Chem 201 problem set 3 mechanisms

Chem 201 Van Vranken
Problem Set 3 - KEY

Due Tuesday, 10/20/17
These problems are relatively challenging. If you get stuck, think backwards; use models; number atoms in
your intermediates. Above all, be persistent!
1. Suggest a plausible arrow-pushing mechanism for the following reaction.1

cat. H 2SO 4
63%
Ac2O
23 °C, 5 min
Answer:
A H +
H
+
H : A-
2. Suggest a plausible arrow-pushing mechanism for the following transformation.2

cat. O
O ArCO2H
CH2Cl2
23 °C, 45 min
Answer:
A-
+ H
O: H A O + :OH
H :A-
+O O

NH
conc. HCl
NH 76%
N H 2O N
110 °C, 3 h H
Me OH Me
OH
OH
OH
Answer:
A NH NH : A-
H
+
H +
NH NH
N N +N N
H H
Me OH Me OH Me Me
OH OH
OH OH
OH OH
4. Chloride A undergoes solvolysis (SN1) 60 times faster than bicylic chloride B. However, ketal C
undergoes solvolysis 10,000,000,000,000 times faster than bicyclic ketal D.4 Explain these results using
appropriate drawings.
Me O O
Me Cl Cl Me OAr
Ar = NO 2
Me OAr
A B C D O 2N
krel 60 1 krel 10 13 1
Answer:
The carbocation formed by B is not quite planar, so the transition state leading to it is higher in energy than
that of A. However, this effect is small compared to the difference between C and D.
n n n n
+ +
O O O O O O
Me O Ar X
+
Me Me σ* p +
O p
σ* Ar
oxocarbenium D no overlap
C ion
The oxygen in C has a lone pair of electrons which is perfectly aligned with σ*CO, making C more readily
ionized. The carbocation formed from C is stabilized by overlap with the lone pair on oxygen (an
oxocarbenium ion), so the transition state leading to this cation is lower in energy. In D, there is no
alignment between the lone pairs of oxygen and σ*CO. Also, the carbocation formed by D does not have
effective overlap with the lone pairs of oxygen (drawing D as an oxocarbenium ion would violate Bredt’s
rule). For these reasons, the transition state to form a carbocation from D is much higher in energy than that
of C.
5. A number of terpene cyclase enzymes generate a neryl cation that cyclizes into a specific terpene product.
Suggest a plausible arrow-pushing mechanism for the enzyme-catalyzed cyclization of a neryl cation into
the following terpene products. As necessary, employ symbolic acids (H-A) and bases (-A:) in place of
active site residues.
Mg
E Z
O O enzyme mechanism?
P P
O O O-
O O +
key
neryl cation
intermediate α-pinene
Answer:
A-
..
H +
α-pinene
+
6. The natural product ptaquiloside leads tumors in animals that eat brackenfern because is alkylates
guanine bases of DNA. Suggest a plausible arrow-pushing mechanism for the reaction. The reaction is
fastest under slightly basic conditions (pH = 8).
O H 2N
Me OH O cat. base NH
N H
HN pH 8 N O
+ Me
H 2N N N H 2O
R
Me
O R N N
Me
+ O
DNA ptaquiloside OH
O
Me
OH Me
HO HO
Answer:
:B
.. +
Me OH O Me OH O Me OH O H B
H -
..
Me Me Me
Me Me Me
OR OR
+ Nu
Me OH2 O Me O Me O
Nu
..
+
Me Me Me
Me Me Me
stable carbocation Nu = HO pterosin B
Nu = DNA tumors
7.a.Suggest a plausible arrow-pushing mechanism for the following reaction.5
BnO BnO OD
SiMe 3 SiMe 3
D 2O SiMe 3
SiMe 3 0 °C, 20 min D
Answer:
A D
D + D +
SiMe 3 SiMe 3 SiMe 3 SiMe 3
BnO SiMe 3 BnO SiMe 3 BnO - SiMe 3 BnO D
-
DO: DO
(or D 2O)
6
b. Suggest a plausible arrow-pushing mechanism for the following reaction.
SiMe 3 O
CF 3CO2H SiMe 3
F 3C O
60 °C, 3 h 60%
Answer:
CF 3
O O
O SiMe 3 O SiMe 3 - SiMe
H H 3
H
F 3C O F 3C O: +
- +
c. Suggest a plausible arrow-pushing mechanism for the following reaction. Hint: the reaction conditions
generate a low concentration of Cl2 in situ.7
O
OH OH
KCl
Ph Cl N Ph H 3CO SiMe 3
CH 3OH
SiMe 3 60 °C, 2 h 81% Cl
O
Answer:
O O
-
-Cl: Cl N Cl Cl N
O O
O O
- -
H 3CO H :N CH 3O: H N
O O
R R + R + R
Cl X
Cl Cl H 3CO SiMe 3
-
SiMe 3 SiMe 3 : OCH3 -SiMe 3 Cl
(or CH 3OH) OCH3
8. Suggest a plausible arrow-pushing mechanism for the following reaction. Note: silica gel
is a mild acid due to the presence of Si-OH groups. Assume that the silica gel can also serve as a source of
water.8
H H
TsO OH O
OMe OMe
silica gel 86% O
MeO Si O Si
RO OR
hexane Si
O 23 °C, 48 h O O O
Me Me OR
O
glass/silica gel surface
Answer:
TsO MeO O: OMe

