L

TOPIC 6. NUCLEOPHILIC SUBSTITUTIONS (chapter 6 and parts of chapter 11)

OBJECTIVES
1. Describe two pathways (mechanisms) to account for substitution at sp3 carbons bearing an electronegative atom (leaving group) 2. Discuss the effect of starting material (substrate), leaving group, reagent (a nucleophile) and reaction conditions on the course of a reaction 3. Recognize functional group transformations and synthesis of new molecules in one step by substitution of an appropriate material 4. Explore the substitution chemistry of alcohols and ethers

D.M. Collard 2007

REACTIONS TO DATE
b su it st io ut ns

H C C H
H2/Pt

Substn Substn

H C C Br
n Substn Subst

d n Ad im El
Addn Elimn

H C C OH
b su it st io ut ns

C C
ns t io di ad

Acid-Base Chemistry
RCOOH + R3N RCOO + R3NH

OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS

Cl KCN CN KCl

S:6.1-6.5

Br Br

NaC C H

NaBr H

NaN3

Cl

Cl

H2O HO

OH 2 HCl

D.M. Collard 2007

C L

Nu

C Nu

We are only considering sp3 (alkyl) substrates in this section. Molecules with leaving groups on sp2 (e.g., vinyl, aryl) or sp (ethynyl) carbons do not react in fashion described in this section

Nucleophiles
Donate a pair of electrons: to an electrophile (lone pair or pi bond) Neutral Anionic

H2O HO

H2C CH2

Electrophiles
Receive a pair of electrons: from a nucleophile Cationic Lacks an octet

C Cl Cl Al Cl

Polar, electrophilic

C X

D.M. Collard 2007

Effect of Leaving Groups on Electrophilicity

Nu

Nu

C-L bond must be polarizable

C-L bond must be relatively weak

L needs to be able to accommodate a pair of electrons

Good leaving groups are weak bases

Substitution: What is the Mechanism?

substitute /sb-,st,t(y)t/ vb: to put in the place of another

What are the rules?

D.M. Collard 2007

TWO CLASSES OF REACTION

Substitution reactions can be performed under different conditions which give rise to dramatically different outcomes. Nucleophilic substitution reactions can be classified as one of two types, based on these experimental observations. In order to develop predictive tools, we need to understand reasons why these observations are important. That is, we need to develop proposals for two different mechanisms which are consistent with the two sets of data and which we can use to predict the outcome of other reactions.

SUBSTITUTION AT 1 SUBSTRATES: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN2)

Examples

S:6.6-6.8 Prob: 6.13-15, 17aj,25,27, 31,33,36

CH3CH2 Br + Na

O CH3

CH3CH2

CH3

I + Na

S CH3

CH3

D.M. Collard 2007

Kinetics
CH3CH2Br + NaOMe CH3CH2OMe + NaBr

[CH3CH2Br] 0.01 M 0.02 M 0.01 M 0.02 M

[NaOMe] 0.01 M 0.01 M 0.02 M 0.02 M

relative rate 1 2 2 4

Conclusion: Rate = k[R-L][Nu]

d1

Mechanism of Nucleophilic Substitution of 1 Alkyl Halides: The SN2 Reaction

D.M. Collard 2007

Slide 15 d1
d-laptop, 8/6/2007

Chirality
Chiral R-L forms R-Nu with opposite stereochemistry (inversion of stereochemistry, Walden Inversion)
CH3 Br H D CH3 H D OH

OH

Interpretation:
Nu L

Nucleophilicity
Basicity and nucleophilicity are not the same, but they are related phenomena A negatively charged nucleophile is more reactive than its conjugate acid. CN > HCN OH > H O RO > ROH 2 In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicity parallels trends in basicity. RO > HO >> RCO2 >> ROH > H2O Steric bulk hinders nucleophilicity

CH3O

H3C CH3 C O CH3

Across a row in the periodic table, nucleophilicity parallels trends in basicity. CH3 > H2N > HO > F NH3 > H2O

D.M. Collard 2007

Down a column in the periodic table, trends in nucleophilicity of anions depend on the choice of solvent.
H2O CH3CO2H MeOH EtOH (CH3)2SO DMSO polar aprotic CH3CN AN (CH3)2NCHO DMF CH3COCH3 CH2Cl2 - THF dimethyl sulfoxide actonitrile N,N-dimethylformamide acetone methylene chloride tetrahydrofuran diethyl ether

polar protic

O
Et2O ether non-polar CH3(CH2)4CH3 benzene

Protic solvents solvate the anions (nucleophiles) by H-bonding and cations (counterions). Small R O H electronegative anions particularly are well solvated, lowering their nucleophilicity. Trends in nucleophilicity in polar protic solvents increases H going down a column of the periodic table O R Polar aprotic solvents cannot hydrogen bond to anions (but do solvate cations). Trends in nucleophilicity in polar aprotic solvents parallels trends in basicity.

