CHEM 633: Advanced Organic Chem: Physical
Problem Set 4
Please do not look up references until after you turn in the problem set unless otherwise noted.
For the following problems, please use Excel (or another graphing program), when necessary. Please submit your graphs
with your problem set.
1. One proposed mechanistic sequence for the Baylis-Hillman reaction is shown below (e.g., J. Org. Chem. 2003, 68,
692). This reaction has recently been studied using the initial rates method (Org. Lett, 2005, 7, 147). You considered the
kinetics of this reaction on Problem Set 3.
O
O
O
OMe
+
M
k1
N
N
OMe
k–1
O
+
N
D
(DABCO)
I
O
R
H
R
N
k2
–DABCO,
proton transfer
N
N
A
OH O
fast
OMe
R
OMe
(a) The authors also evaluated this reaction by analyzing isotope effects. For the illustrated mechanism below (the
generally accepted mechanism), please predict the isotope effects that should be observed at the indicated
positions.
N
O
MeO
O
N
H(D)
O
H(D)
MeO
N
Ar
O
O
H(D)
Ar
MeO
H(D)
N
rate-determining
step
N
O
elimination
H(D)
MeO
& protonation
OH
H(D)
Ar
N
(b) In a recent study, the following isotope effects were measured. What do these isotope effects suggest about the
rate-determining step?
N
O
O
H(D)
MeO
kH/kD = 5.2 ± 0.6
+
O
N
(D)H
OH
MeO
DMSO
NO2
kH/kD = 0.75 ± 0.05
NO2
(c) Propose an alternative mechanistic sequence that accounts for the kinetic and isotope effect data.
2. Is there a linear free energy relationship between enantioselectivity and the size of the substituent (R) in the following
aziridination reaction (ACIE 1998, 37, 3392)? Please propose an explanation for why or why not.
catalyst
pyridine, Ts2O
pyridine N-oxide
Ph
R
CH2Cl2, 3 h
TsN
Ph
R
H
ee (%)
41
85
90
94
R
H
Me
n-Pr
i-Pr
H
N N N
Mn
O
O
catalyst
H
3. Please read this article: Resek & Beak. J. Am. Chem. Soc. 1994, 116, 405.
(a) What is an intramolecular kinetic isotope effect experiment?
(b) Why are the values of the intramolecular and intermolecular kinetic isotope effects different?
4. Hayashi and co-workers developed a Wacker cyclization to convert achiral 1 into chiral benzofuran 2 in high
enantioselectivity (J. Am. Chem. Soc. 2004, 126, 3036).
Me
Pd(MeCN)4(BF4)2 (cat.)
(S,S)-ip-boxax (cat.)
Me
Me
OH
1
benzoquinone
MeOH
O
Me Me
O
*
2
91%, 97% ee
i-Pr
H
N
N
H
i-Pr
O
(S,S)-ip-boxax
(a) Please draw a reasonable arrow-pushing mechanism for this transformation.
(b) The researchers wanted to understand whether the reaction proceeds via an anti or syn oxypalladation step.
1
Pd(II)
R
R
O Pd(II)
vs.
O
H
anti
syn
To answer this question, they designed deuterated substrate 3. Cyclization of 3 gave the 4 products shown below.
Based on these products, is the oxypalladation anti or syn? Please illustrate your reasoning.
H
D
H
5 mol% Pd(MeCN)4(BF4)2
10 mol% (S,S)-ip-boxax
H
benzoquinone
MeOH, 40 °C, 4 h
78% combined yield
OH
3
H
H
H
H
D
O H
O H
4
5
(>95% D)
O H
D
6
(>95% D)
O
D
7
(>90% D)
5. Please draw a Woodward–Hoffmann molecular orbital correlation diagram for the following reaction and use it to predict
the stereochemistry of the product (stereocenters are starred).
Δ
R
* *
R
R
R
6. Please propose an arrow-pushing mechanism for the following transformation. Name and classify each pericyclic
reaction you propose and predict the stereochemical outcome.
Ph
O
Ph
+
O
H O
*
Δ
O
*
Ph
O
Ph
H O
7. Please suggest of mechanism for the following transformation. Your mechanism should be consistent with the observed
stereochemistry of the product. Please name and classify each pericyclic reaction of your mechanism.
H
H
CO2Me
MeO2C
Δ
CO2Me
CO2Me
H
H
8. (a) Please draw a reasonable arrow-pushing mechanism for the following reaction.
O
O
Δ
+
+
O
exo
favored
endo
disfavored
(b) Please explain why the product named “exo” above is favored.
9. Please explain the following trend in reaction rates based on substitution of the styrene dienophile:
Ph
Ph
Ph
Ph
O
Ph
Ph
+
Δ
R
O
Ph
Ph
R
R
p-NMe2
p-OMe
H
p-Cl
m-NO2
p-NO2
k (x 106 mol–1s–1)
338
102
73
78
79
88
10. (a) Please draw an arrow-pushing mechanism for the following reaction (J. Am. Chem. Soc. 2000, 122, 4243).
2
O
Ph
O
Ph
+
O
H
NMe
Me
N Me
H ·HCl (20 mol%)
O
CHO
23 °C
Ph
Me
Ph
Ph
Me
75%
35:1 exo:endo
96% ee
(b) Please rationalize the high exo selectivity. Please note that high exo selectivity was only observed with the benzofuran
diene; with dienes lacking an oxygen atom, the exo selectivity was not as good.
11. Using Dewar–Zimmerman theory, please explain why Diels–Alder cycloadditions proceed suprafacially on both the
diene and dienophile.
From Grossman, Chapter 4
12. Predict the major product (regio- and stereoisomer) of each of the following cycloadditions.
(a)
CH3
H3C
+
NHCO2Bn
CHO
CH3
(d)
+
CHO
OSiMe3
(b)
O2, hv
CH3
H3C
Rose Bengal
N
(e)
(c)
+
OEt
+
O
CO2Me
MsO
CO2R
O
13. Draw the product of each of the following [3,3] rearrangements, including its stereochemistry.
(a)
Ph
H3C
CH3
Δ
(c) H C
3
O
Δ
O
CO2CH3
CH3
CH3
Δ
(b)
Δ
H
(d)
Ph
H
H
14. Please propose a reasonable arrow-pushing mechanism for the following transformation (Schreiber JACS 1984, 106,
4038).
O
OH
KH, THF, Δ;
H
i-Pr
then H3O+ quench
H
i-Pr
15. (a) Please propose a reasonable arrow-pushing mechanism for the following transformation (Jung JACS 1980, 102,
2463).
MeO
OMe
MgX
+
A
NaH
75%
O
*
OMe
OMe
* * *
O
(b) Predict the relative stereochemistry at each of the starred carbons and explain your prediction using clearly drawn
structures.
3