OMe OMe +
O
MeO + MeO
O Me
Me Me
phenonium ion :OH 2
OR: MeO O: MeO O:

OMe OMe
+ +
Me Me
OMe H OMe OMe

O + O
MeO O O
Me O
H +O HO
:
Me Me Me
H
: A–
Practice Problems
The following problems demonstrate important concepts, but will not be graded.
We will cover some of them in discussion section.
(OC) 3Co Co(CO)3 ZnI2 (OC) 3Co Co(CO)3

NaCNBH 3
OBn OBn >75%
HO CH 2Cl 2
OBn OTBS 23 °C, 7 h OBn OTBS
Answer: This is a simple SN1 reaction.
(OC) 3Co Co(CO)3 (OC) 3Co Co(CO)3 (OC) 3Co Co(CO)3 (OC) 3Co Co(CO)3
OBn OBn
R + R
H H
I 2Zn :OH OBn OTBS OBn OTBS
I 2Zn O + –
– B H
metal-carbon bonds NC
H
"push out" the L.G.
and stabilize the cation
10. The introduction of a cyano group slows the solvolysis of the tosylates below.10 Explain (using
appropriate drawings) why an α–cyano group slows the reaction less than a β–cyano group.
CN
OTs OTs OTs
CN
krel 10 5 10 2 1
Answer:
The cyano group is electron-withdrawing, so it makes the transition state to form a carbocation higher in
energy. However, the α–cyano group has a filled π-orbital which overlaps with the empty p-orbital in the
carbocation, stabilizing it and making the transition state lower in energy. The molecular orbitals for this
system are like the allyl cation, but the stabilization is somewhat less due to the electronegativity of
nitrogen. A resonance structure can be drawn for this carbocation; while it is not a very good resonance
structure, it still contributes to the structure of the carbocation.
+ C N C N +
+ = R C N
R
11. Suggest a plausible arrow-pushing mechanism for this enzyme-catalyzed reaction of farnesyl
diphosphate.11 Note: the enzyme acts as an acid catalyst and controls the conformation of the substrate.
(cat. HA)
O O Me Me Me enzyme
P P Me
O O O Me
O O Me
Mg Me
Answer:
Me HA Me Me Me
Me Me Me Me
+ +
Me O Me Me O Me Me Me Me
H –
P O P O A
O O
O O
Mg P O Mg P O
O O
O OH
–
A H A
H
Me Me Me Me
+
+
Me Me Me Me Me
+
+ H Me
Me Me Me Me Me

OH O
Me Me
OH
TsOH
H Al2O3 H
H C6H 6 H
MeO 80 °C, 3 h MeO 92%
Answer:
H A –
H A
+
OH OH 2 O+ O
OH OH OH +
R R R R R
R R R R R
OH
99%
4:1 acetone/water
OTs 56 °C, 15 h
Answer:
Note that water attacks the exo face due to the nonclassical carbocation.
H 2O: H 2O:
OTs OH
+ +
δ+ δ+
nonclassical
carbocation

Cl
6 M HCl Cl
NH 2
60%
1:2 H 2O/EtOH
OMe N
78 °C, 24 h
H
Answer:
Cl Cl Cl
H 2N:
NH 2 NH 2 H 2N
+
+ + Cl
OMe
.. OMe MeO +
H H
H A Cl NH 2
15. Suggest an arrow-pushing mechanism for the following reaction.15

