Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48108 76- 18.059 WEXLER, Allan Jay, 1947- the PHOTOCYCLOADDITION CHEMISTRY of 5-FLUOROURACIL

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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48108 76- 18.059 WEXLER, Allan Jay, 1947- THE PHOTOCYCLOADDITION CHEMISTRY OF 5-FLUOROURACIL. The Ohio State University, Ph.D., 1976 Chemistry, organic

Xerox University Microfiims, Ann Arbor, Michigan 4810 e THE PHOTO CYCLOADDITION CHEMISTRY

OF 5-FLUOROURACIL

DISSERTATION

Presented in Partial Fulfillment of the Requirements for

the Degree Doctor of Philosophy in the Graduate

School of The Ohio State University

Allan Jay Wexler, B. S., M. S.

*****

The Ohio State University

1 9 7 6

Reading Committee: Approved by

John S. Swenton Harold Shechter Gideon Fraenkel )hn S. Swenton, Adviser )epartment of Chemistry This work is dedicated to my parents, Sylvia and

Harry Wolf, and to my grandmother and aunt,

Ida Kaplowitz and Nettie Kaplowitz.

ii A CKNO WLEDGMENTS

I want to thank Professor John Swenton for suggesting the study of a very interesting molecule, 5-fluorouracil. More importantly, however, I want to acknowledge him as a friend, whose dedication and intelligence have earned my profound respect.

Many thanks go also to Roberta Swenton for her help In preparing this manuscript and her warm hospitality.

i l l VITA

October 22, 1947 Born - New York City, New York

1 9 6 8...... B.S. (cum laude) Brooklyn College of The CLCy University of New York

1 9 7 1...... M.S. The Ohio State University

1 9 7 6...... Ph.D. The Ohio State University

PUBLICATIONS

John S. Swenton and Allan Wexler, "A Stereospecific Vinylcyclopropane Rearrangement due to Hindered Rotation in the Biradical, " J. Am. Chem. Soc. 93, 3066 (1971).

Allan Wexler, Robert J. Balchunis, and John S. Swenton, "A Photochemical Synthon for the 5-Uracil Carbanion. Application to the Direct Punctionalization of Unprotected Uracils, '* J. Chem. Soc. Chem. Commun. , 601 (1975).

Allan Wexler and John S. Swenton, "Fluorine Control of Regioselectivity in Photocycloaddition Reactions. The Direct Functionalization of Uracil via a Novel 1,4 Fragmentation, " J. Am. Chem. Soc. , in press.

IV TABLE OF CONTENTS

DEDICATION ...... ii

ACKNOWLEDGMENTS ...... ill

VITA ...... Iv

LIST OF TABLES ...... vU l

LIST OF FIGURES ...... ix

Chapter I. HISTORICAL ...... I

Introduction ...... I 5-Substituted Uracils--Occurrence...... 2 S y n th e s is ...... 4 A New Approach ...... 6

II. RESULTS AND DISCUSSION ...... 18 Introduction ...... 18 Cycloaddition Reactions of Uracil, Thymine, and 6-M ethyluracil ...... 20 Demonstration of Cis Ring Fusions in the Cycloadducts ...... 23 D is c u s s io n...... 26 The Corey-Wagner M echanism ...... 27 Trans Ring Fusions...... 31 Olefinic Products...... 38 Effect of a Beta Methyl Group ...... 43 Effect of an Alpha Methyl G ro u p ...... 47 III. PHOTOCYCLOADDITIONS OF 5 - FLUORO UR A CIL- - A NOVEL FLUORINE SUBSTITUENT EFFECT ...... 49 Introduction ...... 49 Results ...... 51 Cycloaddition of 5-Fluorouracil to Isobutylene ...... 51 Cycloaddition of 5-FluorouraciI to Methylene Cyclohexane Methylene Cyclopentane Methylene Cycloheptane ^ ...... 54 Photocycloaddition of Propene to 5-Fluorpuracil. .... 55 Cycloaddition of 1 -Methyl Cyclopentene, 6^ and 5-Fluorouracil ...... 59 Enol Acetate Cycloadditions...... 60 Cycloaddition of Cyclohexenyl Acetate, 7^ and 5-Fluorouracil ...... 61 Cycloaddition of Cyclopentenyl Acetate, 74, and 5-Fluorouracil ...... 65 Discussion ...... 66 Mechanistic Rationale for Regioselectivity in Enone Cycloadditions. Origin of the Fluorine Substituent E ffe c t...... 69 The PMC Approach...... 70 The Oriented TT Complex...... 78 The Overall Dipole Mechanism...... 85 The Radical Reversion Mechanism...... 86

