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6-1-2001 The ffecE t of rhodium reagents upon the hydroboration and thermal isomerization of quadricyclane Dana DiDonato

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This Thesis is brought to you for free and open access by the Thesis/Dissertation Collections at RIT Scholar Works. It has been accepted for inclusion in Theses by an authorized administrator of RIT Scholar Works. For more information, please contact [email protected]. THE EFFECT OF RHODIUM REAGENTS UPON THE HYDROBORATION AND THERMAL ISOMERIZATION OF QUADRICYCLANE

Dana DiDonato

June 2001

A thesis submitted in partial fulfillment ofthe requirements for the degree of Master of Science in Chemistry

Approved: Terence Morrill Thesis Advisor

Department Head

Department of Chemistry Rochester Institute ofTechnology Rochester, NY 14623-5603 Copyright Release Form

The Effect of Rhodium Reagents Upon the Hydroboration and Thermal Isomerization of Quadricyclane

I, Dana DiDonato, hereby grant pennission to Wallace Memorial Library of the

Rochester Institute of Technology, to reproduce my thesis in whole or in part.

Any reproduction will not be for commercial use or profit.

Date:__'_I_2._'_I_o_,__ Signature: _ TABLE OF CONTENTS

LIST OF FIGURES 2

LIST OF TABLES 3

LIST OF SCHEMES 4

ACKNOWLEDGEMENTS 5

1. ABSTRACT 6

2. INTRODUCTION 7

2.1 Hydroboration 7 2.2 CatalyticHydroboration withRhodium Compounds 12 2.3 A MechanisticInvestigation 15

Evans' 2.4 Other Studies Performed by Group 18 2.5 Beta-Hydride Elimination 19 2.6 Reactivityof Strained Ring Systems 20 2. 7 isomerization of quadricyclane to norbornadiene usingrhodium Catalysts 21 2.8 Previous WorkPerformed on Quadricycianeand itsDerivatives 23 2.9 Results of Hydroborationand Oxidation 28

3. OBJECTIVE 29

4. EXPERIMENTAL 31

4.1 "Classical" Hydroborationand Oxidation of Quadricyciane 32 4.2 "Overfed" Hydroborationand Oxidation of Quadricyciane 33 4.3 "Starved" Hydroborationand Oxidation of Quadricyciane 34 4.4 Isomerization Study of Quadricyciane to Norbornadiene 35

Acetate18 4.5 Preparation of Nortricyclyl 35

Nortricyclanol18 4.6 Preparation of 36 4.7 Preparatory Thin Layer Chromatography 37

Reagent19 4.8 Preparation of p-anisaldehyde Visualizing 37

5. RESULTS 38

6. DISCUSSION 49

REFERENCES 63

APPENDICES 65 LIST OF FIGURES

Figure 5.2: Isomerization of Study Quadricyciane to Norbornadiene using Methanol and

RhCl3 39

Figure 5.3: Isomerization of Study Quadricyciane to Norbornadiene using THF and

RhCl3 40

Figure 5.4: Isomerization Study of Norbornadiene to Quadricyciane using THF and

RhCl3 41

Figure 5.5: Isomerization of Quadricyciane to Norbornadiene using THF and Wilkinson's

Catalyst 42

Figure 5.6: Isomerization Study of Quadricyciane to Norbornadiene using CH2CI2,

Aliquat 336, and RhCl3 43

Figure 5.7: Isomerization of Quadricyciane to Norbornadiene using CH2C12 and

RhCl3 44

Figure 5.10: Isomerization Study of Quadricyciane to Norbornadiene using BH3-THF,

THF, andRhCl3 46

Figure 5.11: Isomerization Study of Quadricyciane to Norbornadiene using THF and

BH3-THF 47 LIST OF TABLES

"Overfed" Table 5.1: Hydroboration - THF 38

Table 5.2: Isomerization Study of Quadricyciane to Norbornadiene using Methanol and

RhCl3 39

Table 5.3: Isomerization Study of Quadricyciane to Norbornadiene using Methanol and

RhCl3 40

Table 5.4: Isomerization Study of Norbornadiene to Quadricyciane using THF and RhCl341

Table 5.5: Isomerization Study of Quadricyciane to Norbornadiene using THF and

Wilkinson's Catalyst 42

Table 5.6: Isomerization Study of Quadricyciane to Norbornadiene using CH2C12, Aliquat

336, andRhCl3 43

Table 5.7: Isomerization Study of Quadricyciane to Norbornadiene using CH2C12 and RhCl3

44

"Overfed" Table 5.8: Hydroboration - CH2C12 45

Table 5.9: "Classical" Hydroboration 45

Table 5.10: Isomerization Study of Quadricyciane to Norbornadiene using BH3-THF, THF,

andRhCl3 456

Table 5.11: Isomerization Study of Quadricyciane to Norbornadiene using BH3-THF and

THF 47

"Overfed" Table 5.12: Hydroboration at Varying Temperature 48 LIST OF SCHEMES

Scheme 2.1: Hydroboration Reagents

Scheme 2.2: Addition of Borane to an Alkene Double Bond

Scheme 2.3: Simple Four - Centered Syn Transition State for the Addition of the Boron -

Hydrogen Bond to Olefins 8

Scheme 2.4: Hydroboration Regiochemistry 9

Scheme 2.5: Mechanism for the Migration of the Boron Group Along a Carbon Chain 9

Scheme 2.6: Oxidation Mechanism 10

Scheme 2.7: Hydroboration and Oxidation of 2 -Pentene 11

Scheme 2.8: Elimination and Addition Reactions for the Isomerization of the Boron Group

Along a Carbon Chain 12

Scheme 2.9: Hydroboration and Oxidation of 5 - Hexen - 2 - one Using Catecholborane and

Wilkinson's Catalyst 13

Scheme 2.10: Mannig - Noth Mechanism 13

Scheme 2.11: Catalytic Cycle of the Hydroboration of 1 -Decene 16

Scheme 2.12: Regioselective Steps of the Hydroboration of 1 -Decene 17

Scheme 2.13: Beta - Hydride Elimination 19

Scheme 2. 14: Stereochemistry and Mechanism of Ionic Cyclopropane Ring Cleavage 23

Scheme 2. 15: Products Resulting from Ionic Cyclopropane Ring Cleavage Using p -

Toluenesulfenyl Chloride 25

Scheme 2. 16: Products Resulting from Ionic Cyclopropane Ring Cleavage Using 2,4 -

Dinitrobenzenesulfenyl Chloride 26

Scheme 2. 17: Products Resulting from the Hydroboration and Oxidation of Quadricyciane Using

Catecholborane and Wilkinson's Catalyst 28 ACKNOWLEDGEMENTS

First, I would like to thank Dr. Terence Morrill for his guidance and patience throughout

the life of this project. I would also like to thank the members of my comrnittee, Dr.

Turner, Dr. Craig, and Dr. Miri and the Chemistry Department who supplied the funding

to make this research possible. In addition I would like to thank my family and friends

for all of their help, continued support, and constant faith in my abilities, which inspired

me to achieve my goals. 1. ABSTRACT

Simple hydroboration of a cyclopropane ring is not a reaction that is easily carried out.

Attempts to hydroborate the three membered ring of quadricyciane, however are encouraged by the high strain energy (96 kcal/mol) of this tetracyclic system.

Observation of nortricyclanol product would be taken as a sign of a successful oxidative

hydroboration of quadricyciane. Some minor successes in earlier hydroborations of quadricyciane with a Rh (I) reagent, Wilkinson's catalyst, encouraged us. Wilkinson's

catalyst was however better at inducing isomerization to norbornadiene than

hydroboration of quadricyciane. The main focus of our research is the hydroboration of

quadricyciane using RhCl3 since this rhodium reagent was very effective in promoting

hydroboration of alkenes. Using RhCl3 we carried out this reaction under various

conditions and we were unable to produce nortricyclanol. We have studied the ability of

RhCl3 to isomerize quadricyciane to norbornadiene and as expected, the ease of this

reaction suggests a the reason why nortricyclanol is not produced. 2. INTRODUCTION

2.1 Hydroboration

Borane (BH3) is a Lewis base and an electron pair acceptor. In its pure form, it exists as a dimer, B2H6, in which two hydrogens bridge the boron atoms. In ethereal solvents borane

acts as an electron acceptor to form Lewis acid - base adducts. It is an electrophilc reagent that, when employed as a THF complex, rapidly undergoes addition reactions

alkenes.1 with

Scheme 2.11: Hydroboration Reagents

H

B l~k .HL /H / \ /B^ /B^ H H H H H

Hydroboration is a highly regioselective and stereospecific reaction. In this reaction, the boron bonds to the less substituted carbon atom of the alkene due to a combination of steric and electronic effects. Upon reaction with 3 moles of alkene, the borane yields a trialkylborane. Unlike the addition of acids to alkenes, the boron, not the hydrogen atom,

is the electrophilic center.

Scheme 2.2: Addition of Borane to an Alkene Bond

? + BH3 -\

H ^B. The addition of the boron - hydrogen bond is a syn addition where borane approaches the

alkene from the less hindered side of the molecule. Both the carbon - boron and carbon -

bond.1 hydrogen bonds form on the same side of the double The addition of the boron -

Zweifel2 hydrogen bond to olefins according to Brown and appeared to be a simple four - centered syn transition state with simultaneous bonding to boron and hydrogen.

Scheme 2.32: Simple Four - Centered Syn Transition State for the Addition of the

Boron - Hydrogen Bond to Olefins

H

Stereoselectivity improves with unhindered molecules. Product mixtures result when there is low regioselectivity and when addition occurs at both faces of the alkene double bond.

It is felt that there is some polar character to both BH3 and the alkene double bond. The small degree of polarity in the alkene double bond favors addition to the more substituted carbocation. Therefore, BH3 will favor addition to the alkene double bond at the more

substituted carbocation. We can rationalize the observed regiochemistry as follows: Scheme 2.4: Hydroboration Regiochemistry

/

H B. H B

160 Hydroboration is a thermally reversible reaction. At temperatures above C, boron

and hydrogen atoms are eliminated from alkylboranes; the equilibrium favors the addition

products. This provides a mechanism for the migration of the boron group along the

carbon chain through a series of eliminations and additions.

Scheme 2.52: Mechanism for the Migration of the Boron Group Along a Carbon Chain

R H R

R R-c R C=CH C-CH3 C=C1 -CH3 + CH2

H B H

H-B. \ H-B. \

R "? -CH^CH^B, H

Migration cannot occur past a quaternary carbon, however, since the required elimination

is blocked. At equilibrium, the major trialkylborane formed is the least substituted or

terminal isomer that is accessible, since this is the isomer which minimizes unfavorable steric interactions. The use of boron reagents containing bulky substituents facilitates boron migration along the carbon chain because there are fewer migrations that occur due

substituent.1 to the

Organoboranes are useful in many reactions. They are most widely used to form alcohols

peroxide.1 by oxidation using alkaline hydrogen

Scheme 2.61: Oxidation Mechanism

/ R R^ x ? R-B-OR R3B + HOCP ? R-^B-O-O-H + Q[) R OR OR ^ | HOC R R ? B^-O-O-H ? B OH0 R2BOR + + R-^ OR

0 f~<

? (OR)2-B-0-0-H ? (RO)3B + OH (RO)2BR + H009 pA

? ROH + (RO)3B + H20 B(OH)3

In the above process, R - O - B bonds are hydrolyzed in solution generating the alcohol.

