilic Substitutions and Eliminations
allylic carbocation
CH2 H2C
Allylic, benzylic carbocation: resonance stabilized,
benzylic carbocation
CH2 CH2 CH2 CH2
Ch.11 Nucleophilic Substitutions and Eliminations
Allylic, benzylic substrates: highly reactive in SN2 and SN1 reactions
Carbocation stability:
~
Ch.11 Nucleophilic Substitutions and Eliminations
B. The Leaving Group
- same reactivity as in SN2 reaction
leaving group ability
H2O
leaving group reactivityless
reactivemore
reactive
Cl- Br- I- TsO-
- neutral water is leaving group in SN1 reaction of alcohols under acidic conditions
Ch.11 Nucleophilic Substitutions and Eliminations
C
CH3
CH3
H3C OH
mechanism of SN1 reaction
+ Br-
C
CH3
CH3
H3C
C
CH3
CH3
H3C Br
+ OH2
HBrC
CH3
CH3
H3C OH
HBr-
RDS
fast
Ch.11 Nucleophilic Substitutions and Eliminations
C. The Nucleophile
• nucleophile is not involved in the RDS, thus does not affect the reaction rate
C
CH3
CH3
H3C OH C
CH3
CH3
H3C Br+ HX + H2O
same rate for X = Cl, Br, I
• Neutral nucleophiles are just as effective as negatively charged ones, so SN1 reactions frequently occur under neutral or acidic conditions. (not under basic conditions)
Ch.11 Nucleophilic Substitutions and Eliminations
D. The Solvent
Solvent effectSN2 reaction: due largely to stabilization or destabilization of the nucleophile reactantSN1 reaction: due largely to stabilization or destabilization of the transition state
HO
H
C
HO H
HOH
HO
HHO H
HOH
Solvation of carbocation: the electron rich oxygen atoms of solvent molecules orient around the positively charged carbocation and thereby stabilize it.
Ch.11 Nucleophilic Substitutions and Eliminations
Dielectric polarization (P): express solvent polarity; measure the ability of a solvent to act as an insulator of electric charges
Aprotic solvents
HexaneBenzeneDiethyl etherChloroformHMPADMFDMSO
1.9 2.3 4.3 4.8303848
Protic solvents
Acetic acidEthanolMethanolFormic acidWater
6.224.333.658.080.4
Polar solvents (water, methanol, DMSO) are good at solvating ions,nonpolar ether, hydrocarbon solvents are very poor at solvating ions
Ch.11 Nucleophilic Substitutions and Eliminations
• SN1 reactions take place much more rapidly in polar solvents than in nonpolar solvents
C
CH3
CH3
H3C Cl C
CH3
CH3
H3C OR+ ROH + HCl
relaticereactivity
EtOH 40% H2O / 60% EtOH80% H2O / 20% EtOH Water
1 100 14,000 100,000
Ch.11 Nucleophilic Substitutions and Eliminations
Large solvent effect but different reasons;
∆G∆G
R+
nonpolarsolvent
polarsolvent RNu + :X-
RX + :Nu-
The effect of solvent on SN1 reaction
SN1 reaction: favored in protic solvents beacuse the transition-state energy leading to carbocation intermediate is lowered by solvation
Ch.11 Nucleophilic Substitutions and Eliminations
Large solvent effect but different reasons;
polar aproticsolvent
proticsolvent
The effect of solvent on SN2 reaction
SN2 reaction: disfavored in protic solvents beacuse the ground-state energy of the attacking nucleophile is lowered by solvation
Ch.11 Nucleophilic Substitutions and Eliminations
A Summary of SN1 Reaction Characteristics
Substrates The best substrates yield the most stable carbocations. As a result, SN1 reactions are best for tertiary, allylic, and benzylic halides.
Nucleophile The nucleophile must be nonbasic to prevent a competitive elimination of HX but otherwise does not affect the reaction rate. Neutral nucleophileswork well.
Leaving group
Good leaving groups (more stable anions) increase the reaction rate by lowering the energy of the transition state leading to carbocation formation.
Solvents Polar solvents stabilize the carbocation intermediate by solvation, thereby increasing the reaction rate.
Ch.11 Nucleophilic Substitutions and Eliminations
11.10 Elimination Reactions of Alkyl Halides: Zaitsev's Rule- most strong nucleophiles are also strong bases
Substitution
H
C
Br
CHO-
+ Br-
H
C
OH
C
- elimination reactions are more complicated than substitution: mixtures of alkenes
Elimination
H
C
Br
C C C H2O + Br-+
HO-
Ch.11 Nucleophilic Substitutions and Eliminations
Zaitsev's rule In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates.
