Chemistry Organic Chemistry I Fall, 2015 Day 19 Wed., Oct., 14, 2015 Chapter 7 Alkyl Halides R δ+ -X δ- (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 S N 2 – 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 Klein, Organic Chemistry 2e

7.4 S N 2 – stereochemistry What do S, N, and 2 stand for in the S N 2 name? How might we use stereochemistry to support the S N 2 mechanism for the following reaction? Practice drawing S N 2 reactions with SkillBuilder Klein, Organic Chemistry 2e

7.4 S N 2 – 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 cannot occur with front-side attack because there is a node on the front-side of the LUMO 7-6Klein, 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 S N 2 – backside attack Transition state symbol 7-7Klein, Organic Chemistry 2e

7.4 S N 2 kinetics Less sterically hindered electrophiles react more readily under S N 2 conditions. To explain this trend, we must examine the reaction coordinate diagram ons, Inc. All rights reserved. 7-8Klein, Organic Chemistry 2e

7.4 S N 2 – 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? 7-9Klein, Organic Chemistry 2e

Which reaction will have the fastest rate of reaction? WHY? 3° substrates react too slowly to measure. 7.4 S N 2 – Rationalizing kinetic data Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-10Klein, Organic Chemistry 2e

7.4 S N 2 – 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 S N 2 reaction relatively quickly or relatively slowly? WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-11Klein, Organic Chemistry 2e

What statement about the S N 2 reaction of methyl bromide with hydroxide is incorrect? 1.The reaction kinetics is first-order in hydroxide. 2.In the transition state the carbon is sp 2 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 S N 1 – a step-wise mechanism What do the S, N, and 1 stand for in the S N 1 name? 7-13Klein, Organic Chemistry 2e

7.5 S N 1 – S N 2 Comparison Consider the following generic S N 2 reaction: If [Nuc: - ] were tripled, how would the rate be affected? WHY? Consider the following generic S N 1 reaction: If [Nuc: - ] were tripled, how would the rate be affected? WHY? Practice with Conceptual Checkpoint 7.13 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-14Klein, Organic Chemistry 2e

7.5 S N 1 kinetics The structure-rate relationship for S N 1 is the opposite of what it was for S N 2. To explain this trend, we must examine the mechanism and the reaction coordinate diagram Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-15Klein, Organic Chemistry 2e

7.5 S N 1 – 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. 7-16Klein, Organic Chemistry 2e

7.5 S N 1 – Rationalizing Kinetic Data HOW do carbon groups stabilize a carbocation? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-17Klein, Organic Chemistry 2e

7.5 S N 1 – 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. 7-18Klein, Organic Chemistry 2e

7.5 S N 1 – stereochemistry For the pure S N 1 reaction below, predict the product(s). Pay close attention to stereochemistry. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-19Klein, Organic Chemistry 2e

7.5 S N 1 – 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. 7-20Klein, Organic Chemistry 2e

7.5 S N – stereochemistry Consider the following reaction What accounts for the 35%/65% product ratio? Is the reaction reacting more by S N 1 or S N 2? What happened to the Cl atom? Practice with SkillBuilder 7.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-21Klein, 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? 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 S N 2

Which of the following is the best nucleophile? 1.H 2 O 2.(CH 3 ) 3 N 3.(CH 3 ) 2 P – 4.(CH 3 ) 2 O 5.CH 3 O –

Which of the following reagents is the best nucleophile for an S N 2 reaction? 1.methanol 2.methoxide 3.acetate 4.hydroxide 5.water

Which of the following is the product of the S N 2 reaction between the hydroxide ion (HO–) and (R)-CH 3 –CHDI? D = 2 H (deuterium)

Select the substrate which would react fastest in the substitution reaction

Select the reagent and solvent combination which would result in the fastest rate of substitution (R = CH 3 in all cases). 1.R-OH, HMPA 2.R-S –, H 2 O 3.R-O –, H 2 O 4.R-S –, DMSO 5.R-SH, H 2 O

How Leaving Groups Affect S N 2

Substrate Steric Effects in S N 2

Which electrophile will react the fastest by the S N 2 mechanism with cyanide (:N ≡ C: – ) in DMF? 1.phenyl iodide (Ph–I) 2.vinyl tosylate (H 2 C=CH–OTos) 3.ethyl bromide 4.cyclohexyl bromide 5.benzyl tosylate (Ph-CH 2 -OTos)

How Solvents Affect S N 2

Which set of reaction conditions represents the best way to carry out the following transformation? 1.AcOH 2.NaOAc in AcOH 3.NaOAc in H 2 O 4.NaOAc in DMSO 5.AcOH in HMPA

Which of the following will give the fastest S N 1 reaction?

7.5 S N – Summary 7-36Klein, Organic Chemistry 2e

Chem Act 13 Exercise 25, Part D, page 200

Problem A “Walden” cycle A B C DE 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 CH 3 -CHCl-CH 2 -Phenyl ?

S N 2 It’s not always straight inversion ! R. Wester, M. Weidem-ller (U. Freiburg), W. Hase (Texas Tech) Science 2008, 319, 183

S N 2 With Retention ! Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds with Retention of Absolute Stereochemistry Chen 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 14409–14412 DOI: /ja508799p Publication Date (Web): September 29, 2014 Chen ZhaoF. Dean Toste*Kenneth N. Raymond*Robert G. Bergman*