Up to three boron - to - oxygen migrations of the alkyl groups can occur and then the

- carbon - boron bonds are replaced with carbon oxygen bonds. Most importantly,

throughout this series of migrations, the resulting C - O shows retained configuration.

Hydroboration occurs at the less substituted carbon of the double bond. Thus after

oxidation this is an anti-Markovnikov hydration process. In effect the proton of water is

bond.1 being added to the less substituted carbon of the alkene double

In 1959, Brown and Subba Rao studied the isomerization and displacement reactions of

organoboranes. Brown and Subba Rao found that hydroboration of 2 - pentene followed

10 by oxidation yields 2 - pentanol and 3 - pentanol in equimolar amounts. However, if the

pentanol.3 solution is heated at reflux then oxidized, the product is primarily 1 -

Scheme 2.73: Hydroboration and Oxidation of 2 - pentene

1 . hydroboration 2. oxidation

25C

1 . hydroboration 2. oxidation

160C

This study determined that the isomerization of trialkylboranes to place the boron atom

on the terminal position provides a simple synthetic route for the conversion of internal

olefins to primary alcohols. In addition it was found that the isomerization of the boron

atom from an internal position on a carbon chain to the terminal position is the result of a

cycle of elimination and addition reactions which are depicted below3:

11 Scheme 2.83: Elimination and Addition Reactions for the Isomerization of the Born Group Along a Carbon Chain H H H H H H - bJ=l H H H B H H / \ B H / \

H H H H H H I I H

H B H H / \ B H / \ H H H

H H B / \

2.2 Catalytic Hydroboration with Rhodium Compounds

In 1985, Mannig and Noth found that hydroboration was catalyzed by rhodium complexes. They hydroborated 5-hexen-2-one using catecholborane. The uncatalyzed

reaction was slow and required temperatures of 70 - 100 C. In addition the carbonyl

reduction of 5-hexen-2-one competed with the desired hydroboration reaction. However, the Rh catalyzed reaction proceeded at room temperature without difficulty, resulting in alkene hydroboration. For example, without a catalyst, 5-hexen-2-one reacts rapidly and quantitatively to give 2-(l-methyl-4-pentenyloxy)-l,3,2-benzodioxaborole, whereas, in the presence of Wilkinson's catalyst, the ketone is preferentially and more readily

formed.4

12 Scheme 2.9 : Hydroboration and Oxidation of 5-hexen-2-one Using Catecholborane and Wilkinson's Catalyst

B-H +

Wilkinson's Catalyst

This study led to the proposal of the Mannig - Noth mechanism for the catalyzed

catalyst.4 hydroboration of an olefin using a Rh (I) species, namely Wilkinson's

Scheme 2.104: Mannig - Noth Mechanism

Rhl_3CI

dissociation

B-H Rhl_2CI

catecholborane

oxidative reductive L = PPh

elimination addition

H /" o V B-Rh. o >L CI

'B-?h\ (v_o I CI \

/ olefin

hydride \ olefin / binding migration\insertion c H \ S B-Rh C D L CI

13 In the mechanism depicted above, catecholborane adds oxidatively to Wilkinson's catalyst, and the adduct formed, {[(C6H5)3P]2Rh(m)ClH[B02C6H4]}, reacts stoichiometrically with olefins, resulting in hydroboration and formation of

[{C6H5)3P}2RhCl]2.4

In 1988 Burgess and Ohlmeyer conducted hydroboration reactions using norbornene and

norbornadiene in the presence of catecholborane and rhodium-DIOP or rhodium-BINAP as a catalyst. Upon oxidation these reactions consistently gave exo-norborneol in about

90% yield. The optical purity of the norborneol produced was inversely related to the reaction temperature. For example, at 40C alcohol of 23% ee was produced. However,

at - 25C the % ee increased to 57. Further temperature decreases had no effect on the optical purity, however it is interesting that alcohols of increased % ee were produced at

such low temperatures. At this point the mechanism of rhodium - catalyzed

hydroboration reactions were thought to involve rhodium - hydride complexes. For example, other groups had shown that stoichiometric amounts of catecholborane and

Wilkinson's catalyst reacted to yield a hydride complex [RhClH(B02C6H4)(PPh3)2] which when reacted with alkenes gives hydroboration products. Therefore, the mechanism of the catalyzed reaction, according to Burgess and Ohlmeyer, may proceed via oxidative addition of catecholborane into the rhodium(I) center, insertion of the

alkene into the rhodium - hydride bond, and reductive elimination of alkyl and boronate

ligands.5

14 2.3 A Mechanistic Investigation

In 1990, David Evans and Gregory Fu of Harvard University performed deuterium labeled rhodium catalyzed hydroboration reactions with olefins. From these studies they were able to determine that the reversibility of the elementary steps in the catalytic cycle

dependent.6 is substrate

Case 1: Hydroboration of 1 -decene

1- Catalyzed hydroboration of decene with deuteriocatecholborane (2% catalyst, THF, 20

C), followed by oxidation, provides the terminal alcohol with 99:1 regioselectivity.

Nonregiospecific incorporation of deuterium can be accommodated within the Mannig -

Noth mechanism if it is assumed that the hydride migration step is reversible. As a result, deuterium was found in the product alcohol and in the recovered alkene. The presence of deuterium in the recovered alkene indicates that migration and olefin binding are

step.6 reversible and are occurring slower than the reductive elimination

15 Scheme 2.116: Catalytic Cycle of the Hydroboration of 1-Decene

Rh(PPh3)3CI

.B-D ^oct ^O

oct J

B-Rh I D alkene 11 alkene dissociation dissociation ff hydride V\ // migration V\ oct D D D oo, -J

,oct

B-Rh oct B-Rh / I D B-Rh B-Rh H

reductive

elimination

D oct

,oct B-Rh

B

16 Scheme 2.126: Regioselective Steps of the Hydroboration of 1-Decene

(RO)2B-H Rh(PPh3)3CI

y^- Ph oct // \

.Ph oct y

(RO)2B-Rh (RO)2B-Rh H H

regioselectivity-

determining step H Ph H

(RO)2B oct -Rh

(RO)2BRh

regioselectivity-

determining step

H H- -Ph

B(RO)2 oct

(RO)2B

17 The distribution of deuterium in the above study lead to the following conclusions:

1. Decomplexation of the olefin is not occurring rapidly relative to hydride migration

2. Hydride migrations and p - hydride eliminations are not proceeding rapidly relative to

reductive elimination of the primary alkylboronate

3. Slow reductive elimination step is the reason for the high level of regioselectivity

observed in the Rh(PPh3)3Cl catalyzed hydroboration of terminal olefins [(1 - ol : 2 -

(99:l)]6 ol) =

2.4 Other Studies Performed by Evans' Group

1 . An experiment was performed where a mixture of two different alkenes were

observed under the following conditions7:

1 - decene was first catalytically hydroborated

1 - dodecene was added and the mixture was oxidized.

No dodecanol was present indicating that the reductive elimination step in the catalyzed

irreversible.7 hydroboration of aliphatic alkenes is

2. Studies of internal vs. terminal alkenes illustrate the following7:

(_ - hydride elimination is sensitive to the steric requirements of the olefin being

produced, leading to a suggested mechanism which involves migration of a

hydride as opposed to migration of boron to the bound olefin.

18 2.5 Beta-Hydride Elimination

Beta - hydride elimination is an important mechanistic concept which has been used to

describe the steps associated with the catalytic hydroboration of olefins. Beta-hydride

elimination is a common reaction in organometallic chemistry. The reaction is simply the

transfer of a hydride (hydrogen atom) from the beta-position on a ligand to the metal

center. While most common in alkyl complexes, it is also observed with other ligands,

Q one example being alkoxide ligands bound to late transition metal complexes :

Q Scheme 2.13 : Beta - Hydride Elimination

M CH2 -CH2 M M CH2 + CH? CH2 j H H CH2 H

O M -O M -CH3 /\ H H CH3

transition state which The mechanism shown indicates a four-center in the hydride is

transferred to the metal. An important prerequisite for beta-hydride elimination is the

metal complex. microscopic reverse of presence of an open coordination site on the The a

reaction.8 beta-hydride elimination is called an olefin insertion

19 2.6 Reactivity ofStrained Ring Systems

In 1947 A.D. Walsh developed a model to describe the bonding in cyclopropane rings.

The primary assumption of Walsh's method to derive the molecular orbitals of

cyclopropane is that only the frontier orbitals of the component fragments interact to

form new carbon - carbon bonds. It is assumed that all other orbitals interactions cancel.

Walsh considered cyclopropane as a combination of three methylene units. However,

the a type and n - type methylene orbitals cannot combine since they have different

symmetries. Therefore, two separate sets of molecular orbitals need to be made for

cyclopropane. His model explains several ways in which cyclopropane differs from

other saturated hydrocarbons. For example, cyclopropane rings (a) undergo addition

reactions, (b) show properties and reactivities consistent with n - type conjugation with

neighboring carbocations and radicals, and (c) the C - H force constants are consistent

sp2hybridization.9 with that of

In 1967 Peterson and Thompson studied cyclopropane ring - opening reactions using

trifluoroacetic acid. Reactions were run with comparable alkenes and as a result it was

determined that cyclopropanes reacted approximately 300 times faster than their

comparable alkenes. Cyclopropane openings showed similar inductive effects but

smaller effects of chlorine participation and (probably) hydrogen participation, compared

with additions to unbranched alkenes and solvolyses of secondary tosylates. The

significance of this study is that, by comparison with previous studies, it provides the

first comparison of carbocation formation through three following pathways: (a)

cyclopropane opening, (b) additions to alkenes, and (c) tosylate solvolyses. Increased

interest in electrophilic ring - opening reactions of cyclopropanes has resulted from

20 studies indicating the intermediacy of equilibrating edge- and/or end - protonated cyclopropane intermediates and of the corresponding species derived from electrophilic

cations.10 attack of bromine or acyl Usually, the n - system of cyclopropanes is less reactive than that of alkene double bonds.

The unusual reactivity of quadricyciane and its derivatives has been attributed to the high strain energy of these systems. The heat of formation of quadricyciane is 77.7 1.0

coworkers11 kcal/mol and its strain energy is approximately 96 kcal/mol. Turner and who measured the enthalpy of hydrogenolysis of quadricyciane to norbornane reported the first thermochemical data on quadricyciane. Turner, et al., also determined the enthalpy of hydrogenation of norbornadiene. These data were combined and they experimentally determined the value for the enthalpy of isomerization of quadricyciane to norbornadiene

to be -24 0.9 kcal/mol. Hall, et al. also calculated a value for the enthalpy isomerization of quadricyciane to norbornadiene using the heats of combustion of each compound. The value determined by this group was -10 0.5 kcal/mol.