H H

R O

R O H

O R R

Large neutral nucleophiles (H2S, PR3) are highly polarizable and can donate more electron density than smaller neutral nucleophiles.

D.M. Collard 2007

Nucleophilicity of Anions

nucleophilicity
base strength Be B C CH3 N NH2 P O F

He

nucleophilicity in APROTIC solvents

nucleophilicity in protic solvents

Li

Ne

OH
S

F
Cl Ar base strength

Na

Mg

Al

Si

SH
Se

Cl
Br

Ca

Ga

Ge

As

Kr

SeH

Br
I

Relative Nucleophilicity (in MeOH)

Relative Nucleophilicity Excellent Nucleophiles CN HS I Good Nucleophiles
OH

Cyanide Thiolate Iodide Hydroxide Bromide Azide Ammonia Nitrite Chloride Acetate Fluoride Methanol Water

126,000 126,000 80,000 16,000 10,000 10,000 8000 5000 1000 630 80 1 1

Br N3 NH3 NO2 Fair Nucleophiles Cl CH3COO F CH3OH H2O

Nucleophilic relative strength is measured by relative rate in an SN2 reaction (but depends on substrate, solvent type, etc.)

D.M. Collard 2007

Leaving Group Ability

Rate: -I > -Br > -Cl >> -F

C-L bond must be broken weaker bonds are more polarizable, easier to break Bond strengths (kcal/mole):
C-F C-Cl C-Br C-I 116 79 66 52

Overall: A good substrate for bimolecular nucleophilic substitution should have: 1. Weak C-L bond 2. Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) 3. Leaving group that can accommodate a pair of electrons

Leaving group Good Leaving Groups I Br Cl RSO3 H2O Very Poor Leaving Groups Iodide Bromide Chloride Sulfonate Water

pKa of conjugate acid -10 -9 -7 -6.5 -1.7

F HS
CN

Fluoride Thiolate Cyanide Hydroxide Alkoxide Hydride

2 3

3.2 7 9.2 15.7 16-18 35 38 48

HO RO H
NH CH

Amino Methyl

D.M. Collard 2007

Alkyl Substrates
Rate: methyl > 1 > 2 ( 3 unreactive)
Me

Nu

HH H

Et

L
iPr

Nu

MeMe Me

tBu

Adjacent alkyl groups also slow the reaction

L L L

Energetics of One-Step (i.e., concerted) Reaction SN2

Reaction coordinate

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Practical Applications of SN2 Reactions: Functional Group Transformations at 1o and 2o Carbons

source of nucleophile
OH OR SR R SR CN R Hal N3 NR'3 C CH R CN R N3 R NR'3 R C CH HC CH R OH R OR ROH RSH Na OH
Na NaH

Na Na CN N3

OR SR

Na Na

NR'3
NaNH2

Na

C CH

Intramolecular SN2 Reactions - Cyclizations

Br NaOH OH O

Br

NaOH OH

D.M. Collard 2007

~ MAKE FLASHCARDS ~
Br
methyl, 1o, and 2o

NaCN

NC
inversion of stereochemistry SN 2

front
Substrate + Reagent (and conditions)

back
Substrate + Reagent (and conditions)

Substrate and Product

Substrate and Product

Reagent (and conditions) and Product

Reagent (and conditions) and Product

Problem: How would you prepare 2-phenylethanethiol from 1-iodo-2phenylethane?