Br
NaOEt
EtOH+H3CHC CHCH3
81% 19%
Br
NaOEt
EtOH+H3CHC CCH3
70% 30%
CH3
Ch.11 Nucleophilic Substitutions and Eliminations
11.11 The E2 Elimination Reactions; elimination, bimolecular
E2 elimination occurs when an alkyl halide treated with a strong base (HO-, RO-)
H
C
X
C C C
B+-H + X-+B:
H
C
X
C
Bδ+
δ-
E2 elimination: one step, concerted mechanism
Rate = k x [RX] x [Base]
Evidence for concerted mechanism: second-order kinetics, stereochemistries of products
Ch.11 Nucleophilic Substitutions and Eliminations
E2 reaction occurs with a periplanar geometry; H-C-C-X are in the same plane; two periplanar geometries are possible
H
C
X
C
X
H
anti periplanar geometry(staggered, lower energy)
H
C
X
C
XH
syn periplanar geometry(eclipsed, higher energy)
Ch.11 Nucleophilic Substitutions and Eliminations
anti periplanar reactant
H
X
anti periplanar TS
H
X
B
Overlap of the developing p orbitals in the transition state requires anti periplanar geometry of the reactant.
Ch.11 Nucleophilic Substitutions and Eliminations
Similarity between SN2 and E2 mechanism
E2 reaction(anti periplanar)
XCNu
SN2 reaction(back-side attack)
CHC X
- an electron pair from nucleophile or C-H bond pushes the leaving group on the opposite site
Ch.11 Nucleophilic Substitutions and Eliminations
H
C
PhBr Br
C
H Ph
Br
Ph HH
PhBr KOH
EtOH
HO-
BrPh
PhH
(Z)
- Antiperiplanar geometry for E2 elimination: the stereochemistry of an E2 elimination product depends on the stereochemistry the reactant
Ch.11 Nucleophilic Substitutions and Eliminations
11.12 Elimination Reactions and Cyclohexane Conformation
H
Cl
H
HCl
H
Cl
H
base
E2+
axial chlorine: H and Cl are anti periplanar
Derek H. R. Barton, 1950; much of the chemical reactivity of substituted cycloalkanes is controlled by their conformation.
Conformation and reactivity
Ch.11 Nucleophilic Substitutions and Eliminations
Conformation and reactivity
H
H
ClH
Hbase
E2
H
Cl
H
H
H
equatorial chlorine: H and Cl are not anti periplanar
No reaction fromthis conformation
Ch.11 Nucleophilic Substitutions and Eliminations
Cl
NaOEt
EtOHfast
Neomenthyl chloride 78 : 22
+
Conformation and reactivity of cyclohexane
Cl
NaOEt
EtOH
slow
Menthyl chloride only
Ch.11 Nucleophilic Substitutions and Eliminations
Cl
HH
NaOEt
trans diaxial
- consider most stable chair conformation first: i-Pr is equatorial- check antiperiplanar geometry: trans diaxial conformation is required for E2 elimination in cyclohexane systems
78 : 22
+
more substituted product formed as major
Ch.11 Nucleophilic Substitutions and Eliminations
Conformation and reactivity of cyclohexane
Cl
NaOEt
EtOH
slow
Menthyl chloride only
200 times slower rate than neomenthyl chloride
Ch.11 Nucleophilic Substitutions and Eliminations
H3C
ClH
HHring-flip
X
No reaction
no antiperiplanar HClCH3
H
only
:B
trans diaxial
CH3
H3C
Ch.11 Nucleophilic Substitutions and Eliminations
11.13 The Deuterium Isotope Effect
CH
HCH2Br
baseCH CH2
CD
DCH2Br
baseCD CH2
Faster reaction
Slower reaction
Deuterium isotope effect: Because a C-H bond is weaker than a C-D bond by 5 kJ/mol (1.2 kcal/mol), a C-H bond is more easily broken than an equivalent C-D bond, and the rate of C-H bond cleavage is faster.
Ch.11 Nucleophilic Substitutions and Eliminations
- support the one-step mechanism of E2 elimination
- the base-induced elimination of HBr is 7.11 times faster thancorresponding DBr elimination
; this result tells us that the C-H (or C-D) bond is broken in the rate limiting step.
; if it were otherwise, we couldn't measure a rate difference
Ch.11 Nucleophilic Substitutions and Eliminations
11.14 The E1 Elimination; elimination, unimolecular
C
CH3
CH3
H3C Br
mechanism of E1 reaction
C
H2C
CH3
H3C
+ Br-
RDSH
base
fastC
CH2
CH3
H3C
Ch.11 Nucleophilic Substitutions and Eliminations
- E1 and SN1 reactions normally occur in competition whenever an alkyl halide is treated in a protic solvent with a nonbasic nucleophile- the best E1 substrates are also the best SN1 substrates, and mixtures of substitution and elimination products are usually obtained.