2.7 Isomerization of Quadricyciane to Norbornadiene using Rhodium Catalysts

In 1967 Hogeveen and Volger studied the isomerization of quadricyciane to

norbornadiene. At high temperature (140C) the thermal isomerization proceeds very

14 hours. the rate of this slowly and the interconversion takes approximately However, isomerization reaction is greatly increased by the introduction of transition - metal

complexes. In addition, the temperature needed for quadricyciane to convert to

reduced. when 2 mole % di-u,-chloro-bis- norbornadiene is greatly For example,

(bicyclo[2.2.1]hepta-2,5-diene)dirhodium(I) is added to a 0.7 M solution of quadricyciane

21 in CDCI3 at - 25C the isomerization proceeds in 45 minutes. The mechanism of the

reaction is thought to involve a coordination of quadricyciane to the transition metal either through an exchange with the originally coordinated olefin or by extension of the coordination around the metal. This coordination may be due to the TC-character of the cyclopropane ring bonds. The valence isomerization of quadricyciane to norbornadiene is thermally forbidden according to the Woodward - Hoffman rule for cycloadditions. The occupied molecular orbitals, which are due to the addition of a rhodium complex, may

allowed.12 cause this process to be

In 1997 George Sluggett and coworkers studied the intercoversion of quadricyciane to

Rh3+ norbornadiene using and photolysis. It is thought that the conversion from quadricyciane to norbornadiene may involve a one-electron oxidation step, followed by

Q*+ valence isomerization of to N"+. Through these studies it has also been determined that the liberation of strain energy as heat is a result of the interconversion of quadricyciane to norbornadiene and that transition metal catalysts help facilitate this interconversion. Sluggett and coworkers studied two Rh(IH) diimine complexes,

Rh(phen)33+ and Rh(phi)2(phen)3+, and found that they clearly sensitize the conversion of

+ quadricyciane to norbornadiene. Specifically, when Rh(phen)3 is used the conversion is

Rh(phi)2(phen)3+ reversible, but when using the conversion is irreversible. Therefore, different reactions will have varying behavior depending on the quencher and sensitizer

Rh(phen)33+ molecules, which are used. For example, has a higher excited - state energy and a higher excited - state reduction potential than Rh(phi)2(phen)3+. The Rh(__) complexes have short - lived singlet excited states so that only triplet-excited states are intercepted by quenchers. The mechanism of these interconversion reactions may involve

22 13 one or all of the following: electron transfer, exciplex formation, or energy transfer.

2.8 Previous Work Performed on Quadricyciane and its Derivatives

Previous studies have shown that cyclopropane ring cleavages via nucleophiles occur by

inversion whereas via electrophiles they occur by retention, inversion, and mixed

processes.14 retention - inversion

In 1971, Morrill et al. studied the stereochemistry and mechanism of ionic cyclopropane

ring cleavage by adding hydrogen chloride to quadricyclanedicarboxylic acid (1). The

mechanism proposed is based in part, on the mechanism for conjugate addition and in

14 part, on normal cyclopropane mechanisms.

Scheme 2.1414: Stereochemistry and Mechanism of Ionic Cyclopropane Ring Cleavage

H+ + ^ COOH

(D

(2) cr

ho. ,OH

COOH

H CI

(3)

H. M

COOH

COOH Protanation of (1) is assumed to occur on one of the carboxy groups to give an ion, which

has properties similar to that of a dihydroxycyclopropylcarbinyl cation. Attack by a

nucleophile to the carboxyl group at C-6 yields exo-5-chloroenediol (4) with inversion.

Attack at position this is favored over the C-4 position because opening the cyclopropane

ring involves a higher release of strain energy. Compound (4) has almost identical steric

environments for proton transfer to either side of the double bond involved in the keto-

enol tautomerization to the carboxylic acid. Therefore, (4a) and (4b) are formed in the

proton transfer step and in essentially equal yields. Thus, the whole process is a

homoconjugate addition rather than a simple addition to the cyclopropane ring. Ionic

additions to quadricyciane must follow different processes than those observed for (1)

because substantial amounts of norbornenes and nortricyclenes are observed. These

results require homoallylic rearrangement pathways and Wagner-Meerwein

rearrangement. Neither of these two rearrangements are observed for additions to (1). It

is thought that additions to quadricyciane involve transformations of protonated

cyclopropanes to carbonium ion intermediates. These are not involved in addition

reactions with (1) because of the electron-attracting character and availability for

protonation of the carboxylic acid groups.

In 1975, Morrill et al. studied the stereochemistry and mechanism of ionic cyclopropane

quadricyciane.15 ring cleavage by adding arenesulfenyl chloride to

Quadricyclanedicarboxylic acid (1) with hydrochloric acid was previously studied by his

group and they found that the stereochemistry of the new proton position in the final

adduct was not a result of direct cyclopropane ring cleavage. Based on these results, the

arenesulfenyl chloride cleavage of (1) was investigated.

24 Scheme 2.1515: Products Resulting from Ionic Cyclopropane Ring Cleavage Using p - Toluenesulfenyl Chloride

C02H

C02R

R = H; Ar = C6H5 C02R

(10)

C02R

R = H; Ar = C6H5 SAr

H C02H (12)

Due to the information known about the mechanism of hydrogen chloride opening of (1), a possible mechanism for the benzenesulfenyl chloride was (a) formation of hydrogen chloride from the reaction of benzenesulfenyl chloride with the dicarboxylic acid followed by (b) cleavage of (1) to form enediol (10) then (c) deprotanation to form (11) and (4) in a nearly 50:50 ratio. It was determined that the reactions studied were controlled kinetically since the products did not interconvert. Therefore, ionic cyclopropane ring cleavage with p-toluenesulfenyl chloride and with benzensulfenyl chloride resulted in electrophilic cleavage of the ring with retention (11 type products) and inversion (12 type products) processes in nearly equal amounts of the two processes occurring in each of the two addition reactions. The carboxyl groups are highly electron

25 - and do not withdrawing therefore, provide the stabilized carbocation necessary for the

product.15 nucleophilic cleavage retention

In et al. - 1981, Morrill studied the reaction of 2,4 Dinitrobenzenesulfenyl chloride with

quadricyciane.16

Scheme 2.1616: Products Resulting from Ionic Cyclopropane Ring Cleavage Using p - toluenesulfenyl Chloride

SAr

Ar =2,4-(N02)2C6H3 or 2-N02C6H4

/ZC^Z-SAr M = 2'4-(N2)2C6H3

CI

(9)

As a result of this study, the following conclusions were made: (a) the reaction of 2,4 -

dinitrobenzenesulfenyl chloride with quadricyciane results in the smooth cleavage of the cyclopropane ring, and the ratio of the products obtained depends on the polarity of the solvent; (b) configuration of the major product arising from the cleavage by sulfur electrophile is (9) with an endo - chlorine which indicates retention of configuration at

this position, which is inconsistent with previous reports but which supports the ion - pair mechanism proposed; (c) the process in acetic acid seems to involve competitive

additions of 2,4 - dinitrobenzenesulfenyl chloride and acetic acid additions to

quadricyciane. The minor proportions of olefinic or nortricyclenic adducts formed as the

attack" result of endo attack by sulfur is negative evidence for "edge - by sulfur.

26 attached" Therefore, it was thought that a "corner (exo - sulfur) species through an exo - bridged sulfonium ion, to olefin (8). The basic argument for corner attack is the fact that

electrophilic attack occurs with inversion. Treatment of quadricyciane with 2,4 -

Dinitrobenzenesulfenyl chloride in acetic acid proceeds along two successive paths: one

is the addition of acetic acid solvent to produce acetates and the other is the subsequent

attack of these acetates by 2,4 - Dinitrobenzenesulfenyl chloride. This second attack

displays characteristics typical of well developed carbocations, namely, (a) the occurrence

solvent.16 of Wagner - Meerwein rearrangement and (b) the incorporation of acetic acid

In 1994, Dr. Morrill and his research group attempted to hydroborate quadricyciane using

catalyst.17 catecholborane and Wilkinson's

Reaction Conditions17:

0.0005 moles Wilkinson's catalyst 20mLTHF

5C

0.054 moles catecholborane

0.054 moles quadricyciane

nitrogen atmosphere

24 hour reaction time

Workup Conditions17:

-40C

15 mL 3M NaOH

20 mL 30% H202

24 hour reaction time at room temperature

27 2.9 Results ofHydroboration and Oxidation

The product sample obtained was 99 % pure. A GC analysis of the product was performed and yielded the following percentages17:

9.9 % nortricyclanol (3)

53.2 % norbornadiene (2)

11.7 % norborneol (4)

25.2 % quadricyciane (1)

Scheme 2.1717: Products Resulting from the Hydroboration and Oxidation of Quadricyciane using Catecholborane and Wilkinson's Catalyst

0) (2) (3) OH

1 n The following conclusions were made from this study :

1. Direct cleavage of the cyclopropane in quadricyciane goes in measurable yield.

2. Isomerization of quadricyciane to norbornadiene gives norborneol upon

hydroboration, which is an uninteresting result.

3. The reaction is temperature dependent.

28 3. OBJECTIVE

Synthesis of nortricyclanol (3) using the Rh(__) catalyzed hydroboration of quadricyciane will be attempted. However, this synthesis may be difficult due to the competing isomerization reaction of quadricyciane to norbornadiene. Reaction of RhCl3 cleaves one of the cyclopropane rings of quadricyciane, facilitating the isomerization reaction.

Therefore, it is necessary for the hydroboration reaction of quadricyciane to occur before the hydrocarbon isomeriztion reaction; thus we wish to obtain nortricyclanol as opposed

to exo-norbornenyl alcohol. The latter would be formed from norbornadiene in a process

that has been known for sometime.

Kevin Gillman attempted the synthesis of nortricyclanol in 1991 using catalytic hydroboration. He used catecholborane as the hydroborating agent and the catalyst he used was Wilkinson's catalyst, a Rh(I) species. Under these conditions he reported a

9.9% yield of nortricyclanol.

In an attempt to produce yield of nortricyclanol, RhCl3, a Rh(__) species, will be employed as the catalyst, and BH3-THF, a stronger hydroborating agent, will be used. By using a rhodium catalyst with a higher oxidation state and a stronger hydroborating agent, it is thought that the hydroboration reaction might occur faster than the competing isomerization reaction, providing a higher yield of nortricyclanol.

After finding that BH3-THF and RhCl3 did not convert quadricyciane to nortricyclanol,

Rh3+ we decided to compare rates of quadricyciane rearrangement promoted by vs. Rh1+.

Thus we'll describe our research in that order.

The isomerization reaction of quadricyciane will extensively be studied to determine, if in fact, Rh(IH) catalyzed hydroboration can compete. In studying this isomerization, the

29 effects of time, temperature, and solvent will be examined to determine if any, or all, of these factors play a significant role in the course of the reaction. Using this information, optimum hydroboration conditions will be determined in an attempt to increase the yield

of nortricyclanol produced.