IV. FRAGMENTATION REACTIONS--RESULTS ...... 94 Introduction ...... 94 The Spectral Properties of U racils...... 94 UV ...... 94 IR ...... : ...... 96 NMR ...... 97 "CMR ...... 97 An Anticipated Fragmentation Reaction ...... 99 Synthesis of 5-(Cyclopentano-2-oxo)uracil 105 ...... 99 Synthesis of 5-(Cyclohexano-2 -oxo)uracil 106 ...... 100 An Unanticipated Fragmentation...... 102 Synthesis of 5-(2-Methyl-2-propenyl)uracil W 8 ...... 102 Synthesis of 5~(I-Cyclohexenylmethyl)uracil 1 1 0 ...... 104 Synthesis of 5-(l-Cycloheptenylmethyl)uracil 111 ...... 106 Synthesis of 5-( 1 -Cyclopentenylmethyl)uracil 112 ...... 106 D is c u s s io n...... 107 Mechanistic Considerations...... 107 Enol Acetate Cycloadducts ...... 107 Cycloadducts of Simple Alkenes ...... 110 Mechanistic Studies...... 112

vi Experimental...... 113 General Procedures...... 113 Photoadditions in Acetone-W ater...... 114 Photoaddilions of 5-Fluorouracll ...... 118 Demonstration that Fragmentation Proceeds without Regard to the Relative Stereochemistry of the Fluorine and A cetate...... 123

Appendix

A. ‘’FMR, "CMR, and PMR SPECTRA ...... 139

B. MOLECULAR ORBITAL CALCULATIONS ...... 149

BIBLIOGRAPHY 17 7

vii LIST OF TABLES

1. Relative Rates of Olefin Photocycloaddition to Cyclohexenone ...... 10 2. Product Distribution for Olefin Photocycloadditions to C yclohexenon e ...... 11 3. The Occurrence of Cis Ring Fusions for Head-to-Head Cycloadducts ...... 34 4. The Effect of Radical Stabilizing Groups on the Ring Fusion of Cyclohexenone Cycloadducts ...... 35 5. Steric Effects of Product Orientation in the Photoaddition of Isobutylene to Methyl Substituted Uracils . . 46 6 . Regioselectivity in the Photoaddition of Simple Alkenes to 5-Fluorouracil...... 67 7. New 5-Substituted Uracils Synthesized by Employing 5-Fluorouracil as a Photochemical Synthon for the 5-Uracil Carbanion ...... 108

viii LIST OF FIGURES

1. Energy Diagram Which May Account for the Absence of Trans fused Products...... 37 2. The Dihedral Angle Dependence of Vicinal ...... 64 3. Interaction Diagram for Olefin Additions to Cyclopentenone...... 73 4. Interaction Diagram for the Photoaddition of Uracil and Isobutylene ...... 7 5 5. Molecular Orbital Diagram Showing the Absence of Any Significant Perturbation of an Enone rr System by an Alpha Fluoro Substituent...... 77 6 . The Effect of Substitution on the Chemical Shift of Olefinic Carbons...... 7 9 7. TT Electron Charges on Uracil and Its Excited State...... 80 8 . values vs. *^C Chemical Shifts ...... 81 9 ^ t o t a l yg liQ Chemical Shifts...... 81 1 0 . The Linear Relationship between the *^C Chemical Shift of C-5 and Total (o-+TT) Charge of C-5 Substituted U r a c ils ...... 82 11. Ultraviolet Absorption Spectrum of Thym ine ...... 95 12. Ultraviolet Absorption Spectrum of Dihydrouracil and. U r a c i l ...... 95 13. Carbonyl Region of the Infrared Spectrum of Thym ine ...... 96 14. NMR Spectrum of Thym ine ...... 98

ix C H A P T E R I

HISTORICAL

Introduction

With the establishment of DNA as the genetic messenger cl living things, the chemistry of its constituents has assumed a special importance. In this regard the photochemistry of uracils and the synthesis of uracils has been of widespread interest. In my research

I have:

1) Examined the use of cyclohexenone photochemistry as

a crude model for the photochemistry of uracil. While

the photochemistry of these compounds was sim ilar in

many respects, as w ill be developed, interesting

differences have emerged in this work. The greater

rigidity of the uracil ring and its complete freedom

from potential steric interactions as compared to the

cyclohexenone ring led to marked differences in their

photochemical reactivity.

2) Developed the previously unexplored photocycloaddition

chemistry of 5-fluorouracil and uncovered a powerful

substituent effect whereby fluorine greatly enhances

1 2

regioselectivity in the addition of simple alkenes.

3) Developed a new synthetic route to a wide variety of

5-substituted uracils. This route employs 5-fluoro-

uracil cycloaddition to enol acetates followed by base

fragmentation as a "photochemical synthon" for the

5-uracil carbanion.

4) Discovered a base catalyzed fragmentation reaction

whereby cycloadducts of 5-fluorouracil with simple

alkenes afford 5-substituted uracils. This extended

the utility of 5-fluorouracil as a photochemical synthon

for the 5-uracil carbanion.

In this section, therefore, I would like to discuss the biological occurrence of 5-substituted uracils and the methods which have been employed in their synthesis. I w ill place particular emphasis on tracing those parallel developments in the chemistry of cyclic enones and uracils which set the stage for my work.

5-Substituted Uracils*-- O ccurrence

The simplest member of this class of materials, 5-methyluracil, or thymine, was first isolated in 1893 by Kossel and

,CH 3

Newmann, ^ and subsequently identified by Steudel^ in 1900. This

structural assignment, based on degradative studies, was later

confirmed by synthesis.®»^ While thymine is one of four bases

ubiquiotously appearing in DNA, it is not the only member of this

class of compounds to appear in DNA. Thus, 5-hydroxymethyluracll,

was identified as a constituent of the DNA of T-even bacteriophage^ where it replaced thymine, and most recently dihydroxy pentyl uracil 3^

OH OH

2 3 has been found to replace thymine in the DNA of bacteriophage SP-15 of Bacillus subtilis.® These discoveries have generated a great deal of activity in the area of synthesis, and the approaches toward that end w ill be discussed shortly.

