12/7/14

CH203 Lecture 37
December 8, 2014

Nucleophilic subs=tu=on
-Elimina=on

Sep. 14, 2006

US 2006/0205953 A1

[0022] 0.14 mmol (12 Ci, carrier-free) ofl2C3H3l is sealed

into a glass reaction bulb With silver nosylate (62 mg, 0.2
mmol) and 5 ml of anhydrous acetonitrile. The reaction is
heated to 80 C. overnight. Labiles are removed, and the
residue dissolves in ethyl acetate. The yield is 6.16 Ci (51%)

12/7/14

EXAMPLE 5

Preparation of [Methyl-3H]-Raclopride (V11)

[0025]

of [methyl-12C3 H]methyl para-nitrobenZenesulfonate (V).

(v11)

The labeled material and authentic cold standard comi grated

on TLC (Whatman LK6DF, hexane-ethyl acetate, 10:3,

Rf=0.5). Stored at 28.4 mCi/ml in hexane-ethyl acetate (8:2)

OH

[3H]MeONs

Cl

DMSO
5N NaOH

gm

at 25 C., the radiochemical purity as determined by TLC as

above is unchanged after 4 months.

70 0., 15min

OH
01

EXAMPLE 4

CT3

Synthesis of [Methyl Ester-3H]Carfentanil (V1)

With [methyl-l2C3H]Methyl Para-nitrobenZene

sulfonate (V)

O-

\O H3CO

01

/ Strong base, good nucleophile

N
H

H3COH

[0023]
01

(V1)

N201,

H3C
O
[0026] Raclopride is prepared at 80.5 Ci/mmol by heating
the reaction to 70 C. in DMSO.HThe
3Cmethyl nosylate (V) is

Strong base, bad nucleophile

able to be dispensed by volume, and the solvent removed to

leave the reagent ready for use in the reaction vessel. In the

methylation of the raclopride precursor, the stoichiometry of

H3C controlled toO

the reaction is able to be carefully
minimize
dimethylation.

Weak base, bad nucleophile

H3C
EXAMPLE 6

O-

H3C

Methylating Comparison C3H3l and Methyl

Nosylate (V)
Z

[0027] The methylating ability of methyl iodide vs. methyl

nosylate is compared in a competition experiment. The
potassium salt of 2-naphthylacetic
I acid is stirred in dimethyl
H C

Good leaving group

3
formamide With one equivalent of cold methyl iodide and

one equivalent of tritiated methyl nosylate (V). The puri?ed

material is determined to be 86 Ci/mmol.
O In this experiment,

[0024] 400 mCi (0.005 mmol) of [methyl-3 H]methyl para

nitrobenZenesulfonate (V) and 1.5 mg (0.0036 mmol) of

the nucleophile had been preferentially methylated by the

tritiated methyl nosylate (V) With only a small fraction

O methyl
S iodide.
3Cunlabeled
reacting instead WithHthe

carfentanil sodium salt are stirred in 0.2 ml of anhydrous

DMF at room temperature overnight. TLC of the reaction
(Whatman LK6DF, chloroform-methanol-ammonium

Better leaving group

CH3

1.1, umol [3H]Methyl nosylate

OK

hydroxide, 100:2:1) shoW only product and unreacted nosy

1.1, umol CH31

DMF, 20 C., 18h

late. Analysis by HPLC on ODS shoW that 91% of the

activity coeluted With cold standard. A portion is puri?ed on
1.1,urnol

HPLC (Zorbax SB-C18, acetonitrile-0.1% tri?uoroacetic

H3C

acid, gradient) to give [Methyl ester-I2C3H]carfentanil (V1).

The speci?c activity is determined to be 80.0 Ci/mmol by

mass spectral analysis, and the radiochemical purity deter

O
Best leaving group

N+

O-

CT3

mined by HPLC as above is 99%.

O
CT3

N
N

-O

O-

-O

O
N+

O
N+

O-

T3C

O
DMF

N
N

12/7/14

Nucleophilic Subs=tu=on SN1 mechanism

In the second mechanism for nucleophilic subs=tu=on, the carbon-leaving
group bond is en=rely broken before the nucleophile approaches to make a
new bond.

