P1254325926yEXtF

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PART THREE
Structure of Tropine
ATROPINE
AN INTRODUCTION TO CLASSICAL METHODS OF
CHEMICAL STRUCTURE PROOF
2
TROPINE
GENERAL FEATURES
3
NOW WE WILL LOOK AT THE TROPINE PIECE
(/-)-atropine
C17H23NO3

• Contains N
• Not chiral
• Basic due to N

hydrolysis
tropine
(/-)-tropic acid

C8H15NO
C9H10O3
C8H18
(INACTIVE)
(RACEMIC)
C8H19NO
mp 63o, bp 233o
- C8H15NO
aD 0o
H4
pKa 3.80 (pKb 9.20)
2 units unsat
2
4
IMPLIES
CHEMICAL TESTING
reacts once
IMPLIES
3o amine
C9H18NOI
CH3-NH2
KOH fusion
methiodide salt
methylamine
CH3I
CH3I dil NaOH
1
2
Tropine
5
3
H2SO4 HOAc
C8H15NO
acetic anhydride
4
-H2O
CH2CO
CrO3 HOAc
Tropidine
C10H17NO2
acetate ester
C8H13N
IMPLIES
IMPLIES
IMPLIES
Tropinone
secondary alcohol
3o N cant acetylate!
C8H13NO
b-hydrogen
ketone (2,4-DNP)
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KOH FUSION
This was a pretty standard investigative
technique used by early alkaloid chemists.
Potasssium hydroxide was ground to a fine powder
using a mortar and pestle. The compound was added
and the mixture was ground some more.
This operation had to be done in the absence of
atmospheric moisture since KOH is hygroscopic.
The mixture was placed in a distillation
apparatus and heated until the mixture fused
(became molten or liquid).
THIS IS A BRUTAL PROCEDURE it tears the
comound apart but many basic amine fragments
survive
Any small amines that are produced are distilled,
collected and identified. The amine piece ripped
out in this fashion gives some structural
information about the environment around the
nitrogen.
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KOH FUSION
(continued)
If a small piece like methylamine or ethylamine
is obtained it tells you only that somewhere in
the molecular skeleton there is an N-methyl or
an N-ethyl group, nothing else.
CH3-NH2
Occasionally, bigger amines are found, such as
pyridine or 3-methylpyridine. These would imply a
six-membered nitrogen- containing heterocyclic
ring is a part of the structure. However, the
double bonds could be artifacts (produced in the
reaction).
This technique probes the environment of the
nitrogen atom.
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FORMATION OF METHIODIDE SALTS
REACTION WITH CH3I and dil NaOH
PRIMARY AMINES REACT THREE TIMES
3 CH3I
..
SN2
NaOH
all electron pairs and hydrogens are replaced
methiodide salt
SECONDARY AMINES REACT TWICE
2 CH3I
..
..
NaOH
TERTIARY AMINES REACT ONCE
1 CH3I
..
NaOH
..
..
ALSO CALLED EXHAUSTIVE METHYLATION
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PARTIAL STRUCTURES
We can begin to assemble tentative structures
from the features that were found by doing the
chemical tests and reactions.
-H2O
O
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THE KETONE ENVIRONMENT IN TROPINONE
C8H13NO
C7H6O
C7H6 O

C7H6 O

C22H25NO3
C8H13NO
C22H21NO
-
H2 O
NaOH
dibenzylidene derivative
-
H2 O
C22H21NO
OH-
HENCE

-H2O
aldol condensation
corrected structure
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AN ACCOUNTING OF WHERE WE ARE
atoms in the part structure
C6H7NO
the missing elements are
2 units unsat
C8H13NO
C8H13NO
- C6H7 NO
C8H15NO
C2H6
3 units unsat
and dont forget the two units of unsaturation
that we showed were in tropine.
Tropinone has three!
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INVESTIGATION OF THE RINGS
HOFMANN DEGRADATIONS
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HOFMANN ELIMINATION
RECALL?
Hofmann found that when the leaving group was
-N(CH3)3 E2 elimination reactions gave the
least-substituted alkene.
BULKY LEAVING GROUPS!
Hofmann
95
5
Zaitsev
31
69
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THE HOFMANN DEGRATION
COMBINES EXHAUSTIVE METHYLATION AND THE
HOFMANN ELIMINATION
in a chain
..
1)
CH3I