Five-substituted uracils appear not only in DNA, but also in t-RNA whose function it is to bring those amino acids required for protein synthesis to the ribosome. Thus, upon either enzymatic or alkaline hydrolysis of RNA a novel base was found and subsequently H

HO OH 4

identified^ as 5-ribosyluracil 4 (psuedouridine). Similarly, 5-carbo-

methoxymethyluracil ^ has been isolated from yeast and wheat

t-RNAS. In addition, at least one 5-substituted nucleoside antibiotic

sparsomycin, has already been characterized.

CH2OH ,

Q 1^ yXvNH- - - C - - - H èHzSCHzSCF^ oXT ^

Synthesis

The synthetic approaches to these materials are rather easily divided into three categories: cyclization, electrophilic substitution, and utilization of the 5-uracil carbanion.

Cyclization

CH,

This approach, the oldest, builds the ring from two fragments.

It was employed in 1903 in the synthesis of thymine.* Sixty-seven

"•>„ "■"•V"’..™ H 3 CS H HCr^H HjCS^N-^H N H 5

years later the same synthetic strategy produced 5-carboxymethy 1 -

uridine which, upon estérification, afforded the minor t-RNA base “

Even more recently this approach has been directed toward arbitrary

chain length extension. **

r,N , 0 . ^ “ c h ^ c o ,h ^ CHONa H H

Electrophilic Substitution

The least exploited approach to date can be generally depicted as

below. While electrophilic substitution results in successful

‘H E "'VN IT . r,® ? N ^ 'N ir , , 0 H halogénation of the uracil nucleus, its successes in carbon-carbon bond formation have been more limited. An early utilization of this approach successfully hydroxymethylated 6 -methyluracil. However,

HCHO, CH2OH

CH H H attempts to extend this into a synthesis of general utility by hydrolysis of 5-(phthalimidomethyl)uracil, yielded only uracil Instead of the desired 5-aminomethyluracil.

N-CH 2OH

H I H

5-Uracil Carbanion Approach

NaOH, HCHO ^ n '

h ^ h o c t^ n '^ I

The 5-uracil carbanion is available either directly, as in this synthesis of 5-hydroxymethyluracil, or via protected 5-lithiouracils as Ulbrecht's synthesis of thymine.**

OCH 3 OCH 3 r A ^ B r CH, CH3I

H 3 C 0 ^ H

A New Approach

While the above approaches had proven useful, it had become clear that a totally new synthesis for these kinds of derivatives was potentially available via a photocycloaddition fragmentation sequence.

The origins of this procedure date back to the beginnings of cycloenone

photochemistry.

In 1930 Triebs^^ had observed that piperitone in ethanol or acetic

acid dimerized on exposure to sunlight. Three years later*® he

sunlight

reported on the similar dimerization of 3-methyl cyclohexenone. It

wasn't until Eaton's**^ studios some thirty years later that these

dimerizations came under further scrutiny. Ho found for O O hv. +

cyclopentenone roughly equal amounts of the head-to-head and head-to- tail dimers, and this observation was later paralleled in the cyclohexe none dimerization. ^

Interest in the lethal effect of ultraviolet light on bacteria led

Beukers and Berends** to investigate the ultraviolet irradiation of thymine. They found, some thirty years after Trieb, that much like other cyclic enones, thymine dimerized. Indeed, they were the first 8

hv ice r H

to comment on the parallel nature of this photochemistry when, with

reference to Schonberg's book, they commented that, "Similar

dimerizations are known in the literature. " This correspondence was

subsequently commented upon by numerous authors. Wacker^* pointed

out that "many a, 8 -unsaturated carbonyl compounds can dimerize . ..

uracil contains an unsaturated carbonyl function . .., " and to

emphasize the importance of this chromophore placed it in boldface ?

I l| (note; Wacker's emphasis)

I H type in his article. Notable also was Burr's^^ comment that, "The photodimer ization of the pyrimidines falls into the pattern of a body of well known, although poorly understood dimerizations of a, p- unsaturated ketones and acids. ..."

Dimerization, however, is not a reaction of notable synthetic utility, and further progress awaited the development of mixed additions. Actually, the first example of a mixed photocycloaddition was an intramolecular one observed in 1 9 0 8^® and later reinvestigated by Buchi in 1957. Interestingly, this corresponds to an addition of hv

isobutylene to a-methylcyclohexenone, an especially poor reaction .. .

when conducted intermolecularly, as will later bo described. Buchi

hv product

"A"

proposed that this reaction proceeded via closure of the excited enone

to the most stable biradical intermediate "A, " a mechanistic rationali

zation which was subsequently adopted with some modification by / Corey. Credit for the first intermolecular mixed addition must be

given to Eaton^^ who demonstrated, by adding cyclopentene to cyclopen tenone, that enone dimer ization was merely a special case of an