C
CH3
CH3
H3C ClH2O
EtOH65oC
C
CH3
CH3
H3C OH C
CH2
CH3
H3C+
64 : 36
Ch.11 Nucleophilic Substitutions and Eliminations
Rate = k x [RX]
Evidence for E1 mechanism- first-order kinetics
- no geometry requirement for E1 elimination - the more stable alkene is formed
- no deuterium isotope effect for E1 reaction: C-H bond cleavage is not the RDS
Ch.11 Nucleophilic Substitutions and Eliminations
ClCH3
HH3C
ClH
HHring-flip
CH3
H3C H3C
1M NaOEtEtOH100oC
+
E2 conditions0.01M NaOEt80% aq.EtOH
160oCE1 conditions
100%68% 32%
Ch.11 Nucleophilic Substitutions and Eliminations
11.15 Summary of Reactivity: SN1, SN2, E1, E2
There is no clear answers.
favored when bases are used
occurs in competition
with SN1no rxn
favored in hydrolytic
solventsR3CX
favored with strong base
can occur with benzylic and allylic halides
occurs in competition
with E2
can occur with benzylic and allylic halides
R2CHX
occurs with strong baseno rxn
highly favoredno rxnRCH2X
E2E1SN2SN1Halide type
Ch.11 Nucleophilic Substitutions and Eliminations
• Primary alkyl halides: - SN2 substitution with good nucleophiles (RS-, I-, CN-, NH3, Br-)- E2 elimination with strong, hindered base (t-BuOK)
BrNaCN
THF-HMPA CN
BrKOt-Bu
90%
85%
Ch.11 Nucleophilic Substitutions and Eliminations
• Secondary alkyl halides: SN2 and E2 compete- SN2 substitution: weakly basic nucleophiles in polar aprotic solvent- E2 elimination: strong base (EtO-, HO-, NH2-)
Br
NaOAc
(weak base)
OAc+
100 : 0
NaOEt
(strong base)
OEt+
20 : 80
- allylic, benzylic halides: SN1 and E1 can occur with weakly basic nucleophiles in protic solvents (EtOH, AcOH)
Ch.11 Nucleophilic Substitutions and Eliminations
• Tertiary alkyl halides: - E2 elimination: base (RO-, HO-)- SN1 and E1: under neutral, hydrolytic condition
C
CH3
CH3
H3C Br
NaOEt
EtOHC
CH3
CH3
H3C OEt C
CH2
CH3
H3C+
3 : 97
EtOH
heatC
CH3
CH3
H3C OEt C
CH2
CH3
H3C+
80 : 20
Ch.11 Nucleophilic Substitutions and Eliminations
Practice
Cl NaOMe
MeOH
Br
HCO2H
H2O
OCHO
Ch.11 Nucleophilic Substitutions and Eliminations
11.16 Substitution Reactions in Synthesis
substitution reaction is the key bond forming reaction in organic synthesis
R NaR'CH2X
R CH2R' + NaX
X = Br, I, OTs
Examples studied
R Na R +
Br
7 : 93SN2 E2
Ch.11 Nucleophilic Substitutions and Eliminations
Examples studied
C
CH3
CH3
H3C OH
+ Cl-
C
CH3
CH3
H3C
C
CH3
CH3
H3C Cl
+ OH2HCl
C
CH3
CH3
H3C OH
H
Cl-SN1
H3CH2C OHHCl
H3CH2C OH2
Cl-
H3CH2C Cl + H2O
SN2
Ch.11 Nucleophilic Substitutions and Eliminations
RCH2 OHPBr3
RCH2HO
Br-SN2
PR'2 RCH2 Br
+P(OH)3
3 3
poor leaving groupgood leaving group
activation of alcohol
Methylation: the most common substitution reaction- in laboratory, use CH3-I- living organism use complex but safer methyl donor
Biological Substitution Reactions
Most biological reactions occur by the same addition, substitution, elimination, and rearrangement mechanisms encountered in laboratotyreactions.
Chemistry @ Work
- CH3Br: used as a fumigant to kill termites and as a soil sterilant; transfer an alkyl group to a nucleophilic amino group (-NH2) or mercapto group (-SH) in enzymes, thus altering the enzyme's normal biological activity.
many simple reactive SN2 substrates are toxic to living organisms
Biological Substitution Reactions
H
N
HOH OH
H HO
N
N
N
NH2
SCH3
HOOC
NH2
S-Adenosylmethionine
NH2
OHHO
HO
a sulfonium ion
Norepinephrine
SN2
H
N
HOH OH
H HO
N
N
N
NH2
SHOOC
NH2NH
OHHO
HO
CH3
+
Adrenaline
Chemistry @ Work
Biological Substitution Reactions
ClS
Cl
Mustard gas
ClS
internal
SN2Cl-
H2N ProteinSN2
HN Protein
SCl
Alkylated protein
mustard gas: chemical warfare agent, used in World War I
Chemistry @ Work