30 4. EXPERIMENTAL

Chemicals used for this research were purchased from the Aldrich Chemical Company.

GC-Mass data Spectrometry were collected using a Hewlett Packard model 6890 Gas Chromatograph and a Hewlett Packard model 5973 Mass Selective Detector.

Column: 60.0 m x 250.0 urn cross linked methyl siloxane capillary column, model number HP 1 909 1 S - 936

GC/MS Methods:

1. Method for Analyzing Hydroboration Reactions: Initial Temp.: 40C

Initial Hold Time: 5 min.

Ramps: # Rate(C /min.) Final Temp.( C) Hold Time(min.) 1 5.00 50 7.00 2 10.00 100 8.00

Post run time: 3.00 min.

Runtime: 27.00 min.

2. Method for Analyzing Isomerization Reactions:

Initial Temp.: 40C

Initial Hold Time: 5 min.

Ramps: # Rate(C /min.) Final Temp.( C) Hold Time (min.) 1 5.00 50 7.00

Post run time: 3.00 min.

Run time: 15.00 min.

NMR Spectroscopy were performed on a Bruker 300 MHz FT - NMR

31 4.1 "Classical" Hydroboration and Oxidation ofQuadricyciane

THF/25C H20

*~ ? isomers BH3-THF NaOH

H202

A 200-mL 3-neck flask fitted with a septum, a guard tube filled with drierite, and a stopper was flushed with nitrogen. To this flask 10 mL THF and 1-mL (0.0107 mol)

quadricyciane were added and stirred for 15 minutes. To this mixture was added 6 mL

(0.006 mol) 1M BH3-THF through a 10 mL syringe. The 1M BH3-THF was allowed to drain into the reaction mixture for 30 minutes after which the remaining reagent was added slowly over an additional 30-minute period. The hydroboration reaction was run for 2 hours (timed from the point when the first drop of 1M BH3-THF entered the reaction mixture). The reaction was then cooled for 5-10 minutes using an ice - water bath. Once the mixture was chilled, 5 mL H20 and 5 mL 3M NaOH were added to quench the reaction. Following this addition, 7 mL 30% H202 was slowly added due to the evolution of heat and foam. The oxidation reaction was run for approximately 2 hours after which the product(s) were extracted. The product was extracted using two 40-

30- mL portions of diethyl ether. The organic layers were combined and washed with one

mL portion of saturated NaCl solution. The organic layer was dried with MgS04 and filtered. The filtrate was concentrated via rotavapor and analyzed by GC/MS. From

these results it was determined that the hydroboration of quadricyciane, to yield

nortricyclanol, could not be carried out in the absence of RhCl3.

32 "Overfed" 4.2 Hydroboration and Oxidation ofQuadricyciane

solvent H20

? isomers RHCI3-xH20 NaOH

BH3-THF H202

A 200-mL 3-neck flask fitted with a septum, a guard tube filled with drierite, and a stopper was flushed with nitrogen. To this flask 10 mL solvent (either THF or CH2C12 were used) and 10 mg (0.000478 mol) RhCl3*H20 were added and stirred for 15 minutes after which 1-mL (0.0107 mol) quadricyciane was added. To this mixture was added 6 mL (0.006 mol) 1M BH3-THF through a 10 mL syringe. The 1M BH3-THF was allowed to drain into the reaction mixture for 30 minutes after which the remaining reagent was added slowly over an additional 30-minute period. The hydroboration reaction was run at either 0C, 25C, or at 60C for 2 hours (timed from the point when the first drop of 1M

BH3-THF entered the reaction mixture). The reaction was then cooled for 5-10 minutes

using an ice - water bath. Once the mixture was chilled, 5 mL H20 and 5 mL 3M NaOH were added to quench the reaction. Following this addition, 7 mL 30% H202 was slowly

added due to the evolution of heat and foam. The oxidation reaction was run for

extracted. The product was approximately 2 hours after which the product(s) were

ether. organic layers were combined extracted using two 40-mL portions of diethyl The

and washed with one 30-mL portion of saturated NaCl solution. The organic layer was dried with MgS04 and filtered. The filtrate was concentrated via rotavapor and analyzed by GC/MS. From these results there was no evidence that nortricyclanol was present.

Instead it appeared that up to 46% of the mixture was exo - norbornenyl alcohol which is

33 known to result from the hydroboration and oxidation of norbornadiene.

"Starved" 4.3 Hydroboration and Oxidation of Quadricyciane

THF/25C H2

isomers RHCI3-xH20 NaOH

BH3-THF H202

A 200-mL 3-neck flask fitted with a septum, a guard tube filled with drierite, and a

stopper was flushed with nitrogen. To this flask 7 mL THF and 10 mg (0.000478 mol)

RhCl3H20 were added and stirred for 15 minutes after which 1-mL (0.0107 mol)

quadricyciane was added. To this mixture was added 0.5 mL (0.0005 mol) 1M BH3-THF

through a 10 mL syringe. The 1M BH3-THF was allowed to drain into the reaction

mixture for 30 minutes after which the remaining reagent was added slowly over an

additional 30-minute period. The hydroboration reaction was run at for 2 hours (timed

from the point when the first drop of 1M BH3-THF entered the reaction mixture). The

reaction was then cooled for 5-10 minutes using an ice - water bath. Once the mixture

was chilled, 5 mL H20 and 5 mL 3M NaOH were added to quench the reaction.

Following this addition, 7 mL 30% H202 was slowly added due to the evolution of heat

and foam. The oxidation reaction was run for approximately 2 hours after which the

product was extracted 40-mL portions of product(s) were extracted. The using two

diethyl ether. The organic layers were combined and washed with one 30-mL portion of

saturated NaCl solution. The organic layer was dried with MgS04 and filtered. The

"starved" filtrate was concentrated in vacuo and analyzed by GC/MS. In this case the

hydroboration reaction was unsuccessful because quadricyciane and norbornadiene were

34 present in the reaction mixture only; no alcohols were observed.

4.4 Isomerization Study ofQuadricyciane to Norbornadiene

solvent

RhCI3

A 200-mL 3-neck flask fitted with a septum, a guard tube filled with drierite, and a

stopper was flushed with nitrogen. To this flask 10 mL THF, 10 mL methanol, or 10 mL

(1.08*10"5 methylene chloride and 10 mg (0.000478 mol) RhCl3H20 or 10 mg mol)

Wilkinson's catalyst were added and stirred for 15 minutes. To this mixture was added

0.5 mL (0.00533 mol) quadricyciane. The isomerization reaction was run at 25C for up

to 3 hours during which time aliquots were removed every 30 minutes. Each aliquot was

quenched with 7 drops of H20 and extracted with 2-mL pentane and analyzed by GC/MS.

Rh3+ From these results it was determined that isomerizes quadricyciane to norbornadiene

faster than does Rh1+. In addition, when comparing the rate of isomerization of

Rh3+ quadricyciane to norbornadiene using and various solvents, the order is as follows:

THF>MeOH>CH2Cl2.

4.5 Preparation ofNortricyclyl Acetate

0.018 MH2S04

. ?

Glacial Acetic Acid

norbornadiene and 125 To a 250 mL round bottom flask was added 25 mL (0.245 mol)

hours. After to room mL 0.018 M H2S04 in acetic acid and refluxed for 2.5 cooling

35 one gram of temperature, Na2C03 was added to neutralize the H2S04. The reaction

mixture was then poured into mL 200 of water and extracted three times with 75 mL

petroleum ether (30 - 60 C). The organic layer was then washed with 50 mL portions of

10% until and Na2C03 basic, then washed twice with 50 mL portions of distilled water.

To this was added 150 mL of acetic acid and 75 mL of an aqueous solution of 7.5 g

KMn04. This solution was stirred for 45 minutes and then filtered. The mixture was

extracted three times with - 50 mL portions of petroleum ether (30 60 C). The organic

layer was washed with 50 mL portions of 10% Na2C03 until basic and then washed twice

with mL 50 portions of distilled water. A short path distillation was carried out on the

concentrated product and it was analyzed using GC/MS. The gas chromatogram showed

only one peak at a retention time of 26.33 min.

Nortricyclanol18 4.6 Preparation of

Anhydrous MeOH

Na \

H

To a 250 mL round bottom flask was added 6.92 g (0.0450 mol) nortricyclyl acetate, see

section 4.5, and 75 mL anhydrous methanol in which 0.2 g sodium metal had been dissolved. The solvent was distilled through a short column packed with glass beads using a heating mantle. After allow the reaction mixture to cool to room temperature, 75

mL ether was added and the ether solution was washed twice with 25 mL portions of distilled water and dried over MgS04. The solution was filtered, concentrated via rotavapor, and analyzed by GC/MS and lH NMR. The gas chromatogram showed a 95%

36 pure sample with a retention time of 20.94 min (pg.76). The JH NMR spectrum showed a

singlet at 3.85 ppm, indicative of nortricyclanol (pg.78).

4.7 Preparatory Thin Layer Chromatography

"overfed" Each preparatory thin layer plate was spotted twice over with the hydroboration

reaction mixture. The plate was place in a developing chamber that contained 100 - mL

of 30:70 ethyl acetate: pentane solvent mixture. The plate was allowed to develop for 45

- minutes - 1 hour. The plate was dried using a heat gun and then a small amount of p

anisaldehyde visualizing reagent was sprayed on the left side of the plate. The visualizing

"nortricyclanol" reagent was dried using a heat gun, whereupon the green - blue spot

"nortricyclanol" could be seen. The band was then extrapolated across the plate and the

extract the silica was scraped off of the preparatory thin layer plate using a spatula. To

- which the fraction from the silica, it was allowed to stir in 100 mL ether overnight after

concentrated via silica was removed via vacuum filtration. The fraction was then

results it was determined that the band rotavapor and analyzed by GC/MS. From these

unable to be thought to be pure nortricyclanol was a mixture of alcohols that were

separated.