O 2CH
HO
84%
HCO 2H/ pentane H
23 °C, 15 min
Answer:
+
OH H
.. OH 2
+
H A
-O
.. O
+ O 2CH
H H
16. Suggest a plausible arrow-pushing mechanism for the following transformation. 16
CH3SO2Cl
HO cat. DMAP
isolongiborneol longifolene
pyridine 65%
100 °C
Answer:
X
+ +
H
-A:
17. Suggest a plausible arrow-pushing mechanism for the following reaction. Ignore the role of acetic
anhydride.17
Me O Me O
MeO 2SO KOAc
H Ac2O H
S H H AcOH H H
100 °C, 0.8 h S
S
S 73%
Answer:
OSO 2Me R R
R R R
+
S S S S R S R
+
S
R
S:
R
S
R SH S
+ : A–
episulfonium ion
Note: R
sigma-bond migration S
is not the same + R
S
18. Provide a plausible arrow-pushing mechanism for the following reaction. Predict the stereochemistry of
the products.18
OH
CH 3SO2Cl
Et 3N N
N
CH2Cl2
0 °C, 5 h 83%
Cl
Answer: We didn’t cover formation of sulfenes using CH3SO2Cl/Et3N so I would accept an alternative
mechanism involving ROH or RO- attack on the sulfonyl chloride.
O O
S
O
O O O O O O O O
S : OH B
B: H S - S H - S
Cl : Cl : O N
R
sulfene
R
OMs Cl Cl
-Cl:
H H H
.. =
Ph N Ph N Ph N
+ Ph N
19. Provide a plausible arrow-pushing mechanism for the following reaction.19
O OAc HO cat. BF 3•OEt 2 O O

AcO AcO
AcO OAc CH 2Cl 2 AcO OAc

OAc 23 °C, 24 h OAc
68%
Answer:
BF 3
.. - +
O F 3B O HOPh
..
+
O O O
.. O O O O+
AcO AcO O AcO :O AcO
AcO OAc AcO O AcO O AcO O

OAc OAc OAc OAc
- +
F 3B O You can't exclude this alternative
one-step ionization based on
O OPh
O O fundamental principals, so I AcO
AcO :O would accept it.
AcO OAc
AcO O
OAc
OAc
20. Provide a plausible arrow-pushing mechanism for the following reaction. Estimate the ΔG° for the
reaction.20
O OMe O OMe
O O
C6H 6 Ph O SPh
Ph O OSO 2Me 80 °C, 18 h
SPh OSO 2Me
99.9%
Answer:
OMs
O O OMe O
O SPh
OMs
O O X Ph O O O OMe
Ph PhS: SPh Ph
MsO: +
-
You don't know how much S.M. was left over; product/S.M. ≥999:1.
Keq = ≥1000
Ignoring the fact that the reaction was at 80 °C, ΔG ≥ 4.2 kcal/mol
21. Provide a plausible arrow-pushing mechanism for the following reaction. Explain the stereoselectivity.21
MeO OMe O OMe
1.2 equiv. NaOAc
OSO2CH 3
H 2O / MeOH Me
Me
MeO 100 °C, 18 h
MeO 97%
Answer:
: A-
H
.. MeO OMe O OMe
MeO OMe MeO OMe + :OH 2 H + OMe
OMs
H Me Me
H
Me + Me
MeO MeO MeO MeO
A- H
.. +
HO O Me O OMe
OMe
Me Me
MeO MeO
22. Rationalize the stereoselectivity in the following reaction.22

O OH
O
80%
O HO Me 2Si
Me 2Si CHCl3 O
NO 2 23 °C, 24 h
NO 2
Answer:
+ OH
+
O: H A O H Si H
Me 2Si Me 2Si
σ* H
OH OH
H H :Nu H Si OH
:Nu
H
Si + Si + + Me 2Si
H
H
p H H HO H Nu
Nu:
σSi-C is donating into the empty p orbital from the
:Nu
bottom face, so the nucleophile attacks from the
opposite face. This is the same reason why +
nucleophiles attack exo on the 2-norbornyl cation.

O
BF 3•Et 2O
O 98%
CH 2Cl 2
N N
H 95 °C, 41 h H
Answer:
- BF 3
+ - - BF 3
O: BF 3 O BF 3 O
O+
+
N N N N
H H H H
+ + +
O
N O BF 3 N O BF 3 N BF 3
H - H - H -
24. Suggest a plausible arrow-pushing mechanism for the following reaction.24 Note: this transformation
occurred under conditions for mesylation with CH3SO2Cl and pyridine in CH2Cl2.
Me Me Me
pyridine
MsO 80%
CH 2Cl 2 Me H
23 °C, 7 h
H Me H Me
Answer:
Me Me Me Me Me Me
Me
MsO +
+ Me H
H Me H Me H B: H CH 2 H Me
H

OSO 2Me K 2CO3
Ac2O O
83%
AcOH O
118 °C, 10 h
Answer: Okay, I admit that this was pretty hard.

