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Fischer-Rosanoff Convention
• Before 1951, only relative configurations could be known.
• Sugars and amino acids with same relative configuration as
(+)-glyceraldehyde were assigned D and same as (-)glyceraldehyde were assigned L.
• With X-ray crystallography, now know absolute
configurations: D is (R) and L is (S).
• No relationship to dextro- or levorotatory.
=>
D and L Assignments
CHO
H
*
CHO
OH
H
CH2OH
D-(+)-glyceraldehyde
HO
H
COOH
H2N
*
H
=>
CH2CH2COOH
L-(+)-glutamic
acid
OH
H
OH
H *
OH
CH2OH
D-(+)-glucose
Properties of Diastereomers
• Diastereomers have different physical
properties: m.p., b.p.
• They can be separated easily.
• Enantiomers differ only in reaction with
other chiral molecules and the direction in
which polarized light is rotated.
• Enantiomers are difficult to separate.
=>
Resolution of Enantiomers
React a racemic mixture with a chiral compound to form
diastereomers, which can be separated.
=>
Chromatographic
Resolution of Enantiomers
=>
Organic Chemistry, 5th Edition
L. G. Wade, Jr.
Chapter 6
Alkyl Halides: Nucleophilic
Substitution and Elimination
Classes of Halides
• Alkyl: Halogen, X, is directly bonded to sp3
carbon.
•Vinyl: X is bonded to sp2 carbon of alkene.
•Aryl: X is bonded to sp2 carbon on benzene ring.
• Examples:
H H
H C C Br
H H
alkyl halide
I
H
H
=>
C C
H
Cl
vinyl halide
aryl halide
Polarity and Reactivity
• Halogens are more electronegative than C.
• Carbon-halogen bond is polar, so carbon has partial
positive charge.
• Carbon can be attacked by a nucleophile.
• Halogen can leave with the electron pair.
=>
H + H C Br
H
Classes of Alkyl Halides
• Methyl halides: only one C, CH3X
• Primary: C to which X is bonded has only
one C-C bond.
• Secondary: C to which X is bonded has two
C-C bonds.
• Tertiary: C to which X is bonded has three
C-C bonds.
=>
Classify These:
CH3
CH CH3
CH3CH2F
Cl
(CH3)3CBr
CH3I
=>
Dihalides
• Geminal dihalide: two halogen atoms are
bonded to the same carbon
•Vicinal dihalide: two halogen atoms are bonded
to adjacent carbons.
H
H
H
C
C
H H
Br
H Br
geminal dihalide
H C C Br
Br H
vicinal dihalide
=>
IUPAC Nomenclature
• Name as haloalkane.
• Choose the longest carbon chain, even if the halogen is not
bonded to any of those C’s.
• Use lowest possible numbers for position.
CH3
CH CH2CH3
Cl
2-chlorobutane
CH2CH2Br
CH3(CH2)2CH(CH2)2CH3
4-(2-bromoethyl)heptane
=>
Systematic Common Names
• Name as alkyl halide.
• Useful only for small alkyl groups.
• Name these:
(CH3)3CBr
CH3
CH CH2CH3
Cl
CH3
CH3
CH CH2F
=>
“Trivial” Names
• CH2X2 called methylene halide.
. •CHX is a haloform.
3
•CX4 is carbon tetrahalide.
•Examples:
–CH2Cl2 is methylene chloride
–CHCl3 is chloroform -CHI3 is iodoform
–CCl4 is carbon tetrachloride
Preparation of RX
• Free radical halogenation (Chapter 4) REVIEW
• Free radical allylic halogenation
– produces alkyl halide with double bond on the
neighboring carbon. LATER
=>
Substitution Reactions
C C
H X
+
Nuc:
-
C C
+
X:
-
H Nuc
• The halogen atom on the alkyl halide is replaced
with another group.
•Since the halogen is more electronegative than
carbon, the C-X bond breaks heterolytically and
X- leaves.
The group replacing X- is a nucleophile.
=>
Elimination Reactions
C C
+
-
B:
C C
+
X:
-
+ HB
H X
• The alkyl halide loses halogen as a halide ion, and
also loses H+ on the adjacent carbon to a base.
•The alkyl halide loses halogen as a halide ion, and
also loses H+ on the adjacent carbon to a base.
•A pi bond is formed. Product is alkene.
Also called dehydrohalogenation (-HX).
Ingold
Ingold
Sir Christopher
Father of Physical Organic Chemistry
Coined such names and symbols as:
SN1, SN2, E1, E2, nucleophile, electrophile
resonance effect, inductive effect/
In print, he often attacked enemies
vigorously and sometimes in vitrolic
manner.
SN2 Mechanism
H
H
H O
H
C Br
H
HO C Br
H H
H
HO C
• Rate is first order in each reactant
•Both reactants are involved in RDS
Note: one-step reaction with no
intermediate
•Bimolecular nuleophilic substitution.
•Concerted reaction: new bond forming
and old bond breaking at same time
INVERSION OF CONFIGURATION
H
-
+ Br
H
SN2 Energy Diagram
• One-step reaction.
• Transition state is highest in energy. =>
Uses for SN2 Reactions
• Synthesis of other classes of compounds.
• Halogen exchange reaction.
Nucleophile

