Chemistry 250-02Organic Chemistry I

Fall, 2015

Day 19

Wed., Oct., 14, 2015 Chapter 7

Alkyl Halides Rδ+-Xδ-

(Ionic Substitution Lab Expt # 6)

Chem Act 13 A, (B), C; D (Today)

R-OH -> R-Cl R-OH -> R-Br

Chapter 7

One Step and Two Step Nucleophilic Substitution

Chem Activity 13A and 13B

7.4 SN2 – a concerted mechanism

• How might you write a rate law for this reaction?

• How would you design a laboratory experiment to test this mechanism?

• Test yourself with conceptual checkpoint 7.6

7-4 Klein, Organic Chemistry 2e

7.4 SN2 – stereochemistry• What do S, N, and 2 stand for in the SN2 name?

• How might we use stereochemistry to support the SN2 mechanism for the following reaction?

• Practice drawing SN2 reactions with SkillBuilder 7.2

7-5 Klein, Organic Chemistry 2e

7.4 SN2 – backside attack• The nucleophile attacks from the back-side

– Electron density repels the attacking nucleophile from the front-side

– The nucleophile must approach the back-side to allow electrons to flow from the HOMO of the nucleophile to the LUMO of the electrophile.

– Proper orbital overlap cannotoccur with front-side attack because there is a node onthe front-side of the LUMO

7-6 Klein, Organic Chemistry 2e

• Draw the transition state for the following reaction. Use extended dotted lines to represent bonds breaking and forming

• Practice drawing transition states with SkillBuilder 7.3

7.4 SN2 – backside attack

Transition state symbol

7-7 Klein, Organic Chemistry 2e

7.4 SN2 kinetics• Less sterically hindered electrophiles react more readily

under SN2 conditions.

• To explain this trend, we must examine the reaction coordinate diagram

ons, Inc. All rights reserved.

7-8 Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data

• How do we use the diagram to make a kinetic argument?

• How do we use the diagram to make a thermodynamic argument?

7-9 Klein, Organic Chemistry 2e

• Which reaction will have the fastest rate of reaction?• WHY?

• 3° substrates react too slowly to measure.

7.4 SN2 – Rationalizing kinetic data

XH

HHNuc:

XH3C

HHNuc:

XH3C

H3CHNuc:

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-10 Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data• An example to consider: neopentyl bromide

• Draw the structure of neopentyl bromide

• Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide?

• Should neopentyl bromide react by an SN2 reaction relatively quickly or relatively slowly? WHY?

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-11 Klein, Organic Chemistry 2e

What statement about the SN2 reaction of methyl bromide with hydroxide is incorrect?

1 2 3 4 5

0% 0% 0%0%0%

1. The reaction kinetics is first-order in hydroxide.

2. In the transition state the carbon is sp2 hybridized.

3. Absolute configuration is inverted from R to S.

4. The reaction is faster in HMPA than in water.

5. The reaction can be catalyzed by I–.

7.5 SN1 – a step-wise mechanism

• What do the S, N, and 1 stand for in the SN1 name?

7-13 Klein, Organic Chemistry 2e

7.5 SN1 – SN2 Comparison• Consider the following generic SN2 reaction:

• If [Nuc:-] were tripled, how would the rate be affected? WHY?

• Consider the following generic SN1 reaction:

• If [Nuc:-] were tripled, how would the rate be affected? WHY?

• Practice with Conceptual Checkpoint 7.13

Nuc: + E LG Nuc E + LG:

Nuc: + E LG Nuc E + LG:

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-14 Klein, Organic Chemistry 2e

7.5 SN1 kinetics• The structure-rate relationship for SN1 is the opposite of

what it was for SN2.

• To explain this trend, we must examine the mechanism and the reaction coordinate diagram

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-15 Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing Kinetic Data• A carbocation forms during the mechanism.

• Recall that if a carbocation is more substituted with carbon groups, it should be more stable.

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-16 Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing Kinetic Data

• HOW do carbon groups stabilize a carbocation?

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-17 Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing kinetic data• To explain why the 3° substrate will have a faster rate, draw

the relevant transition states and intermediates.