O hv excited enone adding to a ground state double bond and that the carbonyl group of the ground state enone was unnecessary for the reaction to take place. This prompted a detailed investigation by

Corey. In his systematic study, a great deal of new information was gathered, and from it, a generalized picture of the reaction was presented. It was found that in competition studies, electron-rich 10

olefins cycloadded fastest (Table 1), and this was taken to indicate that

Table 1. Relative Rates of Olefin Photocycloaddition to Cyclohexenone

R ela tive O lefin Rate Factor*

1 , 1 - Dime thoxy ethylene 4. 6 6 Methoxyethylene 1.57

Cyclopentene 1 . 0 0 Isobutylene .4 0 A lien s .2 3 4 Acrylonitrile far less reactive

*In competition studies against cyclopentene.

the excited enone was a "moderately electrophilic" species in the

reaction. The product distributions indicated that "the dominant cyclo-

addition product is that in which the a-carbon of the enone has attached

itself to the carbon of the olefin which is most nucleophilic. " These

results taken in concert led Corey to postulate the existence of a donor-

acceptor TT-complex whose orientation is determined by charge distri

bution in the excited enone and ground state olefin. Furthermore, cis

.OCH, ■ f

and trans 2 -butenes provided almost identical product mixtures, indicating that a concerted cis addition was improbable and that, more 11

Table 2. Product Distribution for Olefin Photocycloadditions to Cyclohexenone

Cyclohexenone Olefin Products

hv^ + M e C r ^ M e Me Me

hv. (3 isomers) ^ ^ )M e

II ^ VCH,ll O hv. (3 isomers) 'b -C C H ,

A 6^

I hv^

ON hv (4 isomers) CN 12

likely, a high energy biradical intermediate preceded ultimate product

formation. Thus emerged a generalized picture of the reaction:

K* + O oriented TP-complex v^diradical —> cycloaddition product

Even at this stage, Corey's contribution had not ended, for in

this landmark paper he also studied the effect methyl substitution on

the enone moiety had on the reaction. Interestingly, a 2-methyl

hv I + j] > complex mixture ^ H j c A c H j

substituent greatly diminished the rate of photoreaction (relative to 2 - cyclohexenone) and afforded a product yield of 1 0 . 9^ comprised of a mixture of at least seven components. A 3-methyl substituent did not

• rVv adversely affect enone reactivity; however, it was noted that "a 3- methyl substituent can influence the orientational mode of the photo chemical addition. "

At roughly the same period in time the synthetic potential of photocycloaddition was being developed beyond simple cyclobutane

O'-O O O-H 13

hv OH

ÔAc formation. Initial photocycloaddition-fragmentation schemes developed

largely by DeMayo*^'generally employed a reverse aldol reaction to

open up the cyclobutane ring forined in the photoaddition. In 1970 a

general scheme affording alpha substituted enones appeared^* in which

B r hv B r * R X)Ac -GAc GAc R

0 GH

the opening of the cyclobutane ring was accomplished by brominating the intervening cycloadduct and thereby incorporating a leaving group for the subsequent fragmentation. The sequence was successfully

Br?. ^ ,'»Me ^ i 64^ GAc

CHjGH 14

employed in the synthesis of a number of alpha substituted enones of

which the illustrated reaction is but one example. The limitations in

the applicability of the sequence were then discussed and it was pointed

out that while the bromination was highly efficient, only those ketones

whose (*)'d position was nonenolizable could be selectively brominated

in the proper position for fragmentation. This was clearly a serious

limitation which could not be circumvented by employing a-bromo-

cycloenones, whose photo cycloaddition reactions were found to be

unsatisfactory. Regarding the fragmentation process, it was

discovered by a study on a cycloadduct pair epimeric at C-2' that the

fragmentation always proceeded in the same direction independent of

the relative configuration of the bromine and the acetoxy group.

"a" 3 OH O

. u . "b ^ C C H j

Thus, both the exo and endo acetates followed path "a, " with

none of the product from path "b" observed. The authors pointed out

that it would be unlikely that "the cyclobutane ring would in all cases possess an unsymmetrical conformation fulfilling the geometrical 15

requirement for a concerted fragmentation in only one direction. "

Rather, they felt that both pathways were geometrically allowed but

that pathway "a" proceeded via a transition state of lower energy.

A 8 orne what analogous approach was employed a year later,**

hv CHO

with the advantage that hero the fragmentation did not require the

introduction oi a leaving group.

The applicability of these synthetic methods to modifying the

uracil nucleus awaited the development of mixed photocycloadditions

for uracils. While several of these had appeared in the literature, it wasn't until Sw enton**'in 1972 that the first really informative O O

N ,1 U hV j Eto^t CH,CN^ ^ ^ O Et M e 73^ 11^

acetone y h f O C (C H ,), M e M e

..hs) “ ‘ ■ " V i

I H M e M e j , < 16

systematic study appeared. In this study a remarkable parallel

between the behavior of 1,3-dimethyluracil and cyclohexenone was found.

Here, as in the cyclohexenone case, the dominant cycloaddition product

was the one in which the alpha carbon of the enone (dimethyluracll)

attached itself to the carbon of the olefin which was most nucleophilic.

