Chem 334 - Fall 1998 - Organic Chemistry I
Portland State University - Dr. Carl C. Wamser

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Chapter 8 - Nucleophilic Substitution and Elimination

Nucleophilic Substitution

• R-X + Nu:- ----> R-Nu + X:-
• replacement of X- (a leaving group)
• X- often halide
• wide variety of nucleophiles
• very versatile synthetic reaction

Recognizing Nucleophiles

• must have a pair of electrons
• often have a negative charge
• are also basic
  • nucleophiles bond to positive carbon
  • bases bond to positive hydrogen

Solvents

• Protic solvent: a solvent that is a hydrogen bond donor
  the most common protic solvents contain -OH groups
• Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor
  nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity
• Solvents are classified as polar and nonpolar
  the most common measure of solvent polarity is dielectric constant
• Dielectric constant: a measure of the ability of a solvent to insulate opposite charges from one another
• The greater the value of the dielectric constant of a solvent, the smaller the interaction between ions of opposite charge dissolved in that solvent
• Polar protic solvents: water, alcohols, carboxylic acids
• Polar aprotic solvents: DMSO, DMF, acetonitrile, acetone
• Nonpolar solvents: alkanes, cycloalkanes, ethers

The SN2 Mechanism

• concerted (single step)
• involves backside attack
  (simultaneous bond-making and bond-breaking)

SN2 Mechanism - Evidence

• reaction rate proportional to concentration of both reactants
  Rate = k [RX] [Nu]
• kinetics are second-order
• mechanism is bimolecular

SN2 Mechanism - Evidence

• stereochemistry is inverted
• indicates backside attack
  
  

SN2 Mechanism - R Groups

• bulky R groups react much slower
• reactivity order in SN2:
  CH3 > 1° > 2° > 3°
• steric hindrance to attack by the nucleophile slows the rate
  n-Bu > i-Bu > s-Bu > t-Bu

SN2 Mechanism - X Groups

• larger leaving groups react faster
  I- > Br- > Cl- >> F-
• poor leaving groups
  (unstable anions, strong bases)
  OH- , RO- , NH2-

SN2 Mechanism - Nucleophiles

• Nucleophilicity: a kinetic property measured by the rate at which a Nu attacks a reference compound under a standard set of experimental conditions
• Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction
• Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity
• Within a period, nucleophilicity parallels basicity
  CH3- > NH2- > OH- > F-
• Within a family, larger atoms are better nucleophiles (polarizability)
  I- > Br- > Cl- >F- or R2Se > R2S > R2O or R3P > R3N
• With the same nucleophilic atom but different charge type, nucleophilicity parallels basicity
  OH- > H2O or SH- > H2S
• With the same nucleophilic atom, same charge type, nucleophilicity parallels basicity
  OH- > CH3COO-

Solvent Effects on Nucleophilicity

• Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents
• A guiding principle: the freer the nucleophile, the greater its nucleophilicity
• Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF)
  are very effective in solvating cations, but not nearly so effective in solvating anions.
• Because anions are only poorly solvated, they participate readily in SN reactions, and
  nucleophilicity parallels basicity: F- > Cl- > Br- > I-
• Polar protic solvents (e.g., water, methanol)
  anions are highly solvated by hydrogen bonding with the solvent
  the more concentrated the negative charge of the anion, the more tightly it is held in a solvent shell
  the nucleophile must be at least partially removed from its solvent shell to participate in SN reactions
  because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F-

SN1 Mechanism

• two-step mechanism
  first X- leaves, then Nu- bonds
• carbocation intermediate
  R-X ----> R+ + X-
  R+ + Nu- ----> R-Nu

SN1 Mechanism - Evidence

• reaction rate proportional to concentration of RX reactant,
  but independent of concentration of Nu
  Rate = k [RX]
• kinetics are first-order
• mechanism is unimolecular

SN1 Mechanism - Evidence

• stereochemistry is scrambled
• chiral reactant gives racemic product
• carbocation intermediate is achiral

SN1 Mechanism - R Groups

• R groups that make more stable carbocations react faster
  3° > 2° > 1° > CH3
• tertiary RX react by SN1
• CH3 and primary RX react by SN2
• secondary RX react either way

SN1 Mechanism - X Groups

• same effects as for SN2
  I- > Br- > Cl- >> F-

Solvolysis Reactions

• solvent as nucleophile

Neighboring Group Effects - Mustard Gases

• Mustard gases contain either S-C-C-X or N-C-C-X
• What is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile
• The reason is neighboring group participation by the adjacent heteroatom
• The highly strained three-membered ring then reacts with the external nucleophile to open the ring.

