Lecture 1 - Introduction to Organic Reactions

Pharmaceutical Pharmaceutic al Chemistry 126 PHARMACEUTICAL PHARMACEUTICAL ORGANIC ORGANIC CHEMISTR CHEMISTRY 2

INTRODUCTION

What is a REACTION MECHANISM? It provides insight into electron movement and bonding that takes place during a chemical transformation. It provides a useful means of predicting the product(s) of chemical reactions. It provides unequivocal proof of the given pathway (in terms of electron movement and binding) that a reaction follows. follows.

INTRODUCTION

What is a REACTION MECHANISM? It provides insight into electron movement and bonding that takes place during a chemical transformation. It provides a useful means of predicting the product(s) of chemical reactions. It provides unequivocal proof of the given pathway (in terms of electron movement and binding) that a reaction follows. follows.

ORGANIC REACTIONS (Review) R

R C

R 1

R

R

ADDITION

Electrophilic

C

O

Nucleophilic

C R

2

Electrophilic

SUBSTITUTION

EW

Nucleophilic

ELIMINATION R

H

X

C

C

R

ORGANIC REACTIONS (Review) ELECTROPHILES  those that possess: electron-poor species  those  – 

•

formal positive charges, e.g., carbocations, nitronium ions, sulfonates, acylium ions

•

incomplete octets, e.g., free radicals, carbenes

•

greatly reduced electron density, e.g., BF3, AlCl3

ORGANIC REACTIONS (Review) NUCLEOPHILES electron-rich species which may have: • excess negative charges; • fractional negative charges; or • lone pairs of electrons that can readily be used for

formation of bonding molecular orbitals • e.g., carbanions, hydroxides, alkoxides, sulfides, halides, cyanides, carboxylates, phenoxides and azides

ORGANIC REACTIONS (Review) ADDITION ELECTROPHILIC REACTIONS

ORGANIC REACTIONS (Review) ADDITION NUCLEOPHILIC REACTIONS

ORGANIC REACTIONS (Review) ADDITION NUCLEOPHILIC REACTIONS (continued)

ORGANIC REACTIONS (Review) SUBSTITUTION ELECTROPHILIC REACTIONS

ORGANIC REACTIONS (Review) SUBSTITUTION ELECTROPHILIC REACTIONS (continued)

ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS (Nu-)

A substitution reaction in which a nucleophile replaces a leaving group ( L)  – 

δ+

C

X=

 – 

δ-

+

X

Cl

 – 

Br

 – 

I

 – 

Nu-

Nu- =

C

OH

 – 

OR

 – 

 – 

 – 

Nu

SH

 – 

SR

 – 

+

X-

C≡N

NH2

 – 

NHR

 – 

C≡CR

NR2

 – 

ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS

ORGANIC REACTIONS (Review) SUBSTITUTION NUCLEOPHILIC REACTIONS (continued)

ORGANIC REACTIONS (Review) SN2 Nu-

C

X

Nu-

C

X

Nu-

C

SN1

X-

C

NuC

X

C

+

Nu Nu-

Nu

C

X-

ORGANIC REACTIONS (Review) Substitution Nucleophilic Bimolecular (SN2) Rate = k  [RX][Nu-]

ORGANIC REACTIONS (Review)

C6 H13

H

C

C6 H13 Br

CH3 ( )-2-Bromooctane [α] = 39.60 100% OP  – 

 – 

NaOH SN2

HO

C

CH3 (+)-2-Octanol [α] = +10.30 100% OP

H

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review) Substitution Nucleophilic Unimolecular (SN1) Rate = k 1 [RX] k 1

k 2

k 2

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review) SN2

SN1

Second-order kinetics

First-order kinetics

Rate = k [RX][Nu-]

Rate = k1 [RX]

Complete stereochemical inversion

Racemization (and inversion)

Absence of rearrangement

Rearrangement

CH3W > 10 > 20 > 30

30 > 20 > 10 > CH3W

ORGANIC REACTIONS (Review) Factors Affecting Mechanism 1. Nature of leaving group 2. Nature of alkyl group of the substrate 3. Nature of nucleophile 4. Concentration of nucleophile 5. Nature of solvent

ORGANIC REACTIONS (Review) 1. Nature of leaving group

Reactivity of Leaving Group

Rate of Both S N2 and S N1

ORGANIC REACTIONS (Review) 2. Nature of alkyl group of the substrate Steric Hindrance Carbocation Stability SN2 Reactivity Increases

SN1 Reactivity Increases

ORGANIC REACTIONS (Review) 3. Nature of nucleophile Strong nucleophile favors SN2. Weak  nucleophile favors SN1.

Charge Electronegativity Delocalization

   e     l    i     h    p    o    e     l    c    u    N     f    o     h    t    g    n    e    r    t    S

ORGANIC REACTIONS (Review) 4. Concentration of the nucleophile An increase in [Nu-] speeds up the second-order reaction but has no effect on the first-order reaction.

-

[Nu ]

SN2

indirectly favors the SN1

[Nu-]

SN2

favors the SN2

A decrease in [Nu-] slows down the second-order reaction but has no effect on the first-order reaction.

ORGANIC REACTIONS (Review) 5. Nature of solvent Polarity Polar Aprotic Solvent

SN2

ORGANIC REACTIONS (Review)

Polar protic Solvent

SN1

ORGANIC REACTIONS (Review) Rearrangement (1,2-Shift) - takes place to yield a more stable carbocation + C

C +

C

H

C

C +

H

C

H +

C R

C +

C

C R

C +

C R

ORGANIC REACTIONS (Review) Rearrangement (1,2-Shift) H3C CH2

+ CH2

+

H3C CH

CH3 H3C

C

CH3

CH3 + CH2

H3C

+

C

CH3

H CH3 H3C

C CH3

CH3 + CH2

H3C

+

C

CH2

CH3

ORGANIC REACTIONS (Review) Rearrangement (1,2-Shift) CH3 H3C

C

CH2

-

Br 

C2H5O

?

CH3

CH3 H3C

C

CH2

CH3

Br 

C2H5OH

?

ORGANIC REACTIONS (Review) ADDITION-SUBSTITUTION REACTIONS - involving the carbonyl center

ORGANIC REACTIONS (Review) AROMATIC NUCLEOPHILIC SUBSTITUTION -

Cl

O

O

+

O

-

Nu

+

N

N

+

O

-

Nu

+

+

O

-

+

N

N

O

O

Cl

-

O

Nu +

+

-

Nu

H , H2O 

+

Cl

-

Cl

-

ORGANIC REACTIONS (Review) ELIMINATION REACTIONS

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review)

Rate = k 1 [RX]

ORGANIC REACTIONS (Review)

Rate = k  [RX][B-]

ORGANIC REACTIONS (Review)

ORGANIC REACTIONS (Review) Factors Affecting Mechanism (SN vs E) 1. Stability of alkene product 2. Nature of nucleophile

ORGANIC REACTIONS (Review) 1. Stability of alkene Substitution Increases

Elimination Increases R C

R H2C

CH2

C

CH2

CH2

R H

H

R

C R

H C

H C

R

R

R

C

R C

R

R

C R

ORGANIC REACTIONS (Review) 2. Nature of Nucleophile weakly basic nucleophile  substitution  – 

(I-, Br-, RS-, N3-, RCOO-)

strongly basic nucleophile and highly branched elimination

 –