Scratch Paper – Page A

Midterm Exam 1
Chem 3B, Fall 2018
Monday, October 1, 2018
7:00 – 9:00 pm
You have 120 minutes to complete this exam.

Please provide all answers in the space provided. Work drawn

in the margins may not be picked up by the scanner and
therefore will not be graded.

Point values are listed within each question. The exam is worth
200 points total.

This Page is Scratch Paper

Please tear this cover page and the next page (amino acid chart) off at the start of the exam. They will not be
collected, scanned, or graded, so make sure your answers are copied into the appropriate location on your exam.

Chemistry 3B Fall 2018 Midterm Exam #1

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Chemistry 3B Fall 2018 Midterm Exam #1

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Chemistry 3B Fall 2018 Midterm Exam #1

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Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 1 of 8

1. Ramipril, pictured below, is medication used to treat high blood pressure.

A. Fill in each box with the name of each circled functional group. (4 x 2 = 8 pt)

amide amine

Ph
N O
N
H
O O O ester
carboxylic acid O
H

Ramipril
(a blood pressure medication)
B. Fill in one multiple-choice circle per row to indicate the hybridization of each lone pair. (8 pt)

s p sp sp2 sp3
s p sp sp2 sp3
Ph
s p sp sp2 N O
sp3 N
H
s p sp sp2 sp3 O O O
O
s p sp sp2 sp3
H
s p sp sp2 sp3

C. Complete the drawings of the predominant protonation state of Ramipril at each pH by adding hydrogens
and charges. (6 pt)

Ph Ph Ph
N O N O N O
N N N
H2 H2 H
O O O O O O O O O
OH O O

protonation state of Ramipril protonation state of Ramipril protonation state of Ramipril

at pH = 1 at pH = 7 at pH = 12

(add hydrogens and charges to finish these structures)

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 2 of 8
D. Heating an acidic aqueous solution of Ramipril causes two sequential hydrolysis reactions. Reaction A
occurs at moderate temperature, while Reaction B requires high temperature and long reaction time. Draw
the product(s) in each box. (10 pt)

Ph Ph
Reaction A
HCl (excess)
N O N OH HO
N N
H H2O (solvent) H2
O O O O O O
OH OH

Product(s) after ONE hydrolysis (ignore stereochemistry)

(hydrolysis of only the more reactive site)

Reaction B

HCl (excess), H2O (solvent)

high temperature, long reaction time

Ph

NH2 HO OH HO
N
H
O O O
OH

Product(s) after TOTAL hydrolysis (ignore stereochemistry)

E. Explain how resonance (conjugation) causes the difference in reactivity demonstrated by Reaction A vs.
Reaction B. (5 pt)

Nitrogen is a stronger resonance electron donor than oxygen (due to the lower electronegativity of
nitrogen than oxygen).

Conjugation between the heteroatom and the carbonyl, as demonstrated by the resonance structures
below, is a stabilizing effect that makes the carbonyl a less reactive electrophile.

O O
(weaker, less stabilizing)
O O

O O
(stronger, more stabilizing)
N N

answer must address "conjugation" or "resonance" to earn full credit.

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 3 of 8
2. Fill in the missing reagents and structures in the following synthesis schemes. Assume that only one major
product forms in each reaction. Do not combine multiple reaction steps in a single box (no numbered steps
within a box). (9 x 5 = 45 pt)

O
S HCl (excess)
Cl Cl 1. Mg
MeOH (solvent)

OH Cl 2.
CO2 O O
O OMe

CrO3 HCl
H2SO4, H2O
MeOH
O O

OH OH OMe

NH2 1.

