Question I (43 points)

A. J Org Chem, 1983, 48, 1155.

(a) The starting material contains a single (R)-stereocenter.
connectivity = 3
stereohem = 3 1 equiv.
HCl Cl CH3
+
CH3 H H
H CH3 Cl
6

(b) Both of the products from part (a) can be Cl

drawn as two chair conformations. One of
them is the most absolutely stable
conformation from among those CH3
possibilities. Select which molecule that is H
and draw its most stable chair conformation. STEP 1: good chair form = 2 (if no, 0/10)
Draw the four groups shown; the A-values STEP 2: if OK, proper axial/equat bonds = 4
for the non-H groups are 1.70 (CH3), 0.48 proper conformation AND
(Cl), and 1.75 (CH3C=CH2). stereoisomer = 4 10
B. Complete the following as required.
(a) no partial

1) B2H6
ignore +
geometry •
2) H2O2, OH HO
includes an sp atom 5 NaOH
(b) gives a single ionic product SN2
CH2Ph
H3CO H3CO I
N CH2I N
H3CO cation = 3
H3CO + anion = 2
DMSO
H 80 ˚C H OCH3
H3CO OCH3 H3CO
5
(c) C13H14O
Ph
H2 / Pd-BaSO4 (Pd-CaCO3)
CH3 1) Cl H
quinoline, (PbO) Ph CH3
N

connectivity = 3 O
stereochem 2) Cl2, CH3OH (ClOCH3) H3CO H O
AND linear geom = 2 5 H2 = 2; cat = 2; step 2=2 6 + diastereomer
3 each O H
1) Na/NH3 CH3
or Li/NH3 Ph

H O
2) CH3CO3H (RCO3H)
6 + diastereomer
Question II (64 points)
A. Unlike the other halogens, electrophilic fluorine does NOT create 3-membered fluoronium ion
intermediates. This behavior is consistent with the following result, in which an electrophilic
fluorine source (call it “F “), combined with a nucleophilic fluoride source (call it “F “), gives
the following transformation (Org Lett, 2021, 23, 3088).
Cl electrophilic fluorine
F N N BF4 source (F ) F F
H
2 H
Ph nucleophilic fluoride Ph
NH F source (F )

Using F for the electrophilic fluorine and F for fluoride, provide the stepwise mechanism.
F OK to use
reagent F F F F
H H F
H H
Ph
Ph Ph Ph
mech with F+ = 4 carbocation = 4 F-sub carbocation = 4
1 arrow RAR mech 1 arrow = 4 capture mech 1 arrow = 4 20

B. In addition to structure A, there are three other resonance contributors for this structure with all
closed shell atoms and only a pair of atoms with formal charges. Draw them.
(a) Draw these resonance contributors (show nbe pairs and charges). B/C/D CAN BE IN ANY SPACE
A CH3 IV
B C
CH3
D
I CH3 CH3
N N
N O N N N N
N O O O
H3C H3C H3C H3C
III
II S S S S
no partial 3 no partial 3 no partial 3
(b) Circle the letters for the most and next most (c) Rank the bond lengths for bonds I - IV.
significant contributors to the structure. no partial

most significant : A B C D 3 III > I > IV > II

next most significant : A B C D 3 longest shortest
bond no partial bond 5
NEEDS TO BE THE N+/O- FORM (only if correctly drawn)
C. Foradil is used in the treatment of obstructive respiratory disease.
foradil (a) Circle the most acidic proton in foradil. no partial 4

O O
H
H (b) Put a square around the most basic atom in foradil. 4
N N (c) How many stereoisomers are no partial
H 4
represented by this connectivity? 4
O (d) How many delocalizable electron no partial
10
H pairs are in foradil? 4
H3CO
(e) What is the molecular no partial
formula of foradil? C20H26N2O4 4
(f) The conjugate acid of a base that can deprotonate the most between no partial
acidic site with a KEQ > 103, but not favorably deprotonate 13 & 14
any other site (KEQ < 101) will be in what range of pKa values? 4
Question III (53 points)
A. Pyridine N-oxide is formed when pyridine is oxidized by mCPBA.
(a) Pyridine N-oxide undergoes typical EAS reactions, but follows it own pattern for the
regioselectivity of how multiple groups appear after an initial halogenation reaction.
Complete the following. optional
excess or 2 equiv. NO2
mCPBA Cl Cl
Cl2 HNO3 Cl Cl
N N
Fe or FeCl3 or AlCl3 N H2SO4 (opt) N
O
O
OK if FeBr3 etc no partial 3 no partial 3 O
(b) The final product in this sequence can be deoxygenated by DMD (dimethyldioxirane) in a
single experimental step. Provide the full curved arrow mechanism and the intermediate:
(1) an SN2 reaction by the N-oxide on the oxygen-oxygen bond of DMD, and
(2) a one-step fragmention of the intermediate (a single structure with two charged
atoms) to give the three observed products.
Of note: isotopic labeling experiments demonstrate that the oxygen atom from the N-oxide
ends up in the molecule of oxygen formed as a product.
add arrows add intermediate and arrows to products Cl
Cl intermed = 4
O Cl O O2N N
O2N N O O
O O2N N O Cl O
Cl DMD O
2 arrows = 4 4 Cl 3 arrows = 4 8 O
(c) Based on the precedent in part (a), design a reaction sequence for this transformation.
this is no partial no partial no partial no partial no partial CH3
the Br HNO3 O2N
Br2 O2N Br CH3Cl Br
order
derived N FeBr3 N N N
AlCl3
from the O O O O
precedent 3 3 3 3 3
B. Hexastrol is a nonsteroidal estrogen sold under the brand name Synestrol and used in hormone
replacement therapy as well to treat certain hormone-dependent cancers. THESE SCORED
AS CONSISTENT
(a) Provide the Newman projection of (b) As drawn, the
the indicated bond for the most HO configuration of the
stable conformation of the H front atom is:
optically inactive stereoisomer of
S
hexastrol. OH
H no partial 3
OH and of the back
hexastrol atom is:
correct meso conform = 8
other meso conform = 4 8 R
HO no partial 3
(c) How many other stereoisomers are there for hexasterol 2
in addition to this optically inactive one? no partial 3
(d) How many of these other stereoisomers would be
2
classified as chiral diastereomers of this optically no partial 3
inactive one?
Question IV (40 points)