The lower proportion of trans-fused product suggested a less distorted

excited state than in the cyclohexenone case, but in general the

observed photochemistry suggested that "the use of the enone

[cyclohexenone] as a crude model for pyrimidine bases merits further

consideration. " In terms of future synthetic potential, this study

showed that one of the essential criteria, regioselective photoaddition

of polar olefins, had been met.

Two years later the first example of the utilization of a photoaddition-fragmentation scheme to modify the uracil nucleus appeared in the literature.^® It followed directly from the 1 9 71 w o rk in

Experentia. previously described. As an exciting example of the

E tjN DMF 17 potential utility offered by this approach, the recently isolated DNA base, dihydroxypentyluracil, was synthesized.®^

H OH several steps OH C H A P T E R I I

RESULTS AND DISCUSSION

Introduction

The sim ilarities in the photochemistry of the cyclic enonea and the uracils were striking. They shared in common photodimerization and photocycloaddition to olefins, and in the latter, both exhibited high regioselectivity with polar olefins. In an initial study I sought to more rigorously examine the use of cyclohexenone as a model system for uracils. Since isobutylene had been especially rich in its photochemis try with cyclohexenone, it would provide a sensitive probe for differences in reactivity. The questions of interest were;

1) Cyclohexenone gave predominantly trans-fused cyclo-

adducts and moderate amounts of olefinic products.

Would uracil exhibit the same behavior?

+ +

H H H J “V m a jo r? significant?

18 19

2) Alpha methyl substitution on the cyclohexenone ring

drastically reduced reactivity and afforded complex

mixtures. Would this be reflected in uracil photo

ch em istry?

J3H

slow? many products ?

3) Beta methyl substitution had altered major product

orientation. Again, would a sim ilar substituent effect

be observed?

a only cycloadduct? H,

H H

4) A parallel study in the dimethyl uracil series would

serve as a sensitive test of the effect of N-methylation

on the photochemistry. It had often been assumed that

N-methylation did not effect the photochemistry. Was

this a valid hypothesis?

A ll of these questions were clearly of interest both in terms of the nature of the uracil excited state and the potential utility of these additions for synthesis. 20

Cycloaddition Reactions of Uracil. Thymine, and 6 -Methyluracil

Thymine, 3. 17 mmol in 150 ml of acetone-water (4:1) and

6 . 53 g (. 12 mol) of isobutylene were irradiated through Corex at

* II acetone/WgO I VI ' c A n - H ' V k. hv

-7 ° C for 8 h, at which time UV analysis at 260 nm indicated the dis

appearance of starting material. VPC analysis indicated the formation

of two products (92^ yield) in the ratio 72:27. Several fractional

recrystallizations from water afforded the major product 8 pure:

ÇH, H

N M R (C F 3CO2H, 100 MHz): 9.36 (br. s, IH), 7.46 (br. s, IH), 3.72

(d, J = 4 Hz, IH), 2.44 (center of AB, J = 14 Hz, IH), 2.03 (center ofAB, J = 14 Hz, IH), 1. 62 (s, 3H). 1.22 (s, 3H), and 1. 18 (s, 3H)&

The orientation was firm ly established by the appearance of H 3.726 ( 0 as a doublet (split by the adjacent N-H) and H^^^, H^^^ appearing as a sim ple A B . 21

The minor adduct, was isolated by a combination of

chromatography on silica gel and fractional recrystallization. Its Ms.

orientation was also firm ly established by NMR (CF 3CO2H, 100 MHz):

9 .4 7 (b r. s, IH ). 7 . 4 9 (br, s, IH), 3.95 (m, IH), 2.36 (A of ABX,

q of d, J = 8 Hz, J = 12 Hz, IH), 2. 06 (B of ABX, q of d, J = 8 Hz,

J = 12 Hz, IH), 1 .4 9 (s, 3H), and 1.26 (s, 6H) 6. The appearance of

H^ )» as a quartet of doublets [an AB split by H^^^] shows this

adduct to have the head-to-head orientation.

The reaction of 6 -methyluracil, with isobutylene proceeded in sim ilar fashion, wiHi VPC analysis again showing two

acetone/#;O N > - ]

^ N C orex^ I H H

n . ^ 2 products (97^ yield) in the ratio 69:31. They were separated by VPC, and the NMR of the major component, 11, showed (CPgCOgH, 100

100 MHz): 9. 50 (br. s, IH), 7.44 (br. s, IH), 3.32 (t, J = 9 Hz,

IH), 2.08-2. 56 (m, 2H), 1.48 (s, 3H), and 1.22 (s, 6H)6. 22

f b u , CH,

The appearance at 3. 326 as a triplet establishes the major

product as having the head-to-tail orientation. The minor product

N M R (C F 3CO2H, 60 MHz): 9.44 (br. s, IH), 7. 34 (br. s, IH). 3.25 (a.

IH), 2.30 (s, 2H), 1.63 (s, 3H), 1.45 (s, 3H), and 1. 33 (s, 3H)5, has

H^^j 3.256 as a singlet indicating the head-to-head orientation.