LiAlH4
O
O + workup
NH 2. H3O
OMe NH2

(+ MeOH)

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 4 of 8
3. Mechanisms, Catalysts, and Equilibirum
A. Draw a curved arrow mechanism for the following reaction. (10 pt)
O O
+ HO NaH (0.10 equiv.) + HS
R R
S O
O
H (regenerated catalyst)
Na H O
pre-catalyst

O O
O H
+ H H R R
S S O
O S
O R
(generated O
catalyst)

B. Explain the following statement regarding the reaction above: “A catalytic amount of NaH is used in
this reaction, and NaH is not the limiting reagent in this reaction. However, NaH is not acting as a
catalyst in this reaction” (5 pt)

A catalytic amount (< 1 equiv.) of NaH is used. The NaH is not a "catalyst" because it does not get
regenerated ever. The actual catalyst in this reaction is EtONa, a catalytic amount of which is made by NaH
deprotonating EtOH at the start of the reaction.

C. Draw a curved arrow mechanism for the following reaction. (10 pt)
O O
+ HS HCl (cat.) + HO
R R
O S

H Cl Cl
H
O
OH
R
R OH OH OH S
O R R H Cl R
O O O
S S S H HO
H
Cl
HS

D. Draw an equilibrium arrow and select the corresponding Keq, and explain which side (if either) is favored
and why: (5 pt)
O O
R + HS R + HO
O S
equilibrium arrow

Which side of this reaction scheme (if either) is favored? Why?

Keq < 1
Left side is favored.
Keq = 1 The sulfur has larger orbitals and therefore worse conjugation (p orbital overlap) with
the carbonyl pi system than oxygen does, so the thioester is less stabilized and is
Keq >1 more reactive than the ester.
(Compare to the explanation for acyl chloride reactivity)

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 5 of 8
4. Predict the Products
A. Predict the organic product(s) from the following reactions. Where relevant, show all stereoisomers. (3 x
8 = 32 pt)

O O

O D D O H 2N H 2N
O
+ EtO OEt Ph D Ph D
H
N
N O D O
Ph H
EtO OEt
O D O
O
include stereoisomer(s) if relevant N
EtO OEt
H
N
N
Ph D H

O
O O O O O
O +
MgBr

(excess) O O

H
O O N include stereoisomer(s) if relevant
Cy
Boc N
N Cy
H

activated intermediate

Amino group at C terminus is not nucleophilic H 2N

O O
Phe due to amide resonance stabilization Cy
N
C N
H 2N O OH O NH
O O O N O
+ Cy
N O N O N
H H
NH2
O
nucleophilic Pro
site Leu Cy Cy
Boc N N
include stereoisomer(s) if relevant H H

B. Name the peptide product from the reaction above (using 3-letter codes). (hint: use the amino acid chart
handout. Include substituent(s) on the N- and/or C-terminus in the name) (8 pt)
Name the peptide product above (using 3-letter codes) Boc-Leu-Pro-Phe-NH2

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 6 of 8
5. Thionyl Chloride
A. Predict the product of reaction A, and name the new functional group in product A. (5 + 2 = 7 pt)

O O
O Reaction A
OH + Cl
S + SO2 + HCl
Cl Cl

Name of product A functional group acyl chloride

B. Name the new functional group in product B, then draw a curved arrow mechanism for reaction B that
DOES NOT have any intermediates that contain the same functional group as product A. (2 + 10 = 12 pt)
O
O
OH O
+
OH S O + SO2 + HCl
Cl Cl
O O

anhydride Name of product B functional group

Avoid making any intermediates containing the same functional group as product A

OH

O O H O O
Cl
OH
O H O H O
O Cl O O
S O H
O Cl O Cl
O S S Cl
O O O
S
O

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 7 of 8
6. Penicillin and DD-transpeptidase
DD-transpeptidase is an enzyme that catalyzes the crosslinking of peptidoglycan in bacterial cell walls. As
shown in the scheme below, peptidoglycan replaces a D-alanine on a peptide chain.