This mechanism is designated SN1 :

S = Subs=tu=on
N = Nucleophilic
1 = Unimolecular (only one species is involved in the rate-determining
step)

slow
C

Lv

C+

Lv:-

Nucleophilic Subs=tu=on SN2 mechanism

There are two mechanisms for nucleophilic subs=tu=on. The fundamental
dierence between them is the =ming of the bond-breaking and the bond-
forming steps.

If the two processes take place simultaneously the reac=on is designated
SN2 :
S = Subs=tu=on
N = Nucleophilic
2 = Bimolecular (two species are involved in the rate-determining step)

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Nucleophilic Subs=tu=ons - variables

Several experimental parameters govern whether a nucleophilic subs=tu=on
proceeds via an SN1 or an SN2 pathway and at what rate that subs=tu=on will
occur. These are:

1. The structure of the molecule containing the leaving group.
2. The structure of the leaving group.
3. The reac=on solvent.
4. The structure of the nucleophile.

Nucleophilic Subs=tu=ons variables

Op=mizing condi=ons for a subs=tu=on reac=on

SN1

SN2

Electrophile

2o, 3o, allylic, benzylic

Methyl, 1o,2o

Leaving group

Good

Good

Solvent

Polar pro=c

Polar apro=c

Nucleophile

Can be weak

Must be good

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Nucleophilic Subs=tu=ons examples

Variable

Proper1es

SN1

SN2

Electrophile

2o allylic halide, two groups (=ed back in a ring) ++

Leaving group

Bromide, good

Solvent

Moderately polar pro=c

Nucleophile

Ace=c acid, poor

Nucleophilic Subs=tu=ons examples

Predicted product: allyl acetates with racemiza=on of the chiral

center.

Br

10

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Nucleophilic Subs=tu=ons examples

Variable

Proper1es

SN1

SN2

Electrophile

Primary halide, one group

Leaving group

Bromide, good

Solvent

Nonpolar apro=c

Nucleophile

R3P, moderately good (same as or beaer than R3N)

11

Nucleophilic Subs=tu=ons examples

Predicted product: a phosphonium bromide

12

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-Elimina=on

All nucleophiles are also bases. The same molecule which acts as a
nucleophile in a subs=tu=on reac=on might also act as a base to cause an
elimina=on reac=on. In many substrates, there is a compe==on between the
two possible pathways of reac=on. Which pathway predominates will depend
on some of the same factors which governed whether a reac=on went by an
SN1 or an SN2 mechanism: structure of the electrophile, nature of the leaving
group, solvent, and structure of the nucleophile.

13

-Elimina=on

-Elimina=on of the elements of HX is called dehydrohalogena=on. It is

formally the reverse of hydrohalogena=on. -Elimina=on is oden done by
using a strong base.

14

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-Elimina=on
B:
B-H
H
C

X-

As in subs=tu=on reac=ons, there are two main types of -elimina=on

reac=ons. In the reac=on above, bonds are broken and formed in one
simultaneous step. The reac=on below goes in two steps. First the C-X bond
cleaves to leave a carboca=on, then a base removes a hydrogen to form the
alkene double bond.
B:

H
Step 1

H
C
X

B-H

C+

Step 2

C+

X15

-Elimina=on

When isomeric alkenes are possible products, the major product is usually
the more subs=tuted (and therefore more stable) alkene. Note that in the
reac=on above, there are 6 hydrogens whose abstrac=on would lead to the
minor product and only two hydrogens whose abstrac=on would lead to the
major product.

16

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-Elimina=on

The product of a -elimina=on is oden predicted by Zaitsevs Rule:

The alkene formed in greatest amount is the one
that corresponds to removal of the hydrogen from
the -carbon having the fewest hydrogen subs1tuents.

Historical footnote: Zaitsev and Markovnikov worked for
the same professor and ended up biaer enemies ader
gh=ng over the expected products of -elimina=on.

17

-Elimina=on regioselec=vity

18

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-Elimina=on

Zaitsev's Rule predicts that in an elimina=on reac=on, the most stable alkene,
which is usually the most subs=tuted one, will be the favored product.

