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Br2, hv
resonance stabilized>3>2>1>alkenyl
Recognition: X2, hv
Predicting product: Identify which carbon could give the most stable radical, and substitute
a Br for an H on that carbon.
Stereochemistry: Leads to racemic, due to achiral radical intermediate.
Mech: Radical. Be able to draw propagation steps.
Br
Br
Br
Br
slow step
Br
ready
to repeat
first step
+ H-Br
2. SN2 Substitution
Br NaOCH3
OCH3
Br OCH3
OCH3 + Br
3. E2 Reactions.
Br
Mech:
NaOCH3
Br
+ H OCH3
E2: 3>2>1> alkenyl
Recognition:
H
H
OCH3
+ H OCH3 + Br
4. SN1 Reactions.
OCH3
Br
HOCH3
+ H Br
Recognition:
Br
slow
step
HOCH3
Br
OCH3
OCH3
+ H Br
+ Br
HOCH3
E1: 3>2>1
H
Recognition:
slow
step
H
H
Br
+ H Br
+ Br
Br
Br
Br
alkyl halide
vinyl halide
aryl halide
allylic halide
B. 1, 2, 3 Classification
Br
Br
H
Br
2
H
Formal Name
1-chloropropane
Common Name
Propyl chloride
2-bromopentane
Br
2-iodopropane
Isopropyl iodide
6.4 Structure:
A. Polar
C
!+ X
!"
Bond
C-Cl
C-Br
C-I
Bond Strength
81
68
53
A. Substitution
R-X + NaZ or HZ R-Z + NaX or HX
Anion or neutral
2 Variants
1. SN2:
Anionic nucleophile
The R-X bond breaking is simultaneous with R-Z bond formation
Br OCH3
OCH3 + Br
2. SN1:
Neutral nucleophile
The R-X bond breaks first to give a carbocation in the rate determining step;
formation of the R-Z bond comes later
Br
H
slow
step
Br
OCH3
OCH3
HOCH3
+ H Br
+ Br
B. Elimination
H X
C C
+ NaZ or HZ
anion or neutral
C C
+ NaZ or HZ
2 Variants
1. E2:
Anionic base
The R-X and C-H bond breaking is simultaneous with C=C bond formation
Br
H
OCH3
+ H OCH3 + Br
2. E1:
Neutral base
The R-X bond breaks first to give a carbocation in the rate determining step.
C-H bond cleavage and C=C bond formation comes later
Br
slow
step
H
H
+ Br
Br
+ H Br
Z
"nucleophile"
X
C
!+ !"
"electrophile"
+ X
"leaving
group"
H3C
CH3 + Na X
HO
Br
H H
C
H
H H
Br
HO
Br
H
Transition-State
HO
HH
C
+ Br
H
Notes:
Simple, concerted one-step mechanism. No intermediates.
The anion needs to be very reactive and thus not too stable. Normally ANIONIC
NUCLEOPHILE.
Both nucleophile and electrophile are involved in the rate determining step.
Rate = k[anion]1[R-X]1
2nd order rate law is why its called SN2: SubstitutionNucleophilic2nd order
The nucleophile attacks opposite side from the leaving group.
This backside attack (or opposite side attack) results in inversion of stereochemistry
when a chiral, 2 R-X is involved
H Br
+ NaOH
HO H
The transition state involves a 5-bonded, trigonal bipyramidal carbon that is more
cluttered than either the original tetrahedral reactant or the final tetrahedral product
Steric crowding in the transition-state makes the reaction very, very, very sensitive to
steric factors
o For the electrophile R-X: CH3-X > 1 R-X > 2 R-X > 3 R-X for steric
reasons
o For the nucleophile it also helps to be smaller rather than larger
Alcohols
Ethers
O
R-X +
NaO
Esters
R-X + KI R-I
Iodides
Nitriles
R-X +
Alkynes
Etc.