Unfortunately, the reaction of uracil with isobutylene could

not be analyzed directly since VPC showed only one peak which was

acetone/kzO ^ ^ O K . O ^ N JL Corex

14 15 later established to be a mixture of _14 and ^ in 92^ yield. While VPC

showed only one peak, it was clear from the NMR that a mixture was present. No way was found to affect the separation of these materials, so a mixture of ^4 and which had been recrystallized from ethyl acetate-hexane was methylated, affording by VPC a two-component mixture. This mixture could be separated by VPC and the isolated materials were identical with the known compounds and 17. When 23

this procedure was performed on the crude reaction mixture, the ratio

l)N a H

CH 14 15

H,C

of 16 to 17 was found to be 7 5:25. This ratio was in good agreement with that determined by NMR integration of the methyl resonances of the crude reaction mixture. This "NMR (pyridine, 100 MHz) showed two methyl resonances of equal intensity at 1. 16 and 1. 186 (assigned to the minor adduct) in a ratio 76:24.

Demonstration of Cis Ring Fusions in the Cycloadducts

While the orientation of the cycloadducts had been firm ly established, the nature of the ring fusion, be it cis or trans, had yet to be proven. Trans ring fusions in these kinds of systems are known to be unstable, being rapidly isomerized to the cis fused isomer under a 24

.CH .CH,

CH CH

variety of conditions. For example, Corey found that the trans fused

adduct ^ 8 was readily isomerized to when filtered through alumina,

treated with hydroxide, refluxed with p-toluene sulfonic acid, or

heated at 205“C for 40 min. A similar transformation was noted in the

uracil series, when ^ was found to rearrange to 2j^ upon treatment with activity I basic alumina. Based on this information, I devised a

set of conditions whereby this transformation could be readily followed by NMR. Thus, 20 was dissolved in pyridine; to this solution in an

. NaNH; O Et .OEt DM SO -d pyridine O Et CHj CH)

20 21

NMR tube was added two drops of DMSO-d^, and the spectrum recorded. A spatula tip of sodium amide was added and the spectrum recorded at five-minute intervals. Within 10 min, the spectrum of ^ appeared. Since Hyatt, in a study paralleling mine, had found that isobutylene cycloadded to the methylated bases 22, 23, and 2^ I established the nature of the ring fusion in his system and by inference 25

H;C

CH, CH, CH 22 16 17

H,C hv

CH, CH 23 25 26

H ,q , H ,C ^ JL N

CH, CH, CH, 24 27 28

CH, CH, CH, 16 17 +

H,C

CH, 26 26

in the parent (unmethylated) sequence. When XL* and 28 were

subjected to the same conditions which affected the transformation of

the known trans fused ring compound ^ to the known cis fused com

pound XL* no changes in the NMR spectra were recorded.

Clearly, the above procedure was not applicable to the

thymine adducts ^ and Thus, they were synthesized from uracil

precursorsXé nnd XL by a method which necessarily afforded cis fused

25 and 26. These isolated materials were in all ways identical to the

cycloadducts obtained from the photoaddition of dime thy Ithymine and

isobutylene.

Discussion

The photoaddition of isobutylene did prove to be a sensitive probe for differences in the photochemical behavior of uracil and % cyclohexenone. Thus, in its reaction with uracil, no olefinic products or trans ring fusions were produced. Alpha methyl substitution on the uracil ring did not lead to any dramatic rate of retardation, and the reaction cleanly gave two cycloadducts instead of a complex mixture.

Finally, a p-methyl substituent did not reverse major product orienta tion. This behavior stands in marked contrast to that of cyclohexe none. I believe these differences can be accounted for within the framework of an already well-developed mechanism for these photocycloadditions. 27

The Corey-Wagner Mechanism

Corey's mechanism for the photoadditions of olefins to cyclo

hexenone (Scheme I) proposed on the basis of product studies and

Scheme I

K* + O # oriented TT-complex 5s* diradical—> cycloaddition

thermodynamic arguments (see historical section) has since been

supported and extended to the uracil system by the kinetic studies of

Wagner and Buchek. These authors have found that the dimeriza-

tions of cyclohexenone and uracil both proceed from a triplet state

lying about 70 kcal above the ground state. Furthermore, they found that both dimerizations followed very similar kinetic schemes. Thus, for cyclohexenone. Scheme II holds, and for uracil, Scheme III holds.

Scheme I I

10056 hv [ ■ Eo<^k,

Scheme I I I 2pyr k - * p y r -p y r * pyr pyr c d im er where E@, 'E * and *E* represent cyclohexenone in its ground state,

excited singlet, and reactive excited triplet state, respectively. 28

E* is a metastable intermediate formed after the triplet has reacted.

The designations of the various uracil states follow straightforwardly.’

For both schemes, the dimer ization quantum yield is given by

*DIM “ ^iscî\V

^isc where for cyclohexenone k. = 0 , t = 1 isc k. + k. ' J ’ lac J isc k j E ] ~ k—+ k ÎET" ^^Gre E is cyclohexenone or uracil i ^a*- ^

c __ V = ir^-a

The crucial finding, then, of Wagner was that dimerizatlon

was not concerted or irreversible, for had it been so, then would

have been given by , for the simpler kinetic Scheme IV. DIM isc A ^

Scheme IV

hv I JT^E* dimer

In both cases, however, it was found that ^ major source of inefficiency arose after the excited triplet reacted. This necessitated the inclusion of the mechanistic scheme of a metastable dimeric species which would either yield dimer or revert to starting material. Schemes II and III. The probability that this species 29

I continued onto product was then given by and this then accounted for

the diminished It was proposed that for both dimerizations, a

1,4-biradical would be a metastable species consistent with the kinetic

data.