I ?
SH

Problem: How would you make the following compound from 1bromopropane and any other starting materials?
N Br

D.M. Collard 2007

Problem: Which of the following would undergo the fastest reaction with 1-bromopropane? (a) Ph3N or Ph3P

(b) 1.0 M CH3ONa

or

2.0 M CH3ONa

Synthesis of Alkynes and Alkanes: Alkylation of Acetylide Anions

R C C H

NaNH 2

R' R C C Na

Br R C C R' H2/cat R CH2 CH2 R'

R' must be 1

D.M. Collard 2007

SUBSTITUTION AT 3 SUBSTRATES: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN1)

S:6.9-6.13 Prob: 6.16,30,35

Example

Br

H2O

OH

HBr

Experimental observations of kinetics, chirality, substrate structure and effect of nucleophiles for this reaction are inconsistent with the SN2 mechanism

Kinetics
CH3 H3C Br CH3 CH3 H2O H3C OH CH3 HBr

[t-BuBr] 0.01 M 0.02 M 0.01 M 0.02 M

[H2O] 0.01 M 0.01 M 0.02 M 0.02 M

relative rate 1 2 1 2

Result: Rate = k[R-L] independent of concentration of Nu

D.M. Collard 2007

Mechanism of Nucleophilic Substitution of 3 Alkyl Halides: SN1

Practical Applications of SN1 Reactions: Solvolysis

The only practical SN1 reactions are solvolyses, reactions in which the solvent also acts as the nucleophile. These reactions arise because solvents which are polar enough to facilitate dissociation of the substrate are also nucleophilic
RR R S-H Br
(protic solvent)

S-H = HOH, RCO2H, ROH

D.M. Collard 2007

Substrates
Rate: 3 > 2 (1, methyl not reactive) Interpretation:
MeMe Me L

Stability of Carbocations
H C C H H

Carbocation Methyl Ethyl i-Propyl t-Butyl

Relative Energy (kcal/mol) 0 -37 -65 -83

- More substituted carbocation stabilized by hyperconjugation

Effect of Leaving Group

Rate: -I > -Br > -Cl (F: unreactive) MeMe L Me

C-L bond must be broken weaker, polarizable bonds are easier to break Bond strength: C-F > C-Cl > C-Br > C-I Overall: A good substrate for unimolecular nucleophilic substitution should have: 1. Weak C-L bond 2. Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) 3. Leaving group which can accommodate a pair of electrons

D.M. Collard 2007

Effect of Nucleophile/Solvent
Rate independent of concentration of nucleophile (solvent) Rate depends on polarity of solvent

Chirality
A single enantiomer of substrate with the leaving group on the stereogenic center reacts to give product that consists of a mixture of both enantiomers.
Me PrEt Br Me PrEt OH HO Me EtPr

H2O

Energetics of a Two-Step Reaction SN1

Reaction coordinate

D.M. Collard 2007

SUMMARY: FACTORS EFFECTING SN1 AND SN2 REACTIONS

SN1
Nu H L H Nu
L Nu

S:6.15; Prob: 6.18,26

SN2

Nu H L
Dissociation-Nucleohipic addition-Deprotonation

Nu
One-step (concerted) mechanism

Substrate: 3>2>>1or methyl - Stability of carbocation intermediate Rate = k [substrate] - independent of [nucleophile] - rate depends on solvent polarity Chirality - racemization Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H)

Substrate: Methyl>1>2>>3 - Steric bulk hinders attack of Nu Rate = k [substrate] [nucleophile] Chirality - Inversion Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate

A Limitation to Reactions of Alkyl Halides with Nucleophiles

Elimination competes with substitution if the nucleophile is too basic or if the electrophile is too crowded (we will explore this further in Topic 7)
X H L X H L

D.M. Collard 2007

SUBSTITUTION REACTIONS OF ALCOHOLS

S:11.6-11.9

Alcohols as Acids and Bases

R O H R O B H R O H

R O H

H A

Alcohols are weak acids and weak bases. Acid-base chemistry is important in activating the electrophilic and nucleophilic character of alcohols, respectively.

Conversion Of Alcohols To Alkyl Halides

Alcohols do not react with sodium halides to give alkyl halides!
Na Br H3C OH

Alcohol + H-Hal
3o Alcohols: SN1

H Br OH O

H H

D.M. Collard 2007

1o Alcohols: SN2
H O H

OH

HBr

Other reagents

(1 or 2 )

R O H

PBr3

R Br

(1 or 2 )

R O H

SOCl2

R Cl

D.M. Collard 2007

MESYLATES AND TOSYLATES IN SN2 REACTIONS

O Cl R O H O 1o Nu R O S R' O R = Me: mesylate (Ms) 4-methylphenyl: tosylate (Ts) S R' O

S:11.10

R Nu
Nu = Hal RS NC etc.

Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1ethanol?

OH
?