Notes
Most nucleophiles are ANIONS
Various oxygen anions are good to make alcohols, ethers, or esters
Halogen exchange useful route to iodides (more valuable and less accessible)
There are a few neutral nucleophiles (not for test): nitrogen family
Predicting Products for SN2 Reactions
1. Dont change the structure for the carbon skeleton
2. Put the nucleophile in exactly the spot where the halide began
3. Unless the halide was attached to a chiral center; in that case invert the
configuration for the product
If the halide was wedged, the nucleophile should be hashed
If the halide was hashed, the nucleophile should be wedged
4. Dont mess with any spectator portions: whatever was attached to the
nucleophilic anion at the beginning should still be attached at the end
NHNa >
ONa
>
NaF
>
ONa
>
ONa
2. Electrophile
Substrate: Allylic > 1 > 2 > >> 3, alkenyl, aryl
o 3 and alkenyl, aryl never do SN2
o transition-state stability-reactivity principle
o Steric clutter in the transition state explains the 1 > 2 > >> 3 pattern
o Allylic benefits from a complex orbital resonance effect in the T-state
o Alkenyl/aryl halides are bad for some molecular orbital reasons
(backside attack doesnt work, particularly for aryl halides)
HO
H H
Br
HO
HO
Br
H
Transition-State
HH
C
+ Br
H
Br + NaOCH
3
H OCH3
+ NaOCH3
OCH3
NaOCH2CH3
Br H
Br
H OCH2CH3
OH
trans
NaOH
H3C
H cis
H3C
1.
Not, neutral
Br + NaOH
2.
OH
3.
Br
+ NaO
Not, 3
+ NaOCH3
4.
Inversion
H OCH3
Br H
Br H
H OCH2CH3
+ KOCH2CH3
5.
Br
+ KCN
Br
+ CH3OH
CN
6.
7.
Not, neutral
8.
Br
9.
Br
+ NaSCH3
+ NaOH
Br
+ NaOCH3
SCH3
Not, vinyl
H3CO
10.
+ NaOCH 3
11.
Br
Not, 3
Br
+ NaOH
12.
Not, aryl
Inversion
10
11
Br
Br
Br
Br
2
3
1
4
5
6
Issues: SN2 with anion. Iodide > bromide. Allyl > 1 > 2 > vinyl. #4 is sterically
more cluttered than #3
Br (For any problem like this, try to recognize what
2. Rank Reactivity toward
kind of a reaction it is, so that you know what stability/reactivity issues apply).
O
NaOCH3
NaNH2
CH3OH
NaO
1
2
3
4
Issues: Stability/reactivity principles. 1. Anion vs neutral. (Why methanol is way
last) 2. Electronegativity. (N vs O anions) 3. Resonance (#2 vs #3)
3. What nucleophile should you use to accomplish the following transformations?
Br H
Br
H SPh
PhSNa
C
C
Ph
Ph
4. Draw the Products, Including Stereochemistry. (Stereochemistry will matter for SN2
and SN1 reactions anytime the haloalkane is 2)
+ NaOH
Br H
H OH
H 3C
Br
H 3C
+ KCN
H
CN
5. Choose Reactants to make the following, from a haloalkane and some nucleophile.
+
O
Br
12
OH
+ H 2O
+ CH3OH
OCH3
3-Step Mechanism
Br
slow
step
HOCH3
Br
OCH3
OCH3
+ H Br
+ Br
13
Most
Least
O
Solvent
Relative Rate
H2 O
8000
CH3OH
1000
0.001
0.0001
H3C OH
+ H2O
HO CH3
R
S
Racemic Mixture
S
optically active
CH3
Front
Attack
H3C OH2
-H
H3C OH
S
H2O
S
optically active
Achiral cation
Back
Attack
H2O CH3
-H
HO CH3
R
Ex.
H
H3C
CH3
Br
HOCH2CH3
H
H3C
+
CH3
OCH2CH3
H
H3C
OCH2CH3
CH3
14
SN1 Problems: For the following, which are and arent SN1 candidates? If not, why not?
What would be the product if they are SN1 candidates?
I + H2O
1.
Not, 1
+ NaOCH3
2.
3.
Br H
+ HOCH3
4.
Racemic
Br H
H OCH3
H3CO H
5.
Br
+ NaO
+ HO
Br
6.
Br H
H OCH3
+ CH3OH
7.
H3CO H
Racemic
Br
+ CH3OH
8.
Not, vinyl
+ H2O
9.
Br
OH
+ H 2O
10.
