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PART THREE. Structure of Tropine. ATROPINE. AN INTRODUCTION TO CLASSICAL METHODS OF CHEMICAL STRUCTURE PROOF. TROPINE. GENERAL FEATURES. NOW WE WILL LOOK AT THE TROPINE PIECE. (+/-)-atropine. C 17 H 23 NO 3. Contains N Not chiral Basic due to N. hydrolysis. tropine.

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Presentation Transcript
slide1

PART THREE

Structure of Tropine

ATROPINE

AN INTRODUCTION TO CLASSICAL METHODS

OF CHEMICAL STRUCTURE PROOF

slide2

TROPINE

GENERAL FEATURES

slide3

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

[a]D = 0o

H4

pKa = 3.80 (pKb = 9.20)

= 2 units

unsat

2

slide4

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

+CH2CO

-H2O

CrO3

HOAc

Tropidine

C10H17NO2

acetate ester

C8H13N

IMPLIES

IMPLIES

IMPLIES

Tropinone

secondary

alcohol

3o N can’t acetylate!

C8H13NO

b-hydrogen

ketone (2,4-DNP)

slide5

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.

slide6

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.

slide7

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”

slide8

TROPINE

TROPIDINE

TROPINONE

PARTIAL STRUCTURES

We can begin to assemble

tentative structures from

the features that were

found by doing the chemical

tests and reactions.

-H2O

[O]

slide9

TROPINONE

TROPINONE

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

slide10

TROPINONE

TROPINE

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 don’t forget

the two units of

unsaturation that

we showed were

in tropine.

Tropinone has three!

slide11

INVESTIGATION OF THE RINGS

HOFMANN DEGRADATIONS

slide12

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%

slide13

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

an alkene

distill

+

:

+

nitrogen is removed

as trimethylamine

ALL THREE STEPS COMPRISE

ONE DEGRADATION SEQUENCE

slide14

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

1

2

3

..

in a

ring

SEQUENCE ONE

SEQUENCE TWO

breaks the first bond

to the nitrogen

breaks the second bond

to the nitrogen

slide15

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.

slide16

Tropine

Tropilene

Tropidine

Tropilidene

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?

slide17

Tropilidene

Tropilene

POSSIBLE RING STRUCTURES FOR TROPILIDENE

C7H8

toluene

4 units unsat

known compound

not a cycloheptane

What else would fit ?

C7H10O

3 units unsat

slide18

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

slide19

achiral

achiral

HYPOTHESIS !

tropine

CrO3

-H2O

H2SO4

heat

tropinone

tropidine

chiral

slide20

Tropine

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)

slide21

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

slide22

EXPLANATION OF THE OXIDATION REACTIONS

In the Kuhn-Roth oxidation

it is known that tertiary H’s

oxidize first. 3o > 2o > 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

slide23

THE STRUCTURE OF ATROPINE

tropine

tropic acid

atropine is

racemic here

next to C=O

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

slide24

See assignments

page for actual dates.

ASSIGNMENTS

Gold Problem Gray Problem

Already assigned

Due in one week

Blue Problem and Green Problem and Pink Problem

Due in two weeks