37 CH203 Fall 2014 Lecture 37 December 8.pdf

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CH203 Lecture 37 December 8, 2014 Nucleophilic subs=tu=on β-‐Elimina=on

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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%) of [methyl-12C3 H]methyl para-nitrobenZenesulfonate (V). 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) at 25° C., the radiochemical purity as determined by TLC as above is unchanged after 4 months.

EXAMPLE 4

Synthesis of [Methyl Ester-3H]Carfentanil (V1) With [methyl-l2C3H]Methyl Para-nitrobenZene

sulfonate (V)

[0023]

(V1) N201,”

Z

[0024] 400 mCi (0.005 mmol) of [methyl-3 H]methyl para nitrobenZenesulfonate (V) and 1.5 mg (0.0036 mmol) of carfentanil sodium salt are stirred in 0.2 ml of anhydrous DMF at room temperature overnight. TLC of the reaction

(Whatman LK6DF, hydroxide, 100:2:1) shoW only product and unreacted nosy late. Analysis by HPLC on ODS shoW that 91% of the activity coeluted With cold standard. A portion is puri?ed on HPLC (Zorbax SB-C18, acetonitrile-0.1% tri?uoroacetic acid, gradient) to give [Methyl ester-I2C3H]carfentanil (V1). The speci?c activity is determined to be 80.0 Ci/mmol by

chloroform-methanol-ammonium

mass spectral analysis, and the radiochemical purity deter mined by HPLC as above is 99%.

Sep. 14, 2006

EXAMPLE 5

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

[0025]

(v11)

OH 0 [3H]MeONs DMSO

Cl N 5N NaOH

gm 70° 0., 15min OH

01 CT3

\O O / 01

N N H

OH

01

[0026] Raclopride is prepared at 80.5 Ci/mmol by heating the reaction to 70° C. in DMSO. The methyl nosylate (V) is 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 the reaction is able to be carefully controlled to minimize dimethylation.

EXAMPLE 6

Methylating Comparison C3H3l and Methyl Nosylate (V)

[0027] The methylating ability of methyl iodide vs. methyl nosylate is compared in a competition experiment. The potassium salt of 2-naphthylacetic acid is stirred in dimethyl 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. In this experiment, the nucleophile had been preferentially methylated by the tritiated methyl nosylate (V) With only a small fraction reacting instead With the unlabeled methyl iodide.

1.1, umol [3H]Methyl nosylate OK 1.1, umol CH31

DMF, 20° C., 18h

1.1,urnol

CT3

H3C O

O

H3C

H3C

H3C

H3C

H3C

H3C

O

O-

-

-

Strong base, good nucleophile

Strong base, bad nucleophile

Weak base, bad nucleophile

H3C I

H3C O S

O

O

CH3

H3C O S

O

O

N+

O-

O

Good leaving group

Better leaving group

Best leaving group

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NN

O-O O

CT3 O S

O

O

N+

O-

O

NN

OO OT3C

-O S

O

O

N+

O-

O

DMF

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Nucleophilic Subs=tu=on – SN1 mechanism

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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)

C Lv C + Lv:-+slow

Nucleophilic Subs=tu=on – SN2 mechanism

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There are two mechanisms for nucleophilic subs=tu=on. The fundamental difference 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

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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

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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

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

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Nucleophilic Subs=tu=ons – examples

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Variable Proper1es SN1 SN2

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

2 Leaving group Bromide, good + +

3 Solvent Moderately polar pro=c + -‐

4 Nucleophile Ace=c acid, poor + -‐


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

Br

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Variable Proper1es SN1 SN2

1 Electrophile Primary halide, one β group -‐ +

2 Leaving group Bromide, good + +

3 Solvent Nonpolar apro=c -‐ +

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


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Predicted product: a phosphonium bromide

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β-‐Elimina=on

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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.

β-‐Elimina=on

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β-‐Elimina=on of the elements of HX is called dehydrohalogena=on. It is formally the reverse of hydrohalogena=on. β-‐Elimina=on is oden done by using a strong base.

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β-‐Elimina=on

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As in subs=tu=on reac=ons, there are two main types of β-‐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 β hydrogen to form the alkene double bond.