Not, Aryl
Br
Br
Cl
I
3
4
Issues: Allylic > 3 > 2 > 1
5
I > Br > Cl
Cl
15
Nucleophile
Substrate
Allylic effect
Leaving Group
Solvent
Rate Law
Stereochemistry
(on chiral, normally 2 R-X)
Ions
Rearrangements
SN1
Neutral, weak
3 R-X > 2 R-X
Allylic Helps
I > Br > Cl
Polar needed
K[RX]
Racemization
SN2
Anionic, strong
1 R-X > 2 R-X
Allylic helps
I > Br > Cl
Non-factor
k[RX][Anion]
Inversion
Cationic
Problem at times
Anionic
Never
a.
OCH2CH3
SN2, anion, 1
Br
+ H2O
b.
Br
c.
H Br
d.
H Br
e.
+ H 2O
No reaction, aryl
OH
H3CS H
+ CH3SNa
+ CH3SH
H3CS H
H SCH3
Racemic
SN1
c. When the moles of reactant is kept the same, but the volume of solvent is cut in half, the
reaction rate increases by 2-fold?
SN1
d. By 4-fold? SN2
e. 2-bromobutane reacts faster than 1-bromobutane?
SN1
16
Br
H
OH +
H
SN1
+
H
E1
(major E1)
+ HBr
E1
(minor E1)
HOCH3
+ HBr
Br
OCH3
SN1
E1
(major E1)
E1
(minor E1)
Notes
Under SN1 conditions, some elimination product(s) form as well
E1 and SN1 normally compete, resulting in mixtures
o This is not good from a synthetic perspective.
Structurally Isomeric Alkenes can form
o The double bond must involve the original halogenated carbon and any
neighbor carbon (that had a hydrogen to begin with that can be eliminated)
o Normally the alkene with fewer alkene Hs is formed more extensively over
alkenes with more alkene Hs. (More C-substituted alkene is major).
Neutral/acidic (the formula starts neutral, but acid is produced)
1st order rate law
r = k[RX]1
E1 Mechanism: 2 Steps
Br
slow
step
H
H
Br
+ H Br
+ Br
17
6-19 E2 Reaction (2nd Order, Under Anionic/Basic SN2 type Conditions)
Examples
Br
H
NaOCH3
+
H
E2
(major)
H
3 R-X
+ HOCH3 + HBr
E2
(minor E2)
NaOH
+ H2O + HBr
Br
minor
major
3 R-X
Br
NaOH
OH
+
+
SN2
More of this
than either
E2 product
2 R-X
major E2
(of the E2's)
+ H2O + HBr
minor E2
(of the E2's)
NaOH
+ NaBr
Br
SN2
1 R-X
Notes
E2 happens with anionic nucleophiles/bases, when SN2 is hindered
Reactivity: 3 R-X > 2 R-X.
o 1 R-X and vinyl or aryl halides do not undergo E2.
Structurally Isomeric Alkenes can form
o The double bond must involve the original halogenated carbon and any neighbor
carbon (that had a hydrogen to begin with that can be eliminated)
o Normally the alkene with fewer alkene Hs is formed more extensively over
alkenes with more alkene Hs. (More C-substituted alkene is major).
Mech
Br
H
OCH3
+ H OCH3 + Br
18
E2 Summary
Recognition:
SN1 vs E1
SN1
H
C C
H2O
H OH2
C C
-H+
H OH
C C
H
E1
H2O
C C
C C
+ H3O+
Both satisfy the carbocation. They just meet its bonding need with different
electrons.
SN2 vs E2
SN2
H
C C
Br
OH
H OH
C C
OH
+ Br
E2
C C
C C
+ H2O + Br
Br
Both provide an electron pair to displace the C-Br bond pair. They just use
different electrons.
Both involve the anion. Its called the nucleophile in the SN2, the base in the E2.
The SN2 involves a crowded transition state, and thus is strongly impacted by
steric factors. The E2 does not have any steric problems (and in fact alleviates
them).
The difference in steric profile explains why for SN2, 1 > 2 > 3, but that for E2,
the reactivity of 3 is just fine.
19
6-18 Zaitsevs Rule: When E1 or E2 elimination can give more than 1 structurally isomeric
alkene, the more highly Carbon-substituted alkene form will predominate over a less
highly carbon-substituted alkene.
The fewer Hs on the product alkene the better.
o Every Alkene has four attachments. The fewer of these that are Hs, the better.
o When pictures are drawn in which the Hs are not shown, the more highly
substituted alkenes turn out to be the best.