-a

D im e r

2 pyr

In addition to this data supporting the intervention of a biradical, Wagner found his values of k were two to three orders of magnitude greater than for a simple radical-like addition to an olefin.

This he felt pointed to the possibility that a rapidly formed complex preceded biradical formation. Furthermore, since the k values for the photodimerizations of cycloalkenones were very similar in value to the known TT -TT* triplet^^ dimerizatlon of the pyrimidines and some two orders of magnitude greater than the rate constants for the interaction of known n-TT* ketone triplets with cycloalkenes to yield oxetanes, he 30

concluded that cycloalkenone dimerizations also proceeded from a TT -TT*

triplet state. This had been a problem because of the near degeneracy

of the n-TT* and TT -TT * triplets of cycloalkenones.

Since completion of the above studies, strong spectroscopic and

chemical evidence has emerged for the intervention of radical species

in uracil photoreactions. The direct irradiation of uracil^^ in isopropyl

alcohol gave an ESR spectrum of two radicals, one of which was

assigned to the uracil radical 29. Furthermore, THF has been found

V. H,(\ hv N + -ICOH À OO'' f H ) ( / H

i l 22. to add to irradiated DMU. This same reaction could be effected by photolytic decomposition of di-t-butyl peroxide, strongly implying radical intermediates intervene in the photochemical reaction.

o '

O Corex

15^ cyclobutane d im e r

In summary, Wagner's work showed that the photocycloadditions of uracil and cyclohexenone are fundamentally the same reaction. The 31

work of both Wagner and Corey strongly indicates that in photocyclo

additions a biradical intermediate is the immediate precursor to

product formation.

Trans Ring Fusions

The predominance of trans ring fusions in the photoaddition of

isobutylene to cyclohexenone and their absence in the additions to the

uracils can be rationalized by comparing the relevant biradicals. The

biradical derived from cyclohexenone has built into it the flexibility of

30 2 1 the cyclohexane ring. The conformer with the equatorial isobutyl ra d ic a l 2 2 is ideally suited to close to the trans fused product, while the conformer with the isobutyl radical axially disposed can close to cis fused product. The lower proportion of cis fused product relative to trans fused m aterial is caused by the steric interaction between the axial hydrogen and methyl group raising the activation energy for the closure of 21- This argument closely parallels that of Bauslaugh.

The biradical produced from uracil 32 has a planar and more rigid

ring. The torsional strain required to produce trans fused product leads to a large increase in the activation energy for ring closure. 32

o 32

Furthermore, axial hydrogens are not present to interfere with cis

closure; thus, in almost all cases only cis ring fusions are observed.

There is, however, one exception since in the photoaddition of ketene

diethyl acetal to dimethyluracll, a small amount of trans fused adduct

H,C

P E t JL Et CH) CH)CH)

73$ 11$ is produced. This may reflect an increase in the activation energy to cis closure by an unfavorable alignment of dipoles in the transition state, leading to cis closure. This interaction is avoided in transition state leading to trans closure, where the dipoles are

CH, orthoganal. H O Et H,

H)C 'c H ,

E t E t 34 33 33

It is interesting to note that whenever stabilization of the biradical

can occur, a cis fused product will result. Consider the addition of

isobutylene to cyclohexenone. For the head-to-tail cycloadducts, the

A 24^

ratio of trans to cis fused is 4:1, yet no trans fused head-to-head

product is observed. Indeed, every head-to-head product of which I am O

aware is cis fused (Table 3). The observation that electron deficient

olefins afford cis fused cycloadducts^^ is only a specific example of

this general observation since these olefins invariably give head-to- head cycloadducts. It has been proposed^ that only cis ring fused head-to-head cycloadducts are formed because axial hydrogens are no longer present to interfere with ring closure. However, for head-to- tail oriented biradicals, radical stabilizing groups, R, also reduce the proportion of trans fused cycloadducts (Table 4). Thus, it appears that the dominating factor in the exclusive formation of cis fused product for these cyclohexenones is the stability of the intervening 34

Table 3. The Occurrence of Cis Ring Fusions for Head-to-Head Cycloadducts

Ref.

CH CH ene products 45,46 H, A

,CN

45 H,

45 AC 'A •Ac

O s 46 35

Table 4. The Effect of Radical Stabilizing Groups on the Ring Fusion of Cyclohexenone Cycloadducts

trans cis T y fused fused C

+ j l 49 21 2 . 2 M e (j wM e

2 6 38 . 6 8 CH, M e JLCr SDM e ^

+ jl none 97 MeCr S d M c

hv 24 6 4

hv > none 50 36

biradical. Within the framework of the biradical hypothesis, this can

be accommodated if the energy required to reach the transition state

for trans ring fusion is relatively insensitive to substituents (Figure 1).

Stabilized biradicals will lie in too deep a well to reach the transition

state required for trans ring closure.