Reagent19 4.8 Preparation ofp-anisaldehyde Visualizing

- - 2 mL sulfuric 36 - mL p-anisaldehyde, acid, To a 100 mL brown bottle was added 2

acid. mL of 95% ethanol, and 5 or 6 drops acetic

37 5. RESULTS

"Overfed" Table 5.1: Hydroboration - THF

Overfed Retention Times Hydroboration A* B* C* Time Starting Solvent 8.15- 8.80- 9.90- 10.10- 19.20- 79.65- 20.85- 27.20- Material 8.25 8.85 10.00 10.15 19.25 79.75 20.95 27.30

120 mins Quadricyciane THF 0.00 0.00 3.24 4.91 0.00 35.64 46.24 5.66

120 mins Quadricyciane THF 5.48 5.11 5.84 3.51 4.66 33.39 37.82 4.19

120 mins Quadricyciane THF 29.04 0.00 0.00 0.00 0.00 27.27 43.69 0.00

120 mins Quadricyciane THF 28.09 4.88 4.35 0.00 0.00 44.69 18.02 0.00

The hydroboration reactions were carried out using 10 mL THF, 1.0 mL (.01066 mol) quadricyciane, 10 mg (0.000478 mol) RhCl3, and 6 mL (.006 mol) BH3-THF at 25 C for 2 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether. * where A = Norbornadiene, B = exo-norbornenyl alcohol, and C = either nortricyclanol or exo-norborneol (For experimental procedure refer to Section 4.2)

38 Table 5.2: Isomerization Study of Quadricyciane to Norbornadiene using Methanol and RhCl3 Time Quadricyciane Norbornadiene Omins 100 0

30 mins 16.81 83.16

60 mins 1.95 98.05

90 mins 0 100 This isomerization reaction was carried out using 10 mL methanol, 10 mg (0.000478 mol) RI1C13, and 0.5 mL (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 2 hours during which time 2 aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and extracted using mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.2: Isomerization Study of Quadricyciane to Norbornadiene using Methanol and RhCh

Quadricyciane

Norbornadiene

30 60 90

Time (mins)

39 Table 5.3: Isomerization Study of Quadricyciane to Norbornadiene using THF and RhCl3 Time Quadricyciane Norbornadiene

0 mins 100 0

30 mins 49.24 50.76

60 mins 0 100

90 mins 0 100

This isomerization reaction was carried out using 10 mL THF, 10 mg (0.000478 mol) RhCl3, and 0.5 mL (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 1.5 hours during which time aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and extracted using 2 mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.3: Isomerization Study of Quadricyciane to Norbornadiene using THF and RhCl3

100 i^ ,. i. m

90 -

en oU

4> /U

60 - 3 ? Quadricyciane S 50 - Norbornadiene 40-

_ * 30-

on ZU

tu1 c\ 0 *

() 50 100

Time (mins)

40 Table 5.4: Isomerization Study of Norbornadiene to Quadricyciane using THF and RhCl3

Time Quadricyciane Norbornadiene Omins 0 100

30 mins 0 100

60 mins 0 100

90 mins 0 100

This isomerization reaction was carried out using 10 mL THF, 10 mg (0.000478 mol) RhCl3, and 0.5 mL (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 1.5 hours during which time aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and extracted using 2 mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.4: Isomerization Study of Norbornadiene to Quadricyciane using THF and RhCl3

100 Hll"-

80

_

& 60 Quadricyciane a

_ Norbornadiene _ 40

- Oh 20

0 50 100

Time (mins)

41 Table 5.5: Isomerization Study of Quadricyciane to Norbornadiene using THF and Wilkinson's Catalyst

Time Quadricyciane Norbornadiene

0 mins 100 0

30 mins 84.48 15.52

60 mins 78.87 21.13

90 mins 76.53 23.47

120 mins 73.98 26.02

150 mins 71.90 28.10

180 mins 69.81 30.19

,, nn.J _,x T-,7-,, , _!.._ and 0.5 mL (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 3 hours during which time aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and extracted using 2 mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.5: Isomerization of Quadricyciane to Norbornadiene using THF and Wilkinson's Catalyst

Quadricyciane

Norbornadiene

100 200 300

Time (mins)

42 Table 5.6: Isomerization Study of Quadricyciane to Norbornadiene using CH2CI2, Aliquot 336, and RI1CI3

Time Quadricyciane Norbornadiene

0 mins 100 0

30 mins 73.11 26.89

60 mins 69.76 30.24

90 mins 66.53 33.47

This isomerization reaction was carried out using 10 mL CH2C12, 10 mg (0.000478 mol) RhCl3, 1 drop Aliquot 336, and 0.5 mL (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 1.5 hours during which time aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and extracted using 2 mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.6: Isomerization Study of Quadricyciane to Norbornadiene using CH2CI2, Aliquot 336, and RhCl3

Quadricyciane

Norbornadiene

0 50 100

Time (mins)

43 Table 5.7: Isomerization Study of Quadricyciane to Norbornadiene using Ch_Cl2 andRhCl3

Time Quadricyciane Norbornadiene

0 mins 100 0

30 mins 85.43 14.57

60 mins 82.09 17.91

90 mins 79.09 20.91

120 mins 76.06 23.94

150 mins 72.51 27.49

180 mins 78.48 21.52

and 0.5 mL This isomerization reaction was carried out using 10 mL CH2C12, 10 mg (0.000478 mol) RhCl3, (.00533 mol) quadricyciane at 25 C. This reaction was run for a total of 3 hours during which time extracted 2 aliquots were taken every 30 minutes. Each aliquot was quenched with 7 drops H20, and using mL pentane. (For experimental procedure refer to Section 4.4)

Figure 5.7: Isomerization of Quadricyciane to Norbornadiene using CH2CI2 and RhCl3

100 90 80 70 oc

C3 60 -? _> Quadricyciane c 50 - Norbornadiene - 40 _ Ph 30 20 10 0 100 200 300

Time (mins)

44 "Overfed" Table 5.8: Hydroboration - CH2CI2

Overfed Retention Times

A* Hydroboralion- B* C* D* CH2C1; Starting Solvent S.75- 8.80- 9.90- 70.70- 72.00- 79.05- 79.20- 79.50- 79.65- 20.90- 27.20- Material 8.25 8.85 10.00 70.75 72.20 79.75 79.25 79.60 79.75 21.00 27.25

Quadricyciane CH2C12 7.77 0 2.56 5.61 64.92 1.33 0 0 1.3 15.57 0

Quadricyciane CH2C12 7.62 0 2.87 6.80 67.59 1.15 0 0 0 13.96 0

Quadricyciane CH2C12 13.45 1.61 2.79 3.70 18.49 1.26 2.53 1.82 7.30 38.86 4.54

The hydroboration reactions were carried out using 10 mL CH2C12, 1.0 mL (.01066 mol) quadricyciane, 10 mg (0.000478 mol) RhCl3, and 6 mL (.006 mol) BH3-THF at 25 C for 2 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether. * where A = Norbornadiene, B = Quadricyciane, C = exo-norbornenyl alcohol, and D = either nortricyclanol or exo-norborneol (For experimental procedure refer to Section 4.2)

Table 5.9: "Classical" Hydroboration

Classical Retenl ion Times

A' B* C* D* Hydroboration Time Starting Solvent 8.20- 12.00- 79.70- 20.90- 27.25- 22.20- Material 8.25 12.05 79.75 20.95 27.50 22.25

120 mins Quadricyciane THF 6.65 62.76 0.00 6.63 0.00 0.00

300 mins Quadricyciane THF 0.00 0.00 9.02 ^73.376.24 11.37

120 mins Quadricyciane THF 7.71 88.50 0.00 0.00 0.00 0.00

120 mins Norbornadiene THF 0.00 0.00 13.78 77.93 8.30 0.00

The hydroboration reactions were carried out using 10 mL THF, 1.0 mL (.01066 mol) quadricyciane or 1.0 mL (.00927 mol) norbornadiene, and 6 mL (.006 mol) BH3-THF at 25 C for either 2 or 5 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether.

* = = where A = Norbornadiene, B = Quadricyciane, C exo-norbornenyl alcohol, and D either nortricyclanol or exo-norborneol

(For experimental procedure refer to Section 4.1)

45 BH3- Table 5.10: Isomerization Study of Quadricyciane to Norbornadiene using THF, THF, and RhCl3 Time Starting Solvent Norbornadiene Quadricyciane Material

120 mins Quadricyciane THF 76.70 19.83

120 mins Quadricyciane THF 86.53 9.22

The isomerization reactions were carried out using 10 mL THF, 1.0 mL (.01066 mol) quadricyciane, 10 mg (0.000478 mol) RhCl3, and 10 drops BH3-THF at 25C for 2 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether. (For experimental procedure refer to Section 4.4)

BH3- Figure 5.10*: Isomerization Study of Quadricyciane to Norbornadiene using THF, THF, and RhCl3

100

90 9.22 19.83 80

70

tf> 60

_ *_ ? Quadricyciane c 50 ? Norbornadiene _ 86.53 40 Ph 76.7 30

20

10

0

and were run twice to check for reproducibility. These measurements were made after 120 minutes

46 Table 5.11: Isomerization Study of Quadricyciane to Norbornadiene using THF and BH3-THF

Time Starting Solvent Norbornadiene Quadricyciane Material

120 mins Quadricyciane THF 7.79 91.42 120 mins Quadricyciane THF 8.21 91.03

The isomerization reactions were carried out using 10 mL THF, 1.0 mL (.01066 mol) quadricyciane, and 10 drops BH3-THF at 25C for 2 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether. (For experimental procedure refer to Section 4.4)

Figure 5.11: Isomerization Study of Quadricyciane to Norbornadiene using THF and BH3-THF

100

80

60 3 ? Quadricyciane c 91.42 91.03

_ ? Norbornadiene _

_ 40 ffu

20

7.79 8.21

*These measurements were made after 120 minutes and were run twice to check for reproducibility.

47 "Overfed" Table 5.12: Hydroboration at Varying Temperature

"Overfed" Retention Times

llVUlUUUlilUUII ill A B C D Varying Temperature Time Starting Solvent Temp. 8.15- 8.80- 9.90- 10.10- 72.00- 79.75- 79.65- 20.60- 20.90- 27.20- Material 8.25 8.90 9.95 10.15 72.70 79.20 79.75 20.70 20.95 27.25

120 mins Quadricyciane THF 60C 3.59 2.10 5.47 2.73 0.00 6.28 42.51 0.00 32.68 4.66

120 mins Quadricyciane THF 60C 0.00 2.68 5.96 3.49 0.00 4.54 32.86 2.40 42.93 5.13

120 mins Quadricyciane THF OC 24.68 1.82 6.56 10.25 53.09 0.00 0.00 0.00 3.59 0.00

The hydroboration reactions were carried out using 10 mL THF, 1.0 mL (.01066 mol) quadricyciane, 10 mg (0.000478 mol) RhCl3, and 6 mL (.006 mol) BH3-THF at either 60 C or 0 C for 2 hours. The oxidation reactions were run for 2 hours using H202. The samples were quenched with 5 mL H20 and 5 mL 3M NaOH and were extracted using 2 X 40 mL diethyl ether. * where A = Norbornadiene, B = Quadricyciane, C = exo-norbornenyl alcohol, and D = either nortricyclanol or exo-norborneol (For experimental procedure refer to Section 4.2)

48 6. DISCUSSION

The goal of this project was to hydroborate a cyclopropane ring as measured by our

to convert ability quadricyciane to nortricyclanol in measurable yield, using Rh(IH) catalyzed hydroboration. This turned out to be a difficult task. Quadricyciane is a

tetracyclic heptane system, which isomerizes to norbornadiene because this diene is much

lower in strain energy. This isomerization from quadricyciane to norbornadiene occurs

slowly unless a metal catalyst is added to the system. Therefore, we were looking to hydroborate quadricyciane before the isomerization to norbornadiene took place. From

this information it was determined that reaction rates were very important to know in

order to gauge the possible success of this reaction.