Why? Product Stability-Reactivity Rule. Alkenes with more Cs and fewer Hs attached
are more stable.
Alkene Stability is shown below: tetra- > tri- > di- > mono- > unsubstituted
o Why?
Alkene carbons are somewhat electron poor due to the inferior overlap of
pi bonds. (One carbon doesnt really get as much of the other carbons
electron as is the case in a nice sigma bond).
Since alkyl groups are electron donors, they stabilize electron-deficient
alkene carbons.
Analogous to why electron-donating alkyls give the 3 > 2 > 1 stability
pattern for cations and radicals
C
C
>
C C
C
tetrasubbed
H
C C
H
C
>
C C
H
trisubbed
C C
H
H
C C
>
H
di-subbed
>
tetrasubbed
H
H
H
>
C C
C C
H
H
H
H
monounsubbed
subbed
>
>
>
trisubbed
monosubbed
di-subbed
unsubbed
Examples
H 2O
H
Br
H
OH +
H
SN1
+
H
E1
(major E1)
NaOH
+ HBr
E1
(minor E1)
+ H2O + HBr
Br
Br
minor
major
3 R-X
NaOH
OH
+
2 R-X
SN2
More of this
than either
E2 product
+
major E2
(of the E2's)
+ H2O + HBr
minor E2
(of the E2's)
20
6-20 Stereochemistry of E2 Eliminations
For E2 (not for E1) C-H and C-X bonds must be in the same plane (coplanar)
The halogen and the hydrogen being removed must be trans to each
Why?
o Due to orbital overlap requirements.
o In the concerted E2 mechanism, the electrons from the hydrogen must
essentially come in backside to the leaving halide
just as in backside-attack SN2 mechanism
NaOH
Br
+
HD
HD
minor
D
major
"D" is deuterium
isotopically labeled hydrogen
Br
NaOH
NaOH
spin
Can't react
Can React
H CH
3
Br + CH ONa
3
H
CH3
H CH
3
Br + CH ONa
3
CH3
H
H CH
3
CH3
H
CH3
CH3
H
6.21 Comparing E2 vs E1
1
2
3
4
5
6
7
8
9
Nucleophile/Base
Substrate
Allylic effect
Leaving Group
Solvent
Rate Law
Stereochemistry
Ions
Rearrangements
Orientation
E1
Neutral, weak, acidic
3 R-X > 2 R-X
Allylic Helps
I > Br > Cl
Polar needed
K[RX]
Non-selective
Cationic
Problem at times
Zaitsevs Rule: Prefer
more substituted alkene
E2
Anionic, strong, basic
3 RX > 2 RX > 1 RX
Non-factor
I > Br > Cl
Non-factor
k[RX][Anion]
Trans requirement
Anionic
Never
Zaitsevs Rule: Prefer more
Substituted alkene (assuming
trans requirement permits)
21
Elimination Problems: Draw the major Elimination Product for the following Reactions.
Classify as E1 or E2. (There may be accompanying SN2 or SN1 material, but to whatever degree
elimination occurs, draw the major product.)
Br
+ CH3OH
1.
2.
Br
E1
+ CH3OH
E1
Br
+ CH3ONa
3.
4.
Br
Br
5.
6.
7.
8.
E2
+ CH3ONa
E2
+ CH3ONa
H CH
3
Br + CH OH
3
CH3
H
H CH
3
Br + CH ONa
3
CH3
H
H CH
3
Br + CH ONa
3
H
CH3
E2
CH3
CH3
E1
H
CH3
CH3
H
E2
CH3
CH3
E2
22
SN2 only
E2 (anionic) or
SN1/E1 (neutral/acidic)
mixtures common
S N2/E2
Q2: Is substrate
1, 2 or 3 R-X?
1 R-X
S N2 Only
3 R-X
2 R-X
E2 Only
S N2/E2 Mix
(normally favoring SN2)
Note: Aryl and Vinyl Halides will not undergo any of these types of reactions.
If you see Br2/hv type recipe, then youre back in the chapter 4 world of radical
halogenation
1.
Br + NaO
Br
+ NaOH
2.
E2
I
SN2, anionic, 1
OCH3
+ NaOCH3
Anionic, 3
3.
Br
4.
OH
Br
OH
+ H2O
5.
6.
Br + KOH
7.
Br
No reaction, vinyl
+ H2O
No reaction, vinyl
SPh +
+ PhSH
8.
