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Full Name ____________________________________________

Chemistry 3023-01

The University of Tulsa Department of Chemistry & Biochemistry

Organic Chemistry II

Final Examination

May 7, 2014

DO NOT OPEN THIS EXAM UNTIL DIRECTED TO DO SO When the exam begins, please look through every question to assess how to best allocate your time. You must answer all questions. Three bonus problems are also available; they are each worth up to 20 points. The point value for each question is designated in parentheses after each problem. The exam will last from 9:00 AM until 11:25 AM. When time is called, you must put down your pencil immediately and hand in the exam. Please write and draw as clearly as possible in the space provided. If you require additional space and continue an answer on the back of a page, you must clearly indicate this to the grader.

Question 1: Predicting products of organic reactions (20 pts) ____

Question 2: Reagent selection in organic synthesis (20 pts) ____

Question 3: Named reactions in organic synthesis (20 pts) ____

Question 4: Fisher indole synthesis (30 pts) ____

Question 5: Aromatic chemistry (20 pts) ____

Question 6: Multi-step organic synthesis (30 pts) ____

Question 7: Biopolymers and lipids (20 pts) ____

Question 8: Solid-phase peptide synthesis (40 pts) ____

Bonus 1: Grignard reagents in organic synthesis ____

Bonus 2: Transition metal catalysis ____

Bonus 3: The Favorskii rearrangement ____

Total ____

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Question 1: Predict the major product of the reactions below. Draw your proposal in the box provided. Clearly account for stereochemistry and regiochemistry, where applicable. The chemical formulas for the major products are given to assist in your prediction. No explanation is required. (4 x 5 pts)

O

1. LiAlH4, THF

2. H3O+ (workup) C6H12O

HNO3

H2SO4 (catalyst)

C10H13NO2

3

(Question 1 continued)

O

OMe+C9H12O2

NH

O CrO

ClO

OH

CH2Cl2 C7H12O

4

Question 2: Suggest appropriate reagents and/or reaction conditions that will promote the following reactions. Write your proposals in the box above the reaction arrow. If more than one step is necessary, number each step. Be sure to account for stereochemistry and regiochemistry, where applicable. No explanation is required. (4 x 5 pts)

Br

Br

Br

5

(Question 2 continued)

O HO

O CH2

6

Question 3: Give a representative example and mechanism for two of the named reactions listed below. (2 x 10 pts) Upjohn oxidation Sonogashira cross-coupling Cope Rearrangement Friedel-Crafts Acylation Wittig Olefination Fisher Esterification Robinson Annulation Wolff-Kishner Reduction

7

(Question 3 continued)

8

Question 4: Indoles can be synthesized from phenylhydrazines and a ketone. This reaction is known as the Fisher indole synthesis. An example is shown below:

NH

NH2 O+

H+

MeOH NH

phenylhydrazine an indole

The first stage of the reaction leads to a phenylhydrazone. Propose a mechanism for these steps. (10 pts)

NH

NH2 O+

H+

MeOH NH

N

a phenylhydrazone

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(Question 4 continued) In the next stage of the Fisher indole synthesis, the phenylhydrazone undergoes a series of rearrangements. Propose a mechanism for these reactions and classify the sigmatropic rearrangement featured in this transformation. (10 pts)

NH

N

a phenylhydrazone

H+

MeOH NH

NHNH

NH

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(Question 4 continued) The final stage of the Fisher indole synthesis is shown below. Propose a mechanism for these final steps. What is the thermodynamic driving force that favors the products of this stage of the reaction? (10 pts)

NHNH N

Han indole

H+

MeOH+ NH4+

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Question 5: Consider the following reaction and possible mechanisms:

Cl

NaNH2NH3

NH2

Describe how an SNAr mechanism could be experimentally distinguished from a mechanism that features a benzyne intermediate. (20 pts)

12

(Question 5 continued)

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Question 6: The following sequence was featured in Holton’s synthesis of taxusin—an important substructure of the anti-cancer compound taxol.

O

OH

1.

2. AIBN, Bu3SnH, benzene3. H3O+, CrO3

BrOMe

Br

O

O

O

Base, CH2Cl2

Propose a mechanism for the first step of this reaction sequence. Comment on the regioselectivity. Is this reaction an oxidation, reduction, or redox neutral? (10 pts)

O

OH

BrOMe

Br

Base, CH2Cl2

O

O

OMeBr

Mechanism?

14

(Question 6 continued) Propose a mechanism for the next step in the synthesis and identify the product, A. Finally, explain how A is converted to the lactone. Hint: A contains an acetal; the final reaction involves hydrolysis followed by an oxidation. (20 pts)

O

O

OMeBr

AIBN, Bu3SnH, benzeneA

H3O+, CrO3

O

O

O

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(Question 6 continued)

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Question 7: Draw L-glutamine and give its 3-letter and 1-letter abbreviations. (5 pts) Draw a natural fatty acid. What are two key building blocks in its biosynthesis? (5 pts) Draw a disaccharide made from glucose and galactose. (5 pts) One of these compounds can be classified as a terpene. Which one? Explain. (5 pts)

or

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Question 8: During a solid phase peptide synthesis, the dipeptide shown below was found to cleave itself from the resin upon deprotection of the N-terminus:

(solid phase resin)

OFmocLeuProNH

NHN

O

O Propose a mechanism for this undesired reaction. (20 pts)

18

(Question 8 continued) To remedy the self-cleavage problem, the following strategy was used to couple the third residue, alanine:

(solid phase resin)

OTsocLeuPro

TsocLeu =O

OSi

iPr

iPr

iPrNH

O

Fmoc-Ala-F

Bu4NF (initiator)OFmocAlaLeuPro

Propose a mechanism for the coupling shown above. Explain why only a sub-stoichiometric amount of fluoride is required to initiate the reaction. Explain why cleavage from the resin is minimized using this revised strategy. (20 pts)

19

(Question 8 continued)

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Bonus 1: Provide a mechanistic account of the conversion of 1 to 2. Hint: note that 1 is an allylic magnesium reagent and, as such, it is nucleophilic at multiple sites.

Mg

1.

2.3.

OEt

CO2

H+O

Et

O

1 2

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(Bonus 1 continued)

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Bonus 2: Explain the synthesis of the following vinyl boronic acid. Clearly account for stereochemistry.

C6H13 B(OH)2

HC6H13

OB

OH

1.

2. H2O

HO

HO+

23

(Bonus 2 continued)

Propose a full catalytic cycle for the following reaction. Suggest a reason that one would want to synthesize a diene such as the product shown below.

C6H13 B(OH)2H

Br+ Pd(0)

KOHC6H13

H

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Bonus 3: Propose a mechanism for the following reaction, the Favorskii reaction. Hint: a cyclopropanone intermediate is observed for this reaction (see below). Comment on the stereoelectronics of the cyclization step. Finally, what is the thermodynamic driving force and regioselectivity in the conversion of the cyclopropanone to the final ester product?

OCl NaOMe

MeOHOMe

O

O NaOMe

MeOH

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(Bonus 3 continued)