"overfed" The first reactions we ran were hydroboration reactions using quadricyciane in

"overfed" THF solvent. An hydroboration reaction, named by our research group, is a

hydroboration reaction in which there is a stoichiometric amount of BH3-THF as compared to olefin, so that the reaction will go to completion and will produce alcohols

"overfed" as the major products. The term arises since we later examined hydroboration

"starved" with far lesser amounts of BH3, in so - called reactions. This solvent seemed to be the optimum choice because other members of our group have found that THF solubilizes RhCl3 well, giving good hydroboration results. The results from these

"overfed" hydroboration reactions are outlined in Table 5.1. When analyzing the results

generated from these reactions (spectrum pg. 67), we decided that the two peaks at

- retention times 19.65 - 19.75 and 20.85 20.95 minutes were of interest because those two were named by the GC/MS library as bridged polycyclic alcohols with molecular

weights in the range of interest. We hoped that one of these two sets of peaks could

49 represent nortricyclanol. If this was in fact the case, then using Rh(D3) to hydroborate

quadricyciane showed some promise because the yields, as indicated in the table, were as

high as 46.24%. This was important because previous attempts to hydroborate

quadricyciane with Rh(I) only yielded 9.9% nortricyclanol.

Use of these standard compounds revealed quadricyciane had a retention time of 12.00

0.10 minutes (spectrum pg. 74), norbornadiene had a retention time of 8.20 0.10

minutes (spectrum pg. 75), and nortricyclanol had a retention time of 20.90 0.10

minutes (spectrum pg. 77).

"overfed" These standard runs appeared to correspond nicely to results of the initial

hydroboration reactions. From these reactions it seemed that we obtained 43% of

nortricyclanol, a very interesting result considering Kevin Gillman had only reported a

10% yield using Rh1+.

Initially, we thought, the 19.60 - 19.80 - minute peak was due to exo - norborneol

(spectrum pg. 67). In fact, the library on the GC/MS named the major of these side

product peaks as exo - norborneol and used it to check GC/MS retention times.

However, to our surprise exo - norborneol has a retention time of 20.90 0.10 minutes

(spectrum pg. 78), which is virtually the same as that of nortricyclanol.

We then found that the peak at the retention time 20.90 0.10 minutes contained two components, first by using a tool available within the data analysis software of the

GC/MS. This tool allows the user to check each peak for purity and can determine whether or not one or more components lie within that peak. Therefore, even though the

instrument is unable to separate out the components, it is able to inform the user that there

50 is more than one component present. Secondly, we placed the cursor on different parts of

the GC peak and found different MS peaks, revealing two compounds.

Our next - challenge was to separate the two components (assumingly exo norborneol

and nortricyclanol) comprising the 20.90 - minute peak. A mixture, which contained

nortricyclanol and exo-norborneol in equal amounts, was prepared (spectrum pg. 80).

Our first attempt was to separate them by altering the conditions of the gas

chromatogram. We tried lowering the temperature and changing the ramp conditions in

various ways, however that proved to be unsuccessful. We also went so far as to lower

the temperature to 40C and ran the standard mixture isothermally for 60 minutes, which

proved to be unsuccessful as well.

At this point we tried to separate nortricyclanol and exo - norborneol using thin layer

chromatography. Therefore, it was necessary to chose a solvent system that would best

separate the two. Therefore, we started with a solvent mixture of 20:80 = ethyl acetate:

pentane. We chose this solvent system because it had been prepared for the TLC analysis

of cinnamaldehyde made by the undergraduate organic chemistry lab. At the very least it

would be a good starting point and if it proved unsuccessful we could always change the

ratios or change solvents altogether.

In addition, we discovered that both nortricyclanol and exo-norborneol were not

detectable under ultra - violet light so we had to use p-anisaldehyde, a visualizing reagent, to observe the Rf values of each standard. The reagent was sprayed on the thin

layer plate and then heated using a heat gun. Upon heating, the spots became colored and

51 then could be identified.

After the first TLC plate running using the 20:80 ethyl acetate to pentane mixture, we found that this solvent system showed promise. We were able to visualize the two

standard spots on the TLC plate, however the spots ran very close to one another.

Therefore, the ratios of each solvent needed to be modified to get a better separation of

the two standards. The solvent mixture that yielded the best separation was a 30:70 ratio

of ethyl acetate to pentane. When this solvent system was used the identification and

separation of the two standard spots was at its optimum level.

Once these results were obtained, we attempted to separate nortricyclanol from exo-

"overfed" norborneol in one of the hydroboration reactions, that showed two components

at the 20.90 .10 minute peak, using preparatory thin layer chromatography. This was done by using a crude hydroboration product mixture that contained (by GC) 53% of

20.90 - minute peak.

The entire crude product was subjected to TLC analysis using 30:70 = ethyl acetate: pentane. This resulted in only two major spots that had Rf values. The faster spot, Rf =

- slower = 0.714 , corresponded to exo norborneol, the spot, Rf 0.629, corresponded to

nortricyclanol. It became clear after the first removal and analysis of the TLC spots that the alcohols were unstable to p - anisaldehyde/acid spray. The second extraction only

removed substantial enough compound from the slower spot. This fraction was analyzed by GC/MS and the mass spectroscopy data did not correspond to that of pure nortricyclanol. It was then thought that the lower spot could be comprised of another alcohol whose Rf value was the same as that of nortricyclanol. Therefore, we were

unable to isolate nortricyclanol and the attempts at separation were unsuccessful.

52 In conclusion, from the TLC analysis we were able to determine that the peak with a retention time of 20.90 minutes was comprised of two compounds. One of these

components was identified as exo - norborneol, but the identity of the other compound has not yet been determined. We are confident, however, that the other compound is not nortricyclanol. The peak with a retention time of 19.65 minutes is not nortricyclanol, but

could be exo - norbornenyl alcohol. However, due to the inability to obtain the standard compound, this has yet to be proven.

At this point it seemed clear that hydroboration of quadricyciane in the presence of RhCl3 gave no clear indication of nortricyclanol. We then felt it was important to determine the rate at which RhCl3 isomerized quadricyciane to norbornadiene, both for its own intrinsic

Rh1+ value as well as its rate compared to that of isomerization caused by in, e.g., reactions using Wilkinson's catalyst.

We studied the isomerization of quadricyciane to norbornadiene under various conditions. For example, the isomerization reactions were run using different solvents.

The results from the first isomerization reaction we ran are outlined in Table 5.2. This

solvent was chosen due to work done in the area of Rh (HI) promoted isomerizations of quadricyciane to norbornadiene performed by Slugget, et al. His group found that methanol was a good solvent for promoting isomerization from quadricyciane to norbornadiene using bulky Rh (HI) imine complexes and so we wanted to see if RhCl3

and methanol would do the job as well. In fact, we found that after only 90 minutes all

the quadricyciane was isomerized to norbornadiene. Figure 5.2 illustrates the percentage

53 of each isomer over time. Clearly, this graph shows the quick decrease of quadricyciane

and the subsequent increase in norbornadiene. After 30 minutes the reaction solution was

87:13 quadricyciane to norbornadiene, after 60 minutes the reaction solution was 98:2

quadricyciane to norbornadiene and finally, after 90 minutes the reaction solution was

solely composed of norbornadiene. Therefore, methanol would not be a good solvent to

use for the hydroboration reaction because the isomerization of quadricyciane to

norbornadiene occurs quickly under these conditions. Additionally, methanol cannot be

used as a hydroboration solvent because the BH3-THF complex is highly sensitive to

water or other protic solvents and would be destroyed as a hydroborating agent in the

presence of methanol. The second isomerization reaction we ran used THF as solvent

instead of methanol. We chose THF because it is a solvent that was, and still is, used in

hydroboration reactions by other members of our group, including me, because the

hydroborating agent used is a BH3-THF complex and, it was determined, after

experimentation, that RhCl3 is fairly soluble in THF. The results from this experiment are

outlined in Table 5.3 and represented in Figure 5.3. This reaction yielded norbornadiene

from the isomerization of quadricyciane quicker than methanol did. The percentage

increase of norbornadiene and the decrease of quadricyciane over time are depicted in

Figure 5.3. After 30 minutes the reaction solution was a 50:50 mixture of quadricyciane to norbornadiene and after 60 minutes the reaction mixture was solely composed of

norbornadiene. Thus although the THF reaction is slower than the methanol reaction,

THF is still not a good choice for a solvent here even though it has been proven to be a fine solvent for hydroborating other compounds.

54 After running this reaction we wanted to test if norbornadiene would isomerize to

quadricyciane under certain conditions. We knew that this probably would be a thermodynamically difficult reaction because norbornadiene has a lower energy configuration than quadricyciane; however, we felt that it would be at least a good

control reaction. The results for this reaction are outlined in Table 5.4 and depicted in

Figure 5.4. As can be seen after 90 minutes there was no isomerization of norbornadiene

to quadricyciane. However, in the analogous reaction run starting with quadricyciane, the

isomerization took place within 60 minutes. Therefore, this reaction helped to prove that

the isomerization reaction from norbornadiene to quadricyciane is indeed a very

thermodynamically difficult reaction.

In 1994, Morrill et al.16, reported that his group was able to hydroborate quadricyciane

using catecholborane and Wilkinson's catalyst, a Rh(I) species, in THF, in measurable

yield (9.9%). Therefore, we needed to run an isomerization reaction using Wilkinson's

catalyst and THF to determine whether or not the oxidation state of the rhodium catalyst

had an effect on the isomerization of quadricyciane to norbornadiene. Our assumption

was that the Rh(I) might not isomerize the quadricyciane as fast as the Rh(__) did,

therefore that would explain why nortricyclanol could be seen and why we were having

trouble finding it. As can be seen from the results outlined in Table 5.5 and depicted in

Figure 5.5, our assumption was correct. After 240 minutes the ratio of quadricyciane to

norbornadiene was 70:30. Even though the percentage of quadricyciane did decrease

analogous isomerization reaction over time, it was not nearly as rapid as the we ran using

Rh(I_). In the case of the Rh(m) species, it only took 60 minutes for 100% of the

55 quadricyciane to isomerize to norbornadiene. Thus, there is a solvent effect and an effect due to the oxidation state of the rhodium catalyst used. Therefore, we came to the conclusion that nortricyclanol could more easily be isolated in the previous experiments using Rh(I) because the isomerization of quadricyciane to norbornadiene did not completely consume the quadricyciane.

The fourth isomerization reaction was in methylene chloride solvent. In this case one drop of Aliquot 336 was used to increase the solubility of the RhCl3 in the methylene chloride. The results from this experiment are outlined in Table 5.6 and illustrated in

Figure 5.6. In this reaction we observed that the isomerization occurred at a much slower rate than was previously observed. In the case of methylene chloride the ratio of quadricyciane to norbornadiene was 70:30 after 30 minutes and seemed to remain at this ratio during the course of the reaction. Therefore, methylene chloride proved to be a much better possibility than methanol or THF as a solvent that could be used to hydroborate quadricyciane using RhCl3. Since we had some success with methylene chloride we decided to stay with this system and investigate it further to see if we could improve the ratios.