Product
R-I
Class of Product
akyl halide
-

R-OH
alcohol
R-X + OR'
-

R-OR'
ether
-

R-SH
thiol
-

R-SR'
thioether

amine salt

R-NH3+X
R- N3
R-X + CC-R'
-

R-CC-R'
alkyne
-

R-CN
nitrile

R-COO-R'
ester
R-X + I
-
R-X + OH
R-X + SH
R-X + SR'
R-X + NH3
-
R-X + N3
R-X + CN
R-X + R-COO
-
-
azide
=>
SN2: Nucleophilic Strength
• Stronger nucleophiles react faster.
• Strong bases are strong nucleophiles, but not all
strong nucleophiles are basic.
=>
Trends in Nuc. Strength
• Of a conjugate acid-base pair, the base is stronger:
OH- > H2O, NH2- > NH3
•Decreases left to right on Periodic Table. More
electronegative atoms less likely to form new bond:
OH- > F-, NH3 > H2O
Increases down Periodic Table, as size and polarizability
increase: I- > Br- > Cl-
Polarizability Effect
=>
Bulky Nucleophiles
Sterically hindered for attack on carbon, so
weaker nucleophiles.
CH3 CH2 O
ethoxide (unhindered)
weaker base, but stronger nucleophile
CH3
H3C
C
O
CH3
=>
t-butoxide (hindered)
stronger base, but weaker nucleophile
Solvent Effects (1)
Polar protic solvents (O-H or N-H) reduce the
strength of the nucleophile. Hydrogen
bonds must be broken before nucleophile
can attack the carbon.
=>
Solvent Effects (2)
• Polar aprotic solvents (no O-H or N-H) do not form
hydrogen bonds with nucleophile
• Examples:
O
CH3 C N
acetonitrile
H
C
N
CH3
CH3
dimethylformamide
(DMF)
O
C
H3C
CH3
acetone
=>
Crown Ethers
• Solvate the cation, so
nucleophilic strength
of the anion increases.
• Fluoride becomes a
good nucleophile.
O
O
O
K+
O
O
O
18-crown-6
CH2Cl
CH2F
KF, (18-crown-6)
CH3CN
=>
SN2: Reactivity of Substrate
• Carbon must be partially positive.
• Must have a good leaving group
• Carbon must not be sterically hindered.
=>
Leaving Group Ability
• Electron-withdrawing
• Stable once it has left (not a strong base)
• Polarizable to stabilize the transition state.
=>
Structure of Substrate
• Relative rates for SN2:
CH3X > 1° > 2° >> 3°
• Tertiary halides do not react via the SN2
mechanism, due to steric hindrance.
=>
Stereochemistry of SN2
Walden inversion
=>
SN1 Reaction
• Unimolecular nucleophilic substitution.
• Two step reaction with carbocation
intermediate.
• Rate is first order in the alkyl halide, zero
order in the nucleophile.
• Racemization occurs.
=>
SN1 Mechanism (1)
Formation of carbocation (slow)
(CH3)3C Br
+
(CH3)3C
-
+ Br
=>
SN1 Mechanism (2)
• Nucleophilic attack
+
(CH3)3C
+ H O H
(CH3)3C O H
H
• Loss of H+ (if needed)
(CH3)3C O H + H O H
H
(CH3)3C O H
+
+ H3O
=>
SN1 Energy Diagram
• Forming the
carbocation is
endothermic
• Carbocation
intermediate is in
an energy well.
=>
Rates of SN1 Reactions
• 3° > 2° > 1° >> CH3X
– Order follows stability of carbocations (opposite to SN2)
– More stable ion requires less energy to form
• Better leaving group, faster reaction (like SN2)
• Polar protic solvent best: It solvates ions strongly with
hydrogen bonding.
=>
Stereochemistry of SN1
Racemization:
inversion and retention
=>
Rearrangements
• Carbocations can rearrange to form a more
stable carbocation.
• Hydride shift: H- on adjacent carbon bonds
with C+.
• Methyl shift: CH3- moves from adjacent
carbon if no H’s are available.
=>
Hydride Shift
H
Br H
CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
H
H
CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
H
CH3
C C CH3
H CH3
H Nuc
Nuc
CH3
C C CH3
H CH3
=>
Methyl Shift
CH3
Br CH3
CH3
CH3
C C CH3
H CH3
H CH3
CH3
CH3
CH3
C C CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
CH3
CH3
C C CH3
H CH3
Nuc
CH3
CH3 Nuc
C C CH3
H CH3
=>
SN2
• Primary or methyl
• Strong nucleophile
• Polar aprotic solvent
• Rate = k[halide][Nuc]
• Inversion at chiral
carbon
• No rearrangements
or
SN1?
• Tertiary
• Weak nucleophile (may also be
solvent)
• Polar protic solvent, silver salts
• Rate = k[halide]
• Racemization of optically active
compound
• Rearranged products
=>