9.
Br + H O
2
+ Br2
10.
No reaction, neutral, 1
hv
Br
Br
Can't make
an sp center
in a ring, bond angle
reasons
23
24
Design Synthetic Plans for converting the starting materials into the target
molecules.
In each case, more than one chemical operation will be required.
Strategy: R-H R-Br (via bromination) Substitution product (via SN2)
or alkene (via E2)
1. Br2, hv (makes
Br
2. NaOCH3
1.
OCH3
1. Br2, hv (makes
2.
Br
I
2. NaI
1. Br2, hv (makes
4.
(no substitution
side product)
1. Br2, hv (makes
3.
Br
Br
2. HOCH3
(some alkene
would accompany
OCH3
this product)
Keys:
These cant be done directly, in a single operation
Each sequence ends up increasing the number of functional groups in the
ultimate product.
The key reaction for increasing the functionality: R-H R-Br
R-Br
you
can
25
Draw the mechanism for formation of the major product in each of the
following reactions. In some cases where both elimination and substitution might
compete, the problem specifies whether to draw the substitution or elimination
mechanism.
Br
OH
(Subst.)
+ H2O
-H+
OH2
H2O
Br
1.
Br
H
D + NaOCH3
elim.
2.
Cl
Cl
H
H
Br
+ Br2
Br
Br Br
Cl
H
O
3.
H
H
O
H
Br
+ H2O
OH2
H H
CH3
Br
4.
5.
Subst.
+ NaO
CH3
elim
26
Rank the Reactivity of the chemicals shown toward the thing in the box. Keys:
Identify the type of reaction that would be involved
Think about the rate-determining step and how reactant or product or transitionstate stability would influence the rate.
Br
OH
Br
Br
1.
Neutral, SN1/E1
Br2, hv
2.
Radical Halogenation
Radical Stability
Br
O
ONa
ONa
2
resonance
NaOH
H2O
I
1
Solvent: Pentane
5.
6.
Anionic, SN2
Br
3
Neutral
(SN1)
CH3OH
4.
Primary, SN2
H3C CH3
Cl
3.
Radical Halogenation
Reactant Stability/Reactivity
Br
I
2
Br
3
27
Give the Major Product(s) for each of the following. If its likely to give a
mixture of both substitution and elimination, just draw the substitution product.
Designate stereochemical outcomes when stereochemistry is relevant (2
substrates).
Key: Try to recognize what type of reaction will happen first.
Br + NaOCH3
+ Br2
OCH3
hv
Br
Br
SCH3
+ CH3SNa
show sub
only
OCH3
+ CH3OH
H3C Br
OH
+ NaOCH3
OH
Br
+ NaOH
OH
Br
H
show sub
H
only
OH
+ H2O
OH
OH
OH
OH
+
show sub
only
H Br
H
+ NaOCH3
DH
show elim
only
cis/trans
mixture due
to racemization
type process
Provide Reactants for the Following (One of the Starting Chemicals must be an
R-Br)
1
Br
H3C
Br
Br
H3C Br
H
H3C
CH3 + OCH3
(or any other
H
anionic E2 base)
Br H
OH + H2O
7.
Br
show elim
only
show elim
only
(trans only)
(no elimination
side product
formed)
CH3
H
CN
NC H
6.
(no substitution
side product
formed)
OCH3
+ OCH3
+ OCH3
(or any anionic
E2 base)
Br +
CN
CN
28
Cl
H
OH
29
6-15 Cation Rearrangements (and their impact in SN1 and E1 reactions)
1. Carbocations are very unstable, and sometimes rearrange to other carbocations that are more
stable.
2. A rearrangement requires that a superior cation will result. Four cases:
2 3
non-allylic allylic
strained ring unstrained or less strained ring
1 cation 2 or 3 cation (rare, since 1 cations are hard to make and pretty rare)
Hydride Shifts
Alkyl Shifts
CH3
H
H
H H
3
2
H H
2
H
H CH3
3
H H
2 allylic
H
H H
3
H H
H H
2
H
2
H
2
Examples in SN1
OH
Br
H2O
minor
-H
OH
+ some E1 alkenes
+
major
-H
OH2
Path A
OH2
H
Path B
OH2
H2O
HOCH3
OCH3
via
H
+
OCH3
via