Therefore the fifth isomerization reaction we ran was carried out with methylene chloride

as solvent without Aliquot 336. We increased the length of time for this reaction because

we wanted to be sure that an equilibrium between the two isomers could be reached

reaction of quadricyciane. We also to before attempting to run the hydroboration decided

presence influenced the reaction. We omit the drop of Aliquot 336 to see if its really

reaction would decrease the amount of suspected that leaving it out of the norbornadiene

56 formed over time because it was used to increase the solubility of the RhCl3 in the

methylene chloride solvent. It was our assumption that if less RhCl3 was solubilized then

there should be less isomerization of the quadricyciane over time. When analyzing the

results outlined in Table 5.7 and represented in Figure 5.7, it is shown that this in fact

turned out to be the case. The isomerization occurred at a slower rate and after 240

minutes the mixture of isomers in the solution was approximately 70:30 quadricyciane to

norbornadiene, respectively. Therefore, this system seemed to be the best to use to

hydroborate quadricyciane because there was a significant percentage of starting material

remaining after a long period of time. In addition since this percentage of quadricyciane

seemed to remain constant, after an initial drop off, it was reasonable to assume that the

yield of nortricyclanol produced would be at its peak as well.

"overfed" The next type of reaction we ran was an hydroboration reaction of

quadricyciane using methylene chloride as the solvent. As can be seen from the results in

Table 5.8, these reactions were not very successful. The peaks with a retention time of

12.00 - 12.20 minutes (spectrum pg. 68) represent starting material and account for

approximately 65% of the mixture. The peaks at 20.90 - 21.00 minutes (spectrum pg.

68), which account for approximately 15% of the mixture, represent the retention time of two possible alcohols, either nortricyclanol, which is the product of interest, or exo - norborneol, which results from the hydroboration of norbornadiene. After examining the mass spectrometry data of these peaks it appears that they represent the latter, which is a

fact that the is less soluble in less uninteresting result. Therefore, the RhCl3 the

methylene chloride solvent is good from the point of view that there is less isomerization

57 of quadricyciane to norbornadiene. It was, however, clear that without a minimaldegree of solubility of RhCl3 in the methylene chloride solvent the hydroboration reaction of

quadricyciane would not occur readily.

"classical" The next set of hydroboration reactions that we ran were hydroboration reactions; reactions in which no metal catalyst was employed. Therefore, these reactions are very similar to those ran by H.C. Brown, where the reagents are an olefin and a

Gillman18 hydroborating agent only. Kevin ran similar reactions in 1991 and he found that without a Rh(I) species present in the reaction mixture no hydroboration of quadricyciane would occur. Therefore, we expected the same results when RhCl3 was

removed from the system. The results from this reaction are outlined in Table 5.9. From the data it can be seen that a metal catalyst is necessary in order for the reaction to occur.

The two reactions that ran for 120 minutes both show similar results. After hydroboration, the majority of the mixtures, between 60% and 90%, (spectrum pg. 66) represent quadricyciane starting material, whose retention time falls somewhere between

12.00 and 12.05 minutes. The remaining percentages (spectrum pg. 66) represent

norbornadiene (8.20 - 8.25 minutes), the isomerized product of quadricyciane, and either

- nortricyclanol, or exo - norborneol (20.90 20.95 minutes), the hydroboration product of

"classical" norbornadiene. The third hydroboration reaction we ran was similar to the previous two, however we ran this reaction for 300 minutes as opposed to 120 minutes to

see if time had an affect on the results. In fact time proved to be important to this reaction. By increasing the length of time that the reaction was run there was a significant

- increase in the amount of the 20.90 - 20.95 minute peak (spectrum pg. 66). Now

58 instead of only containing either 0% or 6.63%, the mixture contained about 73% of this peak (spectrum pg. 66), which was promising. At this point we thought that increasing the time that the hydroboration reaction was run might improve the yield of nortricyclanol even though there was no RhCl3 present. However, after analyzing the mass spectrometry data it was evident that the compound at this retention time was not nortricyclanol, but

was exo - norborneol. These results confused us because of the absence of RhCl3. If there had been RhCl3 in the system then there would be isomerization of quadricyciane to

norbornadiene, and the exo - norborneol would result from the hydroboration of the isomerized product. The only explanation that we had for this result was that BH3-THF also had the ability to isomerize quadricyciane to norbornadiene. After hypothesizing this, we decided to run a hydroboration reaction starting with norbornadiene to see if we

obtained similar results as those we obtained from the 300 - minute hydroboration of quadricyciane. As can be seen from Table 5.9, these results were very similar. We again

obtained about 70% of the peak at the retention time of 20.90 - 20.95 - minutes

(spectrum pg. 66). Since norbornadiene does not isomerize to quadricyciane in this

system, as was shown earlier, we knew that this product was exo - norborneol and the mass spectrometry data proved our theory.

"classical" As a follow up to this set of hydroboration reaction experiments, we ran another set of isomerization reactions since we were fairly certain that BH3-THF was

responsible for isomerization of quadricyciane to norbornadiene as well as RhCl3. The

first type of isomerization reactions we ran were carried out using THF, 10 mg RhCl3 and

10 drops BH3-THF. The results from this experiment are outlined in Table 5.10 and

59 depicted in Figure 5.10. When a small amount of BH3-THF and RhCl3 are in the system

there is a considerable amount of isomerization of quadricyciane to norbornadiene. In

fact, in the first of the two reactions run, the ratio of quadricyciane to norbornadiene is

76.70:19.83 and in the second reaction the ratio is 86.53:9.22, respectively. In both cases the amount of conversion of norbornadiene to quadricyciane is significantly reduced.

The second type of isomerization reactions we ran were carried out using THF and 10 drops BH3-THF. The results from this experiment are outlined in Table 5.11 and illustrated in Figure 5.11. In this case only a small amount of BH3-THF is used and the

RhCl3 is omitted. Over a 120 - minute time period there is some isomerization of

quadricyciane to norbornadiene, but the degree of isomerization has been drastically

reduced. However, this set of reactions did serve to prove that BH3-THF does isomerize

quadricyciane, but the isomerization is more dramatically influenced by the addition of

RhCl3. In addition, when only 10 drops of BH3-THF is used, which is not a

stoichiometric amount when compared to the amount of quadricyciane used; there is a

small degree of isomerization. Therefore, when 6 - mL (0.006 mol) is used in the

"overfed" hydroboration reactions, this is more than enough to influence the

isomerization reaction, especially since this amount of BH3-THF is coupled with RhCl3.

Thus, there are many factors that influence the isomerization reaction of quadricyciane to

norbornadiene. There is a solvent effect, the effect caused by the addition of a transition

metal catalyst and the effect due to the hydroborating agent, BH3-THF. As stated earlier,

quadricyciane all of these effects must be in order to successfully hydroborate overcome,

which proved to be a difficult task.

60 Because we had extensively studied the isomerization reaction of quadricyciane to

norbornadiene and how it affects the hydroboration of quadricyciane to nortricyclanol at

"overfed" room temperature, we decided to alter the conditions of the hydroboration reaction by running the reactions at different temperatures. We thought that if the isomerization could be stopped, or at least slowed down, by changing the temperature, than maybe we had a good chance at isolating nortricyclanol. Therefore, we decided to run a set of reactions at 60C and a set of reactions at 0C. As can be seen from Table

"overfed" 5.12, the hydroboration reaction ran at 0 C proved to be unsuccessful. In this case, we obtained a small amount, about 4%, of the 20.90 - 20.95 - minute retention time

peak. The majority of the remaining mixture was composed of norbornadiene and

"overfed" quadricyciane. The hydroboration reactions run at 60 C appeared more

successful. As Table 5.12 illustrates, there is very little, if any, of quadricyciane or

- - norbornadiene and a measurable amount, about 30 to 40%, of the 20.90 20.95 minute

of this peak it retention time peak. However, after analyzing the mass spectrometry data

was shown to be exo - norborneol, not nortricyclanol.

61 7. SUMMARY AND CONCLUSIONS

The attempt to synthesize nortricyclanol, in measurable yield, by direct hydroboration of quadricyciane proved to be unsuccessful. The competing isomerization reaction of quadricyciane to norbornadiene could not be overcome by the Rh(__) catalyzed hydroboration reaction. After performing many isomerization experiments it was

determined that different reaction conditions alter the course of the hydroboration

"Optimum" reaction. conditions for the hydroboration reaction of quadricyciane used

methylene chloride as the solvent at 25C for a period of 2 hours. However, when

"optimum" running the hydroboration reactions under these conditions, the reactions

were unsuccessful. This is not surprising as CH2CI2 should not readily solvate BH3.

Therefore, isomerization reactions using a small amount of the hydroborating agent, BH3-

THF were ran to determine whether or not the addition of BH3-THF to the system

affected the hydroboration reaction. Through these experiments it was shown that BH3-

THF does influence the isomerization. The initial assumption that using RhCl3 and BH3-

THF, instead of Wilkinson's catalyst and catecholborane, would be able to hydroborate

quadricyciane faster, overcoming the isomerization reaction to norbornadiene, was false.

In addition, analyzing the GC/MS data was an obstacle that could not be readily

overcome. When small amounts of nortricyclanol appeared to be present in the reaction

mixtures it could not be separated from exo-norborneol due to extreme similarities in

their structures and properties.

The combination of the factors described inhibited the isolation of nortricyclanol in

measurable yield.

62 REFERENCES

1. Carey, F.A. and Sundberg, R.J., Advanced Organic Chemistry; ed 3; (part B);

Plenum Press: New York, 1991, 201 - 204.

2. Brown, H.C. and Zweifel, G. J. Org. Chem., 81, 1960, 4708 - 4712.

3. Brown, H.C. and Subba Rao, B.C. /. Am. Chem. Soc, 81, 1959, 6434 - 6437.

4. Mannig, D. and Noth, H. Angew. Chem. Int. Ed. (Engl), 24, 1985, 878 - 879.

5. Burgess, K. and Ohlmeyer, M. J. Org. Chem. 1988, 53, 5179 - 5181.

6. Evans, D.A. and Fu, G.A. J. Org. Chem. 1990, 55, 2280-2282.

7. Evans, D.A., Fu, G.A., and Anderson, B.A. J. Org. Chem. 1992, 114, 6679 - 6685.

8. http://www.ilpi.com/organomet/betahydride.html

9. http://www.bluffton . edu/~bergerd/chem/walsh/cp . html

10. Peterson, P. and Thompson G. /. Org. Chem. 1968, 33, 968 - 971.

11. Kabakoff, D.; Biinzli, J.G.; Oth, J.F.M.; Hammond, W.B.; Berson J.A. J. Am.

Chem. Soc, 1975, 1510 - 1512.