While eec=ve at predic=ng the favored product for many elimina=on
reac=ons, Zaitsev's Rule is subject to many excep=ons.
19

-Elimina=on

Br

EtO-K+
EtOH
+

+
51%

18%

31%

An E1 done with a strong base will tend to give the more stable subs=tuted
alkene in its more stable stereoisomeric form (here the trans isomer).

20

10

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-Elimina=on E1 mechanism

The E1 (E for Elimina=on and 1 for Unimolecular) is one of the two main types
of -elimina=on reac=ons. In this mechanism, the carbon-leaving group bond
breaks in a slow step to leave a carboca=on. This step is rate-determining,
and as in the SN1 reac=on, the stability of the carboca=on will govern how
fast the overall reac=on goes. In the second step, a base abstracts a hydrogen
to generate the alkane double bond.
21

-Elimina=on E1 mechanism

The E1 is one of the main types of -elimina=on reac=ons. In this mechanism,

the carbon-leaving group bond breaks in a slow step to leave a carboca=on.
This step is rate-determining, and as in the SN1 reac=on, the stability of the
carboca=on will govern how fast the overall reac=on goes. In the second
stop, a base abstracts a hydrogen to generate the alkane double bond.
22

11

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-Elimina=on E2 mechanism
B:
B-H
H
C

C
X

C
X-

The E2 (E for Elimina=on and 2 for Bimolecular) is the other main type of -
elimina=on reac=on. In this mechanism, bonds are broken and formed in one
simultaneous step.
23

-Elimina=on E2 mechanism

The E2 (E for Elimina=on and 2 for Bimolecular) is the other main type of -
elimina=on reac=on. In this mechanism, bonds are broken and formed in one
simultaneous step.
24

12

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-Elimina=on E2 mechanism

HORO-

H
C

C
X

H2NR2N-

The E2 pathway is more likely to dominate in the presence of strong bases

such as hydroxides, alkoxides, or amide anions.

25

-Elimina=on kine=cs
Alkyl halide + base alkene

E1 mechanism:
" The reac=on occurs in two steps.
" The rate-determining step is carboca=on forma=on.
" The reac=on rate (rst order) depends only on the concentra=on of
substrate.

RateE1 = k[alkyl halide]


E2 mechanism:
" The reac=on occurs in one step.
" The reac=on rate (second order) depends on the concentra=on of the
substrate and the base.

RateE2 = k[alkyl halide][base]

26

13

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-Elimina=on regioselec=vity
E1: major product is the more stable alkene. Zaitsev Product.

E2: with strong base, the major product is the more stable (more subs=tuted)
alkene. Zaitsev Product.

Double bond character is highly developed in the transi5on state, so the
transi5on state of lowest energy is the one that leads to the most stable
(the most highly subs5tuted) alkene.

E2: with a strong, sterically hindered base such as tert-butoxide, the major
product is oden the less stable (less subs=tuted) alkene. Non-Zaitsev
Product.

Steric interac5ons prevent the base from removing the hydrogen which
would lead to the most stable alkene.
27

-Elimina=on regioselec=vity
Br

H3C
H3C

CH3
H

CH3
=

small base:

CH3O-Na+
CH3OH

H3C

H3C

H3C

CH3
H

H3C

CH2

H3C

CH3

Br
H3C

CH3

CH3

80% Zaitsev : 20% non-Zeitsev

CH3
H3C
Br

H3C
H3C

CH3
H

CH2
H

large base:

H3C

O-

H3C
(CH3)3CO-Na+
(CH3)3COH

H3C

CH3

H3C

CH2

H3C

CH3

+
H3C

CH3

25% Zaitsev : 75% non-Zeitsev

28

14

12/7/14

-Elimina=on stereoselec=vity

The E2 reac=on nds its lowest-energy transi=on state in the conforma=on

where the hydrogen being abstracted and the leaving group are an= coplanar.
29

-Elimina=on stereoselec=vity

To predict the stereochemistry of the alkene, nd the conformer where the

hydrogen being abstracted and the leaving group are an= coplanar.

