1.
Suggest explanations for the following observations concerning equatorial preferences of
monosubstituted cyclohexanes:
a)
There are significant differences in the A-values for
OH
NH2
OH and NH2 groups in protic (e.g. water, methanol)
aprotic 0.52 1.20
vs. aprotic (e.g. ether, chloroform) solvents.
protic
0.87 1.60
b)
2.
The A-values of the halogens do not increase in the expected sequence F < Cl <
Br < I. The actual values are F 0.15, Cl 0.43, Br 0.38, I 0.43.
Give the necessary reagents/solvents or products to complete the following:
H
H
O
a)
H
NBS
DME/H2O
b)
BnO
O
CH3
c)
CH3
CH3
O
C
B2H6
o
THF, 0 C
then KOH, H2O2
CH
1) Disiamylborane
o
THF, 0 C
2) H2O2, K2CO3/H2O
C17H22O3
8:1 mixture of 2 diastereomers
Which one is the major one?
C11H12O2
1
H NMR includes ~10 ppm, 1H, tr, J ~ 2.5 Hz
d)
CO2CH3
CH3
e)
H2SO4
C15H26O3
HCO2H/H2O (only one isomer is formed - which one?)
3.
Propose a synthetic sequence for the following transformations. More than one step will
be needed.
O
OH
a)
O
NH
b)
1.
Suggest explanations for the following observations concerning equatorial preferences of
monosubstituted cyclohexanes:
a)
There are significant differences in the A-values for
OH
NH2
OH and NH2 groups in protic (e.g. water, methanol)
aprotic 0.52 1.20
vs. aprotic (e.g. ether, chloroform) solvents.
protic
0.87 1.60
b)
The A-values of the halogens do not increase in the expected sequence F < Cl <
Br < I. The actual values are F 0.15, Cl 0.43, Br 0.38, I 0.43.
ANSWER:
Part a: The A-value is a measure of the “effective size” of a substituent on a sixmembered ring. It primarily reflects the 1,3-synaxial interactions between the substituent
(when it is in an axial orientation) and the axial H atoms. Thus, if the A-value for a
group increases on changing solvent, something is apparently making that group behave
as if it is physically bigger. Note that both OH and NH2 are hydrogen-bonding groups,
and that likewise protic solvents are hydrogen-bonding molecules while aprotic solvents
are not. If an OH or NH2 group is hydrogen bonded to one or several solvent molecules,
these will form a tight solvation sphere around that group. This sphere will encounter
steric problems from the synaxial H atoms if the group is axial. Therefore, it is not
surprising that in protic solvents, cyclohexanols and cyclohexylamines have larger
equatorial preferences than they do in aprotic solvents.
Part b: There is no doubt that the atomic radii of the halogens increase going from F to
I. However, their A-values do not reflect this – apparently Cl, Br and I behave more or
less as if they were the same size. Recall that as the radius of the atom increases, the
bond length also increases. This puts the steric bulk of the atom further away from the
1,3-synaxial hydrogens when it is axially oriented. This effect seems to level out the
steric conflicts between the heavier halogens and H-atoms in a cyclohexyl system.
2.
Give the necessary reagents/solvents or products to complete the following:
H
1) NBS, DMSO/H2O
H
2) NaH, THF
O
a)
The point here is that the epoxide is on the
more hindered face of the molecule. Thus,
peroxyacids will not be suitable. Formation
of the bromohydrin proceeds by addition of
Br+ on the less hindered face, so that oxygen
appears on the more hindered face. Base
treatment gives the cyclic ether.
H
H
NBS
DME/H2O
OH
Br
b)
The preferred conformation of the cyclohexene will probably position the
bulky phenyl ring pseudo-axially to avoid allylic A1,2 strain. This means
that the bromonium ion will form preferentially on the "top" face of the
alkene, anti to the phenyl group. Trans diaxial opening of this bridged ion
gives this halohydrin isomer.
BnO
O
CH3
OH BnO
B2H6
o
THF, 0 C
then KOH, H2O2
OH B
+
O
CH3
CH3
O
CH3
CH3
C
Major product
Hydroboration/oxidation occurs by syn addition, with B attached at the less-hindered end
of the alkene. The facial selectivity is controlled by the conformation at the allylic position.
The preferred conformer will be:
BnO
CH3
O
In this geometry, the allylic C-H bond eclipses the C=C, because there is too much steric
hindrance for the furanyl ring or the CH3 group to do so. The furanyl ring blocks approach
to the "top face" of the alkene.
c)
CH3
O
C
CH
1) Disiamylborane
o
THF, 0 C
2) H2O2, K2CO3/H2O
1
d)
CH3
H
CH3
O
CH2
CHO
H NMR includes ~10 ppm, 1H, tr, J ~ 2.5 Hz
Hydroboration/oxidation again. In this case, the internal C=C bond is much more
sterically hindered than the terminal alkyne. Reaction occurs at the alkyne, but the
intermediate enol is unstable with respect to the aldehyde tautomer. The NMR
data indicates the presence of an aldehyde C-H, split by an adjacent CH2 group.
CO2CH3
CH3
CO2CH3
CH3
OH
H2SO4
HCO2H/H2O
H
H+
H2O
CO2CH3
CO2CH3
CO2CH3
CH3
CH3
CH3
H
H
H
e)
3.
This reaction proceeds by a mechanism completely analogous to
the acid-catalyzed hydration of an alkene. Protonation of the
trisubstituted terminal alkene promotes attack by the electron-rich
internal alkene. The resulting cation intermediate is attacked by
the third alkene, and finally water adds to the resulting cation.
All steps are reversible, and so the most-stable isomer is formed:
a trans decalin, in which the ester and OH groups are equatorial.
Propose a synthetic sequence for the following transformations. More than one step will
be needed.
O
OH
OsO4
NMO
acetone/H2O
MnO2
CH2Cl2
OH
OH
a)
O
NH
PCl5
ether
(aq. workup)
NHOH
H2SO4
H2O/THF
OH
b)
Jones'
Reagent
(CrO3,
aq. H2SO4)
acetone
O
NH2OH.HCl
NaOH (Aq.)
EtOH/H2O