Phase-Transfer Catalysis

• A substance that transfers ions from an aqueous phase to an organic phase
• An effective phase-transfer catalyst must have sufficient
  • hydrophilic character to dissolve in water and form an ion pair with the ion to be transported
  • hydrophobic character to dissolve in the organic phase and transport the ion into it

Beta-Elimination Reactions

• another common reaction of alkyl halides,
  usually in competition with substitution
• base removes H+ as X- leaves
  base attacks H
  (nucleophile attacks C)
  

E2 Elimination Mechanism

• concerted (single-step)
• the H and X eliminated must be aligned anti to one another
• the breaking sigma bonds merge into overlapping p orbitals for the pi bond

E2 Stereochemistry

• anti periplanar arrangement of H and X may lead to specific products

Zaitsev Rule

• preferred product is the more stable alkene (more substituted)
  because the product stability is reflected in the transition state

E1 Elimination Mechanism

• two-step mechanism
  first X- leaves, then H+ leaves
• carbocation intermediate
• same first step as SN1

Substitution or Elimination ?

• substitution: nucleophile attacks C
  either attacks RX [SN2] or R+ [SN1]
• elimination: base attacks H
  either attacks RX [E2] or R+ [E1]

Nucleophile or Base?

• most nucleophiles are also bases
  (and vice versa)
• to favor elimination:
  use a strong, hindered base
  e.g., KOtBu
• to favor substitution:
  use a small, unhindered nucleophile

Reactivity Patterns

• CH3X - can only do SN2
• primary (1°) RCH2X :
  SN2 works well, E2 with KOtBu
  SN1 and E1 don't work
• secondary (2°) R2CHX :
  SN2 works with a good nucleophile
  E2 works with KOtBu
  SN1 and E1 occur without strong base or nucleophile
• tertiary (3°) R3CX :
  SN1 works well with a good nucleophile
  E1 often competes with SN1
  E2 works well with KOtBu

Nucleophilic Substitution Mechanisms

What's the difference between SN1 and SN2 ?

	SN2	SN1
Reaction	RX + Nu --> RNu + X	same
Mechanism	concerted	two steps
Intermediate	none	carbocation
Kinetics	second-order	first order
Stereochemistry	complete inversion	nonspecific
Nucleophile	important	unimportant
Leaving Group	important	important
Alkyl Group	CH3 > 1° > 2° > 3° (steric hindrance)	3° > 2° > 1° > CH3 (carbocation stability)
Occurrence	CH3 , 1° , some 2°	3° , some 2°
Solvent Effects	variable	polar, protic

Elimination Mechanisms

What's the difference between E1 and E2 ?

	E2	E1
Reaction	RX + base --> C=C	same
Mechanism	concerted	two steps
Intermediate	none	carbocation
Kinetics	second-order	first order
Stereochemistry	anti periplanar	nonspecific
Base	important	unimportant
Leaving Group	important	important
Alkene Produced	Zaitsev Rule	same

Substitution vs. Elimination

How can you make ... react in an ... mechanism ?

	SN1	SN2	E1	E2
CH3X	No	good nucl.	No	No
1° ( RCH2X )	No	good nucl., weak base	No	strong base, weak nucl.
2° (R2CHX )	No	good nucl., weak base	No	strong base
3° ( R3CX )	good nucl., weak base	No	polar solvent, no base or nucl.	strong base

What's most likely to happen when ... reacts with ... ?

	Good nucl., strong base, e.g., OH-	Good nucl., weak base, e.g., I-	Poor nucl., strong base, e.g., tBuO-	Poor nucl., weak base, e.g., H2O
CH3X	SN2	SN2	SN2	No reaction
1° ( RCH2X )	SN2	SN2	E2	No reaction
2° (R2CHX )	E2	SN2	E2	No reaction
3° ( R3CX )	E2	SN1	E2	SN1