12. Hogeveen H. and Volger H.C. J. Am. Chem. Soc. 1967, 2486 - 2487.

13. Slugget, G.W.; Turro, N.J.; Roth, H.D. J. Phys. Chem. 1997, 8834 - 8838.

14. Morrill, T.C. and Greenwald, B.E.; J. Org. Chem. 1971, 36, 2773 - 2776.

15. Morrill, T.C; Malasanta, S.; Warren, K.M.; J. Org. Chem, 1975, 40, 3032 - 3034.

16. Zefirov, N.S.; Sadovaya, N.K.; Velikokhat'ko, T.N.; Andreeva, L.A.; Morrill, T.C.

J. Org. Chem., 1982, 47, 1468 - 1471.

17. Morrill, T.C; Chen, D.; Gillman, K; Feng, Pingyun. Main Group Metal

Chemistry,17, 1994, 413 - 416.

18. Gillman, K. M.S. Thesis, Rochester Institute of Technology, Rochester, NY, 1991.

63 19. Mohrig, Jerry R.; Hammond, Christina Noting; Morrill, Terence C; Neckers,

Douglas C; Experimental Organic Chemistry; W. H. Freeman: New York, 1998,

825.

64 APPENDICES:

"Classical"

. 1 Hydroboration of Quadricyciane - THF 66

"Overfed" 2. Hydroboration of Quadricyciane - THF 67

"Overfed" 3. Hydroboration of Quadricyciane - CH2C12 68

4. Isomerization Reaction of - Quadricyciane to Norbornadiene using RhCl3 MeOH. . .69

5. - Isomerization Reaction of Quadricyciane to Norbornadiene using RHC13

CH2C12 70

6. Isomerization Reaction of Quadricyciane to Norbornadiene using RhCl3 and Aliquot

336-CH2Cl2 71

7. Isomerization Reaction of Quadricyciane to Norbornadiene using RhCl3 - THF 72

8. Isomerization Reaction of Quadricyciane to Norbornadiene using Wilkinson's

Catalyst -THF 73

9. Quadricyciane Standard - Chromatogram 74

10. Norbornadiene Standard - Chromatogram 75

- 1 1 . Nortricylcyl Acetate NMR Spectra 76

12. Nortricyclanol Standard - Chromatogram 77

- 13. Exo - norborneol Standard Chromatogram 78

14. Nortricyclanol Standard NMR Spectrum 79

and - Norborneol Standard 80 15 . Mixed Nortricyclanol Exo

16. Example of Peak Purity 81

65 1. "Classical Hydroboration of Quadricyciane - THF

Abundance 1IC:DANA31.D 1_05 2000000

1800000

1600000

uooooo; 674

1200000

1000000;

800000,

! i 600000J

400000 8.20

20.93 200000

n.

Time~> 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00 26.00

66 "Overfed" 2. Hydroboration of Quadricyciane - THF

Abundance TIC: DANA57.D 1100000 19r67

1000000

900000 8.18

800000

700000

600000

500000

20.89 400000

300000

200000-; 8.80 9.93 100000) 10.12 ::

8.00 9.00 10.00 11.00 12.00 13.00 14^00 15.00 16:00 17.00 18.00 19:00 20.00 21.00 22.00 23.00 24.00 25.00 26.00 (20.891 min): DANA57.D ..jndance Scan 2395 ! 79 j 55000J

50000 j 94 67 45000J i i 40000! j I I 1 " i 35000

30000

25000

20000

15000 55

10000

5000 110 207 191- i 217224 237 251259267 281 1102 ll,, 119 128 138147155164 177 200 295 0 ' ' 170 180 190 200 210 220 230 240 250 260 270 280 290 z-> 50 60 80 90 100 110 120 130 140 150 160 300

67 "Overfed"

3. - Hydroboration of Quadricyciane CH2C12

1 IC: DANA60.D

9000000 20.96

8000000

7000000

6000000

5000000

4000000

3000000

2000000

1000000

ILa

,ie-> 16.00 17!00 18.00 19:00 20.00 21:00 22:00 23.00 24:00 25.00 26.00 Scan 1001 (20.857 min): UANA60.U 67

260000,

240000

220000

200000

180000.

160000 79 140000

120000

91 100000 i

80000

60000 130 40000 53 i

20000 I 100 20027 II. !. 1 10 119 j 138 147155163 177 191 221 235 249257265273 294

0 Oj' 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 -./_-> 50 60 70 "80 90 100 110 120

68 4. Isomerization Reaction of Quadricyciane to Norbornadiene Using RhCl3 MeOH

Abundance IIC:UISOMER1._ 8:21 1.4e+07

, 1.35e+07

1.3e+07

! 1.25e+07

1.2e+07

' 1.15e+07

; 1.1e*07J

' 1.05e+07j ; i 1e+07)

9500000 I

9000000 j i 8500000: i

000000 I 1 i 7500000-: j 7000000:

6500000: ,

6000000

5500000;

5000000J i 4500000; i 4000000 j

3000000 12.04

2500000] i 2000000;

1500000

1000000

500000

e-> 7.50 8.00 8.50 9.00 9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13:50 14.00 14.50

69 5. Isomerization Reaction of Quadricyciane to Norbornadiene Using RhCl3 - CH2C12

-.e-> 7.50 8.00 8.50 9.00 9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

70 6. Isomerization Reaction of Quadricyciane to Norbornadiene Using RhCl3 and Aliquot

336 - CH2C12

"TIC:QIS02 1.D

90000001

7000000 '

6000000.

5000000J

4000000-

3000000:

2000000]

1000000.

-r.e-> 7.50 8.00 8.50 9.00 9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

71 7. Isomerization - Reaction of Quadricyciane to Norbornadiene Using RhCl3 THF

Abundance TIC:ISOM_K1.D 1.55e+07 8:23 fs]

1.5e+07

1.45e+07

1.4e+07

1.35e+07

1.3e+07

; 1.25e+07j ! | , 1.2e+07| ! | j 1.15e+07!

] 1.1e+07j 12.12 i Q ! 1.05e+07.! I I ! I 1e+07j 1 i . 9500000 | I 9000000] I I .500000 \ I 8000000,'

1 I 7500000:

! 7000000! i 1 j 6500000!

i 6OOOOO0!

, 5500000] 5000000 j 4500000] ! I il : 4000000] I 3500000 j 1 ! 3000000;

2500000

2000000

1500000

1000000

500000

' e-> 7.50 8.00 8.50 9.00 9.50 10.00 10.50 11.00 11.50 12:00 12.50

72 8. Isomerization Reaction of Quadricyciane to Norbornadiene Using Wilkinson's

Catalyst - THF

1.4e+07

1.3e+07 I ; 1.2e+07

i 1.1e+07 i 1e+07

i 9000000 l

| 8000000 i i 1 7000000; i i j 6000000

; 5000000

4000000

| 3000000 | ! 2000000-

: 100000o!

te-> 7.50 8.00 8.50 9.00 9.50 10:00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

73 9. Quadricyciane Standard -Chromatogr;am

Abundance " 1 IC: QUAD.D 12.38 1.5e+07

1.45e+07

1.4e+07

1.35e+07

1.3e+07

! 1.25e+07 I ; 1.2e+07

1.15e+07 i i 1.1e+07i 8.20 i 1.05e+07] 1e+07j i 9500000!

9000000, ! 8500000] I joooooo! i 7500000; 7000000;

6500000:

6000000

5500000

50000001

4500000, i 4000000

3500000

3000000

2500000

2000000

1500000

1000000

500000 A me-> 8.00 9.00 10.00 11.00 12.00 13X>0 14.00 15.00 16.00 17X0 18.00 19.00 20;00 21:00 22:00 23^0 24!00 25.00 26 00

74 10. Norbornadiene Standard - Chromatogram

Abundance TIC: NOR_OK.LT 8:30

1.7e+07

1.6e+07

1.5e+07

1.4e+07

1.3e+07! I

1.2e+07

1.1e+07-!

1e+07i

9000000,

8000000;

7000000J

6000000;

5000000

: 4000000

3000000

2000000

1000000

/\

8.50 9.00 9.50 10^0 10:50 IVOO 11.50 12.00 12.50 13.00 13_.Q 14_0 14.50 .me-> 7.50 8.00

75 11. Nortricylcyl Acetate Standard - NMR Spectrum

Z3 S00'68 3 s EIB'I

8180

992 8

_o

tejSaiui

76 12. Nortricyclanol Standard - Chromatogram

TTCT_TDN-OH.D~

20.97

1e+07; I 9000000 | :

8000000:

7000000

6000000

5000000

4000000

3000000

2000000 19.68

1000000

I.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00 26.00 Scan 2409 (20.972 min): STDN-OH.D 79

1100000- 66

1000000-

900000-: 91

800000-

700000.

600000, 55 110 500000]

400000 ;

I 300000: i I 200000,

100000!

281 102 118125133 147155163 177 191199207214 223 235 249 257 267 293 190 200 210 220 230 240 50 60 70 80 90 100 110 120 130 140 150 160 170 180 250 260 270 280 290 300

77 - 13. Exo Norborneol Standard - Chromatogram

Abundance "TICTEXONOR.D' ! j 2094 4000000'

3500000-

3000000-

25000001

2000000-

1500000-

1000000

500000

.ne-> 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00 26.00 Abundance Scan 2406 (20.956 mm): EXONOR.D 79 280000^

260000- 94

240000-

220000] 67

200000;

180000:

160000-

i4oooo;

120000!

100000-

80000; i 60000; 57 i i I 40000! ; i 20000] :! 103111119 133 147155 165 177 191198 207215222230 239 251259267 281289 298 0 180 190 _-> 50 60 70 80 90 100 110 120 130 140 150 160 170 200 210 220 230 240 250 260 270 280 290 300

78 14. Nortricyclanol Standard - NMR Spectrum

W88

IQ[_g

L_ZJ __fr'6 A

H

tejBsiui

79 15. Mixed Nortricyclanol and Exo - Norborneol Standard

Abundance TIC: STD.D

9000000

20.94

8000000

7000000

6000000

5000000

4000000-

3000000

2000000:

1000000

8.00 9.00 10:00 11.00 12:00 13.00 14:00 15.00 16:00 17:00 18.00 19.00 20.00 21.00 22:00 23.00 24.00 25.00 26^0 Aoundance Scan 2413 (20.995 min): STD.D I 32000 79

30000 i 28000

26000 67 24000

22000

20000 94

18000 j j 16000

14000

12000

10000 55

8000J 207

6000

110 4000

2000 281 H9 133 1t7155l63 177 221229237 251259267 l! 102 J i. 1?1199 295

-z-> 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300

80 16. Example of Peak Purity

Abundance DANA60.D- Ion 95.00 (94.70 to 95.30): 1 1350000: Ion 79.00 (78.70 to 79.30): DANA60.D 1 Ion 94.00 (93.70 to 94.30): DANA60.D i ; ! 1300000]

I 1250000] j 1200000;

1150000]

1100000]

; 1 050000 ;

1000000-

950000-

900000

800000;

750000 ;

700000-

650000

600000

550000-

500000,

] 450000;

400000;

350000]

300000:

250000^

200000:

150000] / // 1 t :

100000; j Hi 50000;

0=- j_ rime-> 20.70 20.75 20.80 20.85 20.90 20:95 21.00 21.05 21.10 21.15 21.20 21.25

81