OMs
+
+ O + AcO
+
..
cyclopropyl- 3° cyclobutyl 3° cyclopropyl- O-
carbinyl carbinyl
+
O
or -
O:
References
1
J. W. Barton, M. K. Shepherd “Synthesis and rearrangements of 1,1-bi(benzocyclobutylidene) and its
derivatives“ J. Chem. Soc., Perkin Trans. 1 1987, 1561 – 1565.
2
John E. Baldwin, Samuel Bonacorsi Jr., Robert G. Carlson, Forest D. Graber “Cyclohexyl(2-
methylenecyclopropyl)carbinyl carbocationic rearrangements” J. Org. Chem. 1993, 58, 981-984. The
epoxide was produced in situ using mCPBA.
3
Harley-Mason, J.; Waterfield, W. R. Tetrahedron 1963, 19, 65.
4
Briggs, A. J.; Evans, C. M.; Glenn, R.; Kirby, A. J. J. Chem. Soc. Perkin Trans. II 1983, 1637-1640.
5
Hibino, J.-I.; Nakatsukasa, S.; Fugami, K.; Matsubara, S.; Oshima, K.; Nozaki, H. J. Am. Chem. Soc. 1985,
107, 6416.
6
Salimgareeva, I. M.; Zhebarov, O. Zh.; Bogatova, N. G.; Yur'ev, V. P. J. Gen. Chem. USSR (Engl.
Transl.) 1981, 51, 420.
7
Lee, J.; Oh, Y.; Choi, Y. K.; Choi, E.; Kim, K.; Park, J.; Kim, M.-J. ACS Catalysis 2015, 5, 683.
8
Nagumo, S.; Ono, M.; Kakimoto, Y.-i.; Furukawa, T.; Hisano, T.; Mizukami, M.; Kawahara, N.; Akita, H.
J. Org. Chem. 2002, 67, 6618.
9
Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1995, 2849.
10
Gassman, P. G.; Katsuhiro, S.; Talley, J. J. J. Am. Chem. Soc. 1980, 102, 7613-7615.
11
Faraldos, J. A.; Zhao, Y.; O’Maille, P. E.; Noel, J. P.; Coates, R. M. Chem. Bio. Chem. 2007, 8, 1826-
1833.
12
Bull, J. R.; Grundler, C.; Laurant, H.; Bohlmann, R.; Mueller-Fahrnow, A. “Cycloaddition mediated
synthesis and rearrangement of 16-functionalised 14α,17α-etheno-19-norsteroids” Tetrahedron 1994, 50,
6347-6362. Note: it’s just another norbornyl cation problem.
13
Lenoir,D.; Schleyer, P. v. R.; Ipaktschi, J. Justus Liebigs Ann. Chem. 1971, 750, 28-38.
14
Starling, S.M.; Vonwiller, S.C. “Tandem Wagner-Meerwein rearrangement-carbocation trapping in the
formation of chiral heterocyclic ring systems” Tetrahedron Lett. 1997, 38, 2159-2162.
15
Johnson, W.S.; Bravestock, M.B.; Parry, R. J.; Myers, R. F.; Bryson, T. A.; Miles, D. H. “Acetylenic
bond participation in biogenetic-like olefinic cyclizations. I. Formation of five-membered rings in model
systems” J. Am. Chem. Soc. 1971, 93. 4330-4332.
16
David L. Kuo; Thomas Money “ An enantiospecific synthesis of longiborneol and longifolene”
J. Chem. Soc., Chem. Commun. 1986, 1691-1692
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Chem 201 problem set 3 mechanisms

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Chem 201 Van Vranken

Problem Set 3 - KEY

1. Suggest a plausible arrow-pushing mechanism for the following reaction.1

2. Suggest a plausible arrow-pushing mechanism for the following transformation.2

3. Suggest a plausible arrow-pushing mechanism for the following reaction.3

TsO MeO O: OMe

OR: MeO O: MeO O:

OMe H OMe OMe

9. Suggest a plausible arrow-pushing mechanism for the following reaction.9

(OC) 3Co Co(CO)3 ZnI2 (OC) 3Co Co(CO)3

Answer: This is a simple SN1 reaction.

12. Suggest a plausible arrow-pushing mechanism for the following reaction.12

13. Suggest a plausible arrow-pushing mechanism for the following reaction.13

14. Suggest a plausible arrow-pushing mechanism for the following reaction.14

15. Suggest an arrow-pushing mechanism for the following reaction.15

16. Suggest a plausible arrow-pushing mechanism for the following transformation. 16

19. Provide a plausible arrow-pushing mechanism for the following reaction.19

O OAc HO cat. BF 3•OEt 2 O O

AcO OAc CH 2Cl 2 AcO OAc

AcO OAc AcO O AcO O AcO O

22. Rationalize the stereoselectivity in the following reaction.22

23. Suggest a plausible arrow-pushing mechanism for the following reaction.23

25. Suggest a plausible arrow-pushing mechanism for the following reaction.25

Answer: Okay, I admit that this was pretty hard.

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