A. The mechanism includes an acyl enzyme intermediate, using an active site catalytic triad that includes a
base and a nucleophilic serine side chain. Choose the statement that best describes the reaction, then draw
the mechanism in the space below, and circle and label the “acyl enzyme intermediate” (12 pt)
peptidoglycan replaces D-Ala at the amino terminus of the peptide
(choose one)
peptidoglycan replaces D-Ala at the carboxyl terminus of the peptide

R' R'' Enz OH R' R''

O O
H H
Pep N EnzB: Pep N R + H 2N
N O + H 2N R N O
H H
O DD-transpeptidase O
(an enzyme) D-Ala
Pep-D-Ala-D-Ala peptidoglycan Pep-D-Ala-peptidoglycan
- Ignore stereochemistry
- Circle and label portions of the pre-printed structures above to define any abbreviations you use
- Circle and label the "acyl enzyme intermediate" in your mechanism
H H R' H
Enz O Enz O R' N N
R'' R''
Enz O
EnzB: O O
EnzBH
Pep-D-Ala-D-Ala
EnzB H

R O H2
R'
N
H Enz O R' H 2N R''
O H2N R R'' Enz O
N O
H
Enz O R' D-Ala
(see alternatives below) Acyl Enzyme
Intermediate
EnzB:

R R

O NH NH
Pep-D-Ala-peptidoglycan
Enz O Enz O O
R'
R'
EnzB H
Enz OH
EnzB:
EnzB H
R
R R Enz O
EnzB:
H or NH
O N N H O
H O H
Enz O R' Enz O Enz OH R'
R'
EnzB: EnzB: Pep-D-Ala-peptidoglycan

Chemistry 3B Fall 2018 Midterm Exam #1

Name _______________________ SID____________________ Page 8 of 8

B. Penicillins are a class of antibiotics that kill bacteria by inhibiting DD-transpeptidase, leading the cell
walls to weaken and eventually burst open. The penicillin structure mimics the peptide-D-Ala-D-Ala
structure, as demonstrated by the numbering on the structures below.

i. Select the multiple choice options that best describe the nitrogen 4 geometry and lone pair hybridization
in Pep-D-Ala-D-Ala. (4 pt)
ii. Add stereochemistry (wedged or dashed bonds) to the Pep-D-Ala-D-Ala structure above based on the
name “D-Ala”, and add the corresponding stereochemistry to the Penicillin structure, based on the
structure alignment. (6 pt)

linear H 5 H H
Pep N (R) R N S
trigonal planar 1 2 H 1
(R) 5
2
tetrahedral O 3 4
N (R)
8
O 3 4
N (R) 8
6 6
geometry of nitrogen 4 O 7 O 7
OH OH
s p sp sp2 sp3 O O

hybridization of nitrogen 4 lone pair

Pep-D-Ala-D-Ala Penicillin
modify to show stereochemistry modify to show stereochemistry
(make bond(s) wedged or dashed) (make bond(s) wedged or dashed)
based on the name based on comparison to Pep-D-Ala-D-Ala

iii. The nitrogen labeled “4” in the Penicillin structure is forced into a tetrahedral geometry due to ring
strain. How does that affect the reactivity of Penicillin relative to Pep-D-Ala-D-Ala in the enzyme active
site? Explain the relationship between this geometry and reactivity, being specific about the type of
reactivity. (Hint: see mechanism on previous page) (5 pt)

Carbonyl 3 is the electrophilic site in both molecules. The conjugation with nitrogen 4 in the
Pep-D-Ala-D-Ala structure (lone pair in p orbital) stabilizes it and makes it less electrophilic.

The tetrahedral shape in Penicillin prevents conjugation (lone pairs need to be in a p orbital
to participate in resonance) so carbonyl 4 in Penicillin is more electrophilic.

iv. Draw the structure of the inactivated enzyme, which could be described as “the active site serine has
been acylated by penicillin”. (10 pt)

R
H 1
R N 2 5 S O NH
1
3 O 2
O N Enz OH 3
5 S
O 4 6
O HN
OH EnzB: 4 6
O
Enz OH
Penicillin transpeptidase enzyme O
( + EnzB:)
the active site serine has been acylated by penicillin
(ignore stereochemistry)

Chemistry 3B Fall 2018 Midterm Exam #1