A. In the first space, provide the missing reagent(s)/conditons for these transformations. The
connectivity of the product is shown. In the second space, complete the redrawing of the
product so that it is the single stereoisomer in which all stereocenters have an (R)-configuration.

(a) HO
H D 2 points each
D D
H
O O OCH3
OCH3 cat. H2SO4 (etc) O O
O
2 points each 4 OCH3
4
H3C Br
no partial
(b) H3C H3C OH HO CH3
Br H2O H3C H3C
Br Br

not NaOH no partial

4
4

(c) H3CS Br (CH3)3COK H3CS no partial

or comparable H3C
H3C H bulky base H3C
H3CS
no partial 4
4
B. Unfamiliar chemistry alert! Triethylaluminum reacts with 1-butene in the presence of a
zirconium (IV) salt to give an intermediate that, when exposed to oxygen and water, gives a
product with the following properties. From these data, deduce the structure of the product.
data about the product
1) (CH3CH2)3Al / Zr(IV) salt
• molecular formula: C6H14O
product
• 13C-NMR: 4 signals
2) O2, H2O
• 1H-NMR: 5 signals (6:4:2:1:1)
no partial • treatment with hot phosphoric
acid (H3PO4) gives C6H12
• the isolated C6H12 compound
HO undergoes hydroboration-
oxidation to give the identical
6
C6H14O product originally observed
C. Draw: (S,E)-5-methoxy-3-hexen-1-yne

-2 per error
chain length
position of pi bonds/groups OCH3
stereochem 10
Question V (40 points)

In 1883, a preparation of pyrazoles was reported that came to be known as the Knorr pyrazole
synthesis (Ber Dtsch Chem Ges, 1883, 16, 2597). In a single experimental step, two simple starting
materials are heated with catalytic acid and, 12 or so mechanistic steps later, a pyrazole plus two
equivalents of water result.
H
O O H N
H N
+ N H N H + 2 H2O
H H heat,
H H H
acid cat. H pyrazole
H
(a) Part of the driving force for this reaction is the loss of water as it is boiled away. But even under
conditions where the water is not removed, the pyrazole structure forms instead of other isomeric
forms. What structural features of this product favor its formation (mark all that apply)?
the nitrogen atoms both have localized electron pairs X pyrazole is an aromatic ring
has nothing to do with
pyrazole hydrogen bonds with the water pyrazole has other resonance
forming the structure -
contributors with uncharged
forms when water is lost
the most acidic proton in pyrazole is readily deprotonated atoms 4
(b) What are the hybridizations and observable geometries for the two nitrogen atoms in pyrazole?
H
no partial
hybridization: sp2 N N hybridization: sp2 no partial
4 4
observable no partial H H observable no partial
bent
geometry: 4 geometry: trigonal planar 4
H
(c) Using lines, dashes, and wedges for the all directionality must be shown H
directionality of sigma bonds and hybridized no wedge/dash at all
H N
nbe pairs p-orbitals for pi bonds and any N
unhybridized nbe pairs, draw a 3D orbital N N
picture for pyrazole. Fun fact: although
H
pyrazoles were first prepared in the1880s, the H H H
first naturally occurring pyrazole was not sudden only
discovered until 1959 (in watermelon seeds). death H if OK, then H
Advice: keep the plane of trigonal planar atoms 5xsp2 localized e 5 p-orbitals,
in the plane of the paper. framework = 5 parallel, overlap = 5 10
(d) The conjugate acid of pyrazole has a pKa value of 2.5. Only one of the two nitrogen atoms is a
Brønsted base. Draw this conjugate acid. Why is the other nitrogen atom not observed to be basic
at all (mark all that apply)?
conjugate acid of pyrazole X the nbe pair on the other N is delocalized
H H no partial X protonation of the other N would disrupt
N N the aromaticity of the ring no partial
protonation of the other N creates an
H H antiaromatic ring
the localized nbe on the other N is
H 5 highly stabilized by its %s character 5