changes iodide to hydroxide, Ag2O is essentially
Ag(OH)
2)
Ag2O
3)
D
distill
an alkene



nitrogen is removed as trimethylamine
ALL THREE STEPS COMPRISE ONE DEGRADATION SEQUENCE
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HOFMANN DEGRADATIONS
DISCOVERING THE NITROGEN RING ENVIRONMENT
It takes more than one Hofmann sequence to remove
nitrogen from an amine if the nitrogen atom is
in a ring (two required) or if it is located at a
ring junction (three required).
Using this method alkaloid chemists could
determine if a nitrogen atom was in a chain, in a
ring, or at the junction of two rings.
..
..
1
2
3
2
3
1
..
SEQUENCE ONE
SEQUENCE TWO
in a ring
breaks the first bond to the nitrogen
breaks the second bond to the nitrogen
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WORK THIS ONE THROUGH YOURSELF
1 2 3
1 2 3
1 2 3
..
..
three complete sequences are required
ring junction
CAUTION This reaction is carried out in hot
NaOH, which sometimes
causes the double bonds to rearrange after they
first form, especially if
they can become conjugated!
Sometimes a fourth step is added. In this
modification each double bond is hydrogenated (Pd
/ H2) right after it is formed. This strategem
avoids all confusion due to rearranged bonds.
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HOFMANN DEGRADATION OF TROPINE
achiral
2,4-DNP ()
C8H15NO
Pd H2
C7H12O
-H2O
1) xs CH3I / NaOH 2) Ag2O 3) D
KOH
C9H15N
C7H10O (CH3)2NH
H2O
1) 2) 3)
C8H13N
chiral
C7H8 (CH3)3N H2O
cycloheptane
C7H14
look how few hydrogens !
Pd 3H2
4 units of unsaturation
two sequences implies two rings
What kind of structure can fit this?
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POSSIBLE RING STRUCTURES FOR TROPILIDENE
C7H8
toluene
4 units unsat
known compound
not a cycloheptane
What else would fit ?
C7H10O
3 units unsat
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PUTTING IT ALL TOGETHER
Remember, we started the Hofmann Degradations
with tropidine which already had a double bond
and is chiral.
Each Hofmann sequence broke a bond to nitrogen
and removed a ring.
MOST LIKELY
NO!
NO!
achiral
chiral
Bredt Rule
We need to prove our choice...
aziridine not likely, small ring
achiral, but small ring
chiral
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HYPOTHESIS !
tropine
CrO3
-H2O
H2SO4
heat
tropinone
tropidine
chiral
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KUHN-ROTH OXIDATION OF TROPINE
PROOF AT LAST !
KMnO4
Tropinic Acid
a diacid
H2SO4
C8H15NO
C8H13NO4
1) CH3I, NaOH 2) Ag2O 3) D 4) H2 / Pd
CrO3
Kuhn Roth
H2SO4
1) CH3I, NaOH 2) Ag2O 3) D 4) H2 / Pd
PROVES 5-RING
PROVES 7-RING
pimelic acid
N-methylsuccinimide
(known compound)
(known compound)
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THE ANSWER IS OBTAINED BY SUPERIMPOSING THE TWO
RINGS
CH3
N
not chiral
COOH
5 7
COOH
tropine
squiggly lines are used to indicate that
the stereochemistry is not known
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EXPLANATION OF THE OXIDATION REACTIONS
In the Kuhn-Roth oxidation it is known that
tertiary Hs oxidize first. 3o gt 2o gt 1o
KMnO4
H2SO4
CrO3
H2SO4
KMnO4 cleaves ketones by a-hydroxylation, then
the diketone is formed, and finally the
diketone is cleaved into two carboxylic acids.
1) 2) 3)
1) 2) 3)
two Hofmann sequences remove the nitrogen bridge
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THE STRUCTURE OF ATROPINE
tropine
tropic acid
atropine is racemic here next to CO
This was the end of the classical structure
work. Notice that the early chemists could not
establish the absolute stereochemistry at
three points.



In the next set of slides we will show how
that was accomplished.
an ester !
atropine
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