C C

H

X

B:

C C

B-H

X-

C C

H

X

C C

H

X-

+ C C

H

B:

+ C C

B-H

Step 1 Step 2

β-‐Elimina=on

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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.

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β-‐Elimina=on

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The product of a β-‐elimina=on is oden predicted by Zaitsev’s Rule: The alkene formed in greatest amount is the one that corresponds to removal of the hydrogen from the β-‐carbon having the fewest hydrogen subs1tuents. Historical footnote: Zaitsev and Markovnikov worked for the same professor and ended up biaer enemies ader figh=ng over the expected products of β-‐elimina=on.

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β-‐Elimina=on – regioselec=vity

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β-‐Elimina=on

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

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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).

β-‐Elimina=on

Br EtO-K+EtOH

+ +

51% 18% 31%

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β-‐Elimina=on – E1 mechanism

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The E1 (E for Elimina=on and 1 for Unimolecular) is one of the two main types of β-‐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.

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The E1 is one of the main types of β-‐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.


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

C C

H

X

B:

C C

B-H

X-

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


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The E2 pathway is more likely to dominate in the presence of strong bases such as hydroxides, alkoxides, or amide anions.


C C

H

X

C C

HO-

RO-

H2N-R2N-

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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 (first 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]

β-‐Elimina=on – kine=cs

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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.


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H

H3C Br

CH3

CH3

H

H3C CH3Br

CH3H3C

H3C

=

small base:

H3C

H3C CH3

CH3 H3C

H3C CH2

CH3

+

80% Zaitsev : 20% non-Zeitsev

CH3O-Na+

CH3OH

H

H3C Br

CH2

CH3H3C

large base:H3C

H3C CH3

CH3 H3C

H3C CH2

CH3

+

25% Zaitsev : 75% non-Zeitsev

(CH3)3CO-Na+

(CH3)3COHH

O

H3C

H3C

H3C -

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β-‐Elimina=on – stereoselec=vity

The E2 reac=on finds its lowest-‐energy transi=on state in the conforma=on where the hydrogen being abstracted and the leaving group are an= coplanar.

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To predict the stereochemistry of the alkene, find the conformer where the hydrogen being abstracted and the leaving group are an= coplanar.

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An an= coplanar configura=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.

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β-‐Elimina=on – stereoselec=vity H

Br

H

Br

H

Br

H

Br

H

Br

H

Br

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β-‐Elimina=on – summary

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β-‐Elimina=on – cyclic substrates

In the more stable chair conformer of this cis cyclohexane deriva=ve, the chloride is axial. There are two β 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 different alkenes. The more subs=tuted alkene is observed as the major (Zaitsev) product.

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β-‐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 β 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.

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Subs=tu=on vs. Elimina=on

Nucleophilic subs=tu=on and β-‐elimina=on pathways oden are in compe==on with each other. The ra=o of products will depend on which mechanism is faster.

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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.

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Subs=tu=on vs. Elimina=on examples

Variable Proper1es SN1 SN2 E1 E2

1 Electrophile Primary -‐-‐ -‐-‐

2 Nucleophile Good nucleophile, strong base, not sterically hindered

+ -‐

3 Solvent Pro=c medium polarity

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1 Electrophile Ter=ary -‐-‐

2 Nucleophile Weak base, weak nucleophile -‐

3 Solvent Polar pro=c + +

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1 Electrophile Secondary -‐-‐

2 Nucleophile Weak base, moderate nucleophile + -‐

3 Solvent Polar pro=c + +

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1 Electrophile Secondary

2 Nucleophile Weak base, good nucleophile + -‐

3 Solvent Polar apro=c + +

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1 Electrophile Ter=ary -‐

2 Nucleophile Weak base -‐

3 Solvent Polar apro=c -‐ -‐

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Neighboring group par=cipa=on

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ClS

Cl

Cl Cl

ClS

OH

Cl OH

H2O

H2O

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

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 first order in the mustard only.

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Two chemotherapy drugs based on nitrogen mustards.

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

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37 CH203 Fall 2014 Lecture 37 December 8.pdf

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