SH

Problem: How would you make the following product from 1-propanol and any other starting materials?

? OH N + Cl

D.M. Collard 2007

S:11.11-12

SYNTHESIS OF ETHERS
Synthesis of Ethers: Williamson Ether Synthesis
Overall Reaction and Mechanism
1 or 2o

Prob: 11.32

R Br (Cl or I)

R O

Na

Designing Williamson Ether Syntheses You could suggest making either C-O bond of the ether.
O O CH3 Br

H3C Br

O CH3

CH3

D.M. Collard 2007

Synthesis of Symmetrical Ethers: Dehydration of Alcohols

OH H2SO4 140 oC O

At higher temperature a competing reaction predominates (elimination of water to form an alkene, see Topic 7)
OH H2SO4 180 oC

Reaction of Ethers: Acid-catalyzed Hydrolysis

R O R' HBr R OH HBr + Br R'

D.M. Collard 2007

HBr

Br

CH3 HBr

OH

Br

CH3

SUBSTITUTIONS IN SYNTHESIS
You should prepare a chart of all of the types of reactions that have been covered so far .well add more later.
tit bs su io ut

Prob: 6.17,20, 32a-h,33

H C C H
H2/Pt

Br2, h

H C C Br
HBr Subst

ns

Br

im El

C C

Addn Elimn

H C C OH
st ub s

ns io t itu

D.M. Collard 2007

S:4.18-19

ONE-STEP SYNTHESES
It is important to recognize transformations which can be performed in a single step. Use the thought process:
- What can the product can be made from? PRODUCT STARTING MATERIAL

- The synthesis itself is STARTING MATERIAL PRODUCT

Problem: How would you prepare the following from appropriate alkyl chlorides?

(a) CH3CH2SH (b) (CH3)2CHCN

(c)

CH2 C C CH3

from starting materials with 7 or fewer carbon atoms

D.M. Collard 2007

Problem: Why does the following reaction not take place?

CH3CH2CH3 + HO

CH3CH2CH2OH + H

Problem: Explain why reaction of 1-bromopropane with potassium cyanide gives a mixture of CH3CH2CH2CN (major product) and CH3CH2CH2NC (minor)? Draw Lewis structures of the products and nucleophiles.

D.M. Collard 2007

Problem: How can you prepare the following two compounds from the appropriate alkyl bromide?

(a) Methyl phenyl ether, Me-O-Ph

(b) (S)-2-Pentanol, CH3CH(OH)CH2CH2CH3

Problem: How could you perform the following synthesis? [An introduction to designing multi-step syntheses]
N3
from

OH

D.M. Collard 2007

Problem: Predict the structure of the product of the following reaction

Cl NaOH EtOH C6H10S

SH

An important limitation on acid catalyzed SN reactions tert-Butanol must be protonated to make the hydroxyl group a better leaving group. Ammonia is nucleophilic So why doesnt this reaction work?

OH

NH3 H2SO4

NH2

Why cant you do this sequentially? i.e.,

OH

H2SO4

OH2

NH3

NH2

Acid promoted SN2 reactions are limited to cases where the nucleophile is very weakly basic (i.e., reaction with H-Hal). For other nucleophiles, convert the alcohol to the tosylate or mesylate first.

D.M. Collard 2007

The role of nucleophilicity, leaving group ability, and substrate on SN processes. Which of the following proceed efficiently?

H3C Br

H2O

H3C OH

H3C Br

NaOH H2O NaOH H2O

H3C OH

Br

H2O

OH

Br

OH

OH

NaBr H2O

Br

OH

HBr H2O

Br

Br NaOH H2O

OH

OH HBr H2O

Br

What about secondary alkyl halides?

1 R-L: 3 R-L: 2 R-L: might display features of both SN1 and SN2 reactions (!) Under conditions strongly favoring SN1 reactions SN1 Under conditions strongly favoring SN2 reactions SN2.

..but strongly basic nucleophiles promote elimination! (see Topic 7)

What about vinyl halides and aryl halides?

D.M. Collard 2007

TOPIC 6 ON EXAM 3
Types of Questions
- Recognize factors which influence the mechanism of nucleophilic substitutions - Predict outcomes of substitution reactions - The problems in the book are good examples of the types of problems on the exam.

Preparing for Exam 3

- Work as many problems as possible. - Work in groups. - Do the Learning Group Problem at the end of the chapter. - Work through the practice exam

D.M. Collard 2007