ch 11: substitution and elimination substitution...

CH 11: Substitution and Elimination Substitution reactions

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Things to sort out: Nucleophile Electrophile -- > substrate Leaving Group SN2 SN1 E1 E2 Analysis Scheme

• Kinetics – Reaction profile • Substrates and steric concerns • Strength of nucleophile • Leaving Group Ability • Solvent Effects • Stereochemistry

SN2 – Nucleophilic Substitution involving two molecules in RDS. Kinetics The classic one step reaction!

CH3 LGNu: Nu CH3+ + LG

Rate = k [R-LG] [Nu:-] bimolecular mechanism – requires collisions between two molecules. Transition state – Orbital view, in which Nu = LG.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Generalized Reaction Profile, in which Nu =/= LG

Note the reversibility and the positions of the reactants and products.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Substrates and Sterics

R group Rxn rate

CH3 1 CH3CH2 3.3 x 10–2

CH3CH2CH2 1.3 x 10–2 (CH3)2CH 8.3 x 10–4

(CH3)3CCH2 2.0 x 10–7 (CH3)3C 0

Strength of the Nucleophile A nucleophile is like a base.

The strength of a base is determined from the pKa of the conjugate acid. If HA is a strong acid, A is a weak base. What is the pKa range? If HA is a weak acid, A is a stronger base. What is the pKa range? What is the difference between a base and a nucleophile? How would you classify HS- vs HO- in terms of basicity? In terms of nucleophilicity?

Reasonable nucleophiles

Not-so-good nucleophiles

Hot nucleophiles

Relative Nucleophilic Strength Species Name Relative nucleophilicity

NΞC– cyanide 126,000 HS– thiolate 126,000 I– Iodide 80,000

HO– hydroxide 16,000 Br– Bromide 10,000 N3

– Azide 8,000 NH3 Ammonia 8,000 NO2

– Nitrite 5,000

Cl– chloride 1,000 CH3CO2

– acetate 630 F– fluoride 80

CH3OH methanol 1 H2O Water 1

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Trends in Nuclephilicity

Good nucleophiles have high or low negative charge. Good nucleophiles are large and polarizable or small and compact. Which direction in a row increases nucleophilicity? In a column? How do nucleophiles differ from bases? Effect of Leaving Group Poor bases are better LG; good bases are poor LG.

Good LGs are stabilized as anions. Good LGs are CBs of of strong acids. Poor LGs are less stable anions. Poor LGs are CBs of weak acids.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf

Classic Issue in organic chemistry: Alcohols are stable because OH- is a poor LG

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Alternative strategy is to associate O with an atom that makes a stronger bond than the C-O bond. The O-S bond stabilizes the negative charge on O. Highly oxidized SO4

2- called sulfate, organo version R-SO3- called sulfonate, the most popular one is

called tosylate.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Solvent Effects Polar solvents are necessary to separate ions and stabilize the rather polar transition state. How is the polarity of solvents measured? NaOH is not soluble in hexane. NaOH is soluble in water. How about acetone? Alcohol?

However, protic solvents inhibit small compact nucleophiles (especially F- and –OH). Protic solvents essentially are H-bonding solvents.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Polar Aprotic Solvents Resonance Structures

CH3

O

CH3 CH3

S

O

CH3

H

O

NCH3

CH3

P

O

(H3C)2NN(CH3)2

N(CH3)2

CH3 N

acetone DMSO

Acetonitrile

DMFHMPA

CH3

C+

O-

CH3 CH3

S+

O-

CH3

H

O-

N+

CH3

CH3

P+

O-

(H3C)2NN(CH3)2

N(CH3)2

CH3 C+

N-

acetone DMSO

Acetonitrile

DMFHMPA

Polar Protic Solvents H2O CH3OH CH3CH2OH CH3NH2

Stereochemistry SN2 reactions proceed with inversion of stereochemistry. Does R always go with S? http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf SN1 Nucleophilic Substitution with one molecule in RDS -- unimolecular SN2 cannot always take place if the factors above prevent it. When substitution occurs anyway, the mechanism must be different.

Mechanism

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Rate = k [(CH3)3Br] only the concentration of the 30 alkyl halide


3

42

BrNaI

acetoneI I

3

42

(R) (S)

Br

HClH3C

INaOHHO HO

HCl

CH3

IH2O

Reaction as such as it is. Reaction is usually solvolysis.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf The reaction rate is proportional to the stability of the cation Rate is proportional to

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Stability of C+ R3C+ ~ benzylCH2+ > R2HC+ ~ allylC+ > H2RC+ >> H3C+ Role of Nucleophile


Leaving Group Ability

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Would SN1 favor good or poor LG? Role of Solvent:

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Solvent stabilizes the heterolytic cleavage – formation of cation and anion. What does this mean to SN2 reactions? Stereochemistry leads to racemization

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Examples -- Solvolysis

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf What is the role of the solvent? Why is there a slight ee in this reaction?

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf There is no clear distinction between the two mechanisms, but there are trends.

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206sub.pdf Classify these reactions as SN1 or SN2 http://www.cem.msu.edu/~reusch/VirtualText/alhalrx1.htm#hal1

CH3

CH2CH2

CH2Br

+ CNalcohol

(fast)CH3

CH2CH2

CH2

CN+ Br

-

CH3

Br

H

H

R + CN

alcohol

(slower)

CH3

H

CN

H

S

CH3 C

CH3

CH3

CH2 Br + CNalcohol

(slower)No reaction

CH3

C

CH2

H

CH3

Br +alcohol

(fast)

CH3 SR

CH3

C

CH2

H

CH3

S

CH3

S+ Br

-

CH3

C

CH2

H

CH3

Br +alcohol

(slower)

CH3 SHR

CH3

C

CH2

H

CH3

S

CH3

S+ Br

-

CH2

C

CH2

CH3

CH3

Br

CH2CH3

+acetonitrileS

H2O CH2

C

CH2

CH3

CH3

OH

CH2CH3

S

CH2

C

CH2

CH3

CH3

OH

CH2 CH3

RBrH

Predict products and mechanisms from these substitution reactions:

Answers at http://www.cem.msu.edu/~reusch/VirtualText/alhalrx2.htm#hal4 Elimination Elimination is the formation of an alkene by removing H-LG from a molecule.

http://www.cem.msu.edu/~reusch/VirtualText/alhalrx3.htm#hal6 Is the nucleophile a base (H-seeker) or a C-seeker

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf

E1 Mechanism

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf SN1 vs E1

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf Zaitseff’s Rule and Regiochemstry

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf There must always be a Beta-H available for elimination to occur.

Mechanism of SN1 elimination

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf E2 – Bimolecular elimination – always needs strong base

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf Rate = k [R-LG] [base] E2 vs SN2 Base vs Nucleophile


E2 vs SN2 Substrate too hindered

http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf E2 vs SN2 --Beta-H available and sterics sufficient

Mechanism of E2 process


E2 occurs with anti-periplanar relationship between LG and Beta-H This can lead to stereoselectivity.


http://www.sci.kun.nl/chemistry/onderwijs/oc1-2001/College%20H%206el.pdf Explain the product ratios. Why do you get both cis and trans alkenes?

ch 11: substitution and elimination substitution...

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