• Primary substrates react too slowly to measure.• Practice with SkillBuilder 7.4

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-18 Klein, Organic Chemistry 2e

7.5 SN1 – stereochemistry• For the pure SN1 reaction below, predict the

product(s). Pay close attention to stereochemistry.

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-19 Klein, Organic Chemistry 2e

7.5 SN1 – stereochemistry• The formation

of ion pairs can cause inversion to occur slightly more often than retention

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-20 Klein, Organic Chemistry 2e

7.5 SN – stereochemistry• Consider the following reaction

• What accounts for the 35%/65% product ratio?

• Is the reaction reacting more by SN1 or SN2?

• What happened to the Cl atom?• Practice with SkillBuilder 7.5

ClNaOH

OH OH

35% 65%

+

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.

7-21 Klein, Organic Chemistry 2e

Consider the reaction of (S)-(–)-1-iodo-2-methylbutane to produce (+)-2-methyl-1-butanol.

What is the absolute configuration of the product?

I + HO OH + I

1 2 3 4 5

0% 0% 0%0%0%

1. R

2. S

3. R and S (racemic mixture)

4. R and S (unequal amounts-scalemic)

5. There is no chiral center in the product

How Nucleophiles Affect SN2

Which of the following is the best nucleophile?

1 2 3 4 5

0% 0% 0%0%0%

1. H2O

2. (CH3)3N

3. (CH3)2P–

4. (CH3)2O

5. CH3O–

Which of the following reagents is the best nucleophile for an SN2 reaction?

1 2 3 4 5

0% 0% 0%0%0%

1. methanol

2. methoxide

3. acetate

4. hydroxide

5. water

Which of the following is the product of the SN2 reaction between the hydroxide ion (HO–) and

(R)-CH3–CHDI? D = 2H (deuterium)

1. 2.

3.

4. 5.

Select the substrate which would react fastest in the substitution reaction.

1. 2.

3.

4. 5.

CH3NH2

CH3CN?

1 2 3 4 5

20% 20% 20%20%20%

Select the reagent and solvent combination which would result in the fastest rate of substitution

(R = CH3 in all cases).

I25 oC

?

1 2 3 4 5

20% 20% 20%20%20%

1. R-OH, HMPA

2. R-S–, H2O

3. R-O–, H2O

4. R-S–, DMSO

5. R-SH, H2O

How Leaving Groups Affect SN2

Substrate Steric Effects in SN2

Which electrophile will react the fastest by the SN2 mechanism with cyanide (:N≡C:–) in DMF?

1 2 3 4 5

20% 20% 20%20%20%

1. phenyl iodide (Ph–I)

2. vinyl tosylate (H2C=CH–OTos)

3. ethyl bromide

4. cyclohexyl bromide

5. benzyl tosylate (Ph-CH2-OTos)

How Solvents Affect SN2

Which set of reaction conditions represents the best way to carry out the following transformation?

Br OAc

1 2 3 4 5

20% 20% 20%20%20%

1. AcOH

2. NaOAc in AcOH

3. NaOAc in H2O

4. NaOAc in DMSO

5. AcOH in HMPA

Which of the following will give the fastest SN1 reaction?

1. 2.

3.

4. 5.

1 2 3 4 5

20% 20% 20%20%20%

7.5 SN – Summary

7-36 Klein, Organic Chemistry 2e

Chem Act 13 Exercise 25, Part D, page 200

Problem A “Walden” cycle

A B C

D E

What is the purpose for making B ? Why is [α]D for B positive ?What kind of reaction is B -> C and what is the mechanism ? What is the optical purity of C and what are the % ’s of the two enantiomers of C ?How could you make C from B with 100 % enantiomeric excess (i.e. optically pure) ?What kind of reaction is D -> E and what is the mechanism ?How can you convert A into CH3-CHCl-CH2 -Phenyl ?

SN2 It’s not always straight inversion !R. Wester, M. Weidem-ller (U. Freiburg), W. Hase (Texas Tech)

Science 2008, 319, 183

SN2 With Retention !Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds

with Retention of Absolute StereochemistryChen Zhao , F. Dean Toste , Kenneth N. Raymond , and Robert G. Bergman

Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, California 94720, United States

J. Am. Chem. Soc., 2014, 136 (41), pp 14409–14412DOI: 10.1021/ja508799p

Publication Date (Web): September 29, 2014