30

15

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-Elimina=on stereoselec=vity

An an= coplanar congura=on maximizes overlap between the breaking C-H

sigma bonding orbital, which retains two electrons on losing H to the base,
and the empty C-Lv sigma an=bonding orbital. The adjacent carbons
rehybridize from sp3 to sp2 in order to share the two electrons in p orbitals,
forming the new alkene double bond.

Br

Br

Br

H
Br

-Elimina=on stereoselec=vity

Br

31

H
Br

32

16

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-Elimina=on summary

33

-Elimina=on cyclic substrates

In the more stable chair conformer of this cis cyclohexane deriva=ve, the
chloride is axial. There are two hydrogens which are trans and axial to the
chloride and thus also an= coplanar. The alkene might be formed by
elimina=on to give two dierent alkenes. The more subs=tuted alkene is
observed as the major (Zaitsev) product.

34

17

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-Elimina=on cyclic substrates

In the trans isomer, the chloride is axial only in the less stable chair conformer
where the isopropyl group is forced to be axial as well. In this conformer
there is only one hydrogen which is trans and axial to the chloride and thus
also an= coplanar. The only alkene which can be formed is the less
subs=tuted (non-Zaitsev) product.

35

Subs=tu=on vs. Elimina=on

Nucleophilic subs=tu=on and -elimina=on pathways oden are in

compe==on with each other. The ra=o of products will depend on which
mechanism is faster.

36

18

12/7/14

Subs=tu=on vs. Elimina=on

Nucleophilic subs=tu=on and b-elimina=on pathways oden are in

compe==on with each other. The ra=o of products will depend on which
mechanism is faster.

37

Subs=tu=on vs. Elimina=on

Nucleophilic subs=tu=on and b-elimina=on pathways oden are in

compe==on with each other. The ra=o of products will depend on which
mechanism is faster.

38

19

12/7/14

Subs=tu=on vs. Elimina=on

Nucleophilic subs=tu=on and b-elimina=on pathways oden are in

compe==on with each other. The ra=o of products will depend on which
mechanism is faster.

39

Subs=tu=on vs. Elimina=on examples

Variable

Proper1es

Electrophile

Primary

Nucleophile

Good nucleophile, strong base, not sterically

hindered

Solvent

Pro=c medium polarity

SN1 SN2 E1 E2
--

--
+

40

20

12/7/14

Subs=tu=on vs. Elimina=on examples

Variable

Proper1es

Electrophile

Ter=ary

Nucleophile

Weak base, weak nucleophile

Solvent

Polar pro=c

SN1 SN2 E1 E2
--
-
+

41

Subs=tu=on vs. Elimina=on examples

Variable

Proper1es

SN1 SN2 E1 E2

Electrophile

Secondary

--

Nucleophile

Weak base, moderate nucleophile

Solvent

Polar pro=c

-
+

42

21

12/7/14

Subs=tu=on vs. Elimina=on examples

Variable

Proper1es

SN1 SN2 E1 E2

Electrophile

Secondary

Nucleophile

Weak base, good nucleophile

Solvent

Polar apro=c

43

Subs=tu=on vs. Elimina=on examples

Variable

Proper1es

Electrophile

Ter=ary

Nucleophile

Weak base

Solvent

Polar apro=c

SN1 SN2 E1 E2
-
-
-

44

22

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Neighboring group par=cipa=on

45

Neighboring group par=cipa=on

H2O
Cl

Cl

Cl

OH

slow, rate = k[alkyl halide][H2O]

H2O

S
Cl

Cl

S
Cl

OH

fast, rate = k[alkyl halide]

The hydrolysis of a primary alkyl chloride is slow in water. The rate is second
order as expected for an SN2 reac=on.

The hydrolysis of a sulfur mustard is rapid in water. The rate is rst order in
the mustard only.
46

23

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Neighboring group par=cipa=on

47

Neighboring group par=cipa=on

Two chemotherapy drugs based on nitrogen mustards.

48

24

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Neighboring group par=cipa=on

The mustards cause cell death by chemically altering the DNA bases and
interrup=ng DNA replica=on.
49

50

25