An alternate mechanistic hypothesis is that trans fused product

arises via a nonthermally equilibrated biradical. The intervention of

photochemically generated "hot" 1,4-biradicals in solution has already

been proposed."*® If, paralleling thermodynamic stabilities (the cis

compound is an estimated 10 kcal/mole more stable than the trans),

the activation energy required to effect trans ring closure is greater

than that for cis ring closure, only hot biradicals may possess suffi

cient energy to effect closure to trans fused product. Within this

mechanistic framework, resonance delocalized biradicals with diminished spin density at C-a ring close more slowly, and complete thermal equilibration of the biradical occurs. The thermally equili brated biradical, then, does not possess sufficient energy to close to trans fused cycloadduct.

Finally, it must be noted that there is contradictory evidence as to whether the cis and trans fused products have a common precursor. 37

E A +

bbiradical ira d ic a l potential surface

trans

cis

Figure 1. Energy diagram which may account for the absence o ftrans fused products 38

Chapman**^ has repo rted d iffe re n tia l quenching of the ra te of form ation

of cis and trans fused adducts by di-tert butyl nitroxide in the addition

of 4, 4-dimethylcyclohexenone to ketene acetal. From this he con

cluded two different triplets were involved.®® On the other hand, in

studies on oxaenone photoadditions, Margaretha®* found a linear

relationship between the log of the product ratio /C and the reciprocal

hv DOC + T G of the absolute temperature. This indicated a common intermediate which proceeded onto products by two concurrent and rate-determining steps. This would seem to eliminate mechanisms involving two

1 . )c - >-•'

separate intermediates for cis and trans fused adducts. Here a single biradical which can close to cis or trans fused product fits the data.

Olefinic Products

For the sake of simplicity in the previous section I omitted reaction pathways available to the biradicals other than ring closure. 39

However, disproportionation is a well-known process of biradicala and

a significant question raised by this study is why olefinic products are

observed for cyclohexenone but not for uracil cycloadditions. Again,

the answer can be obtained by examining the relevant biradicals. For

the hydrogen transfer process shown below, I would like to propose

that a reasonable transtion state is one in which the numbered atoms

adopt a six-membered ring chair conformation. As is seen in 34 this

is readily accomplished when the cyclohexenone ring itself is in a

chair conformation. Critical to the transfer are the requirements: a) that p-orbital "1" complete the chair and b) that p-orbital "4" eclipse H^. While the cyclohexenone derived biradical can readily adopt this transition state, the more rigid uracil biradical cannot.

For example, when a chair is constructed (35), p-orbital "1" is

4 H

35 36 40

parallel to and cannot complete the chair. Alternatively, a aix-

membered ring boat (36 ) can be completed by p-orbital "1” but now p-

orbital ”4" Is orthoganal to

Consider the application of this concept to a question raised by

Meinwald. He points out that while citral, 37 , and carvone,

hv CHO OR

40 37 41 2 : 1

undergo intramolecular photoreactions, only with citral does hydrogen

abstraction take place, and he states that the correct explanation for

this difference in behavior is not known. In the original work on

citral, Cookson®^ suggested that an attractive mechanism involved initial five-membered ring closure to give biradical ^ which can

hv, .CHO

37 41

either form a second C—C bond to give D or transfer a hydrogen to give

41. Correspondingly, Buchi in the work on carvone has proposed ,

initial five-membered ring closure to give biradical 42. Biradical 39

38 42

from citral can easily form the required transition state for hydrogen

transfer. In the first view the top of p-orbital "2" nicely completes the

H3 a

chair and a side view shows that in this transition state, p-orbital"3 "

and Hi are eclipsed. The rigid biradical 4^ from carvone cannot

assume the transition state.

An alternate mechanism hypothesis is that the olefinic products arise from an n-TT * state of cyclohexenone in which hydrogen abstrac tion by the carbonyl oxygen is followed by radical recombination. The excited state of uracil being TT -TT * does not hydrogen abstract and thereby only affords cycloadducts. This kind of argument was used to explain the differing photochemistry of chromone, 4^,®^ and coumarin,

44, where the formation of 45 in Reaction I was especially significant since it could only be produced by an initial hydrogen abstraction. The 42

Reaction I®*

hv + Pyre;t

46 45

Reaction II®*

iOC

44 absence of olefinic products in II and their presence in I was attributed to differing triplet states.

" CHs CHa + 4^ + 46 oCUz CHj O

Corey^® rejec ted the hydrogen abstraction ra d ic a l recom bination mechanism in the cyclohexenone reaction largely because it did not account for the absence of olefinic products in additions to cyclic 43

olefins such as cyclopentene, whereas hydrogen abstraction from a

O o

1,4-biradical in such cases is unlikely. In an elegant labeling study,

Swenton®^ has recently shown that an equilibrated radical pair is not

hv +

H3 CH,

involved in olefin product formation since scrambling of deuterium to the olefinic carbon was not observed by *^CMR.

CB +

Effect of a Beta Methyl Group

The reaction of isobutylene with 3-methyl cyclohexenone is

hv JL + 47 48 49 14^ 509 S 27^ 44

interesting in that products derived from the head-to-head biradical

predominate and in that the only product from the head-to-tail biradical

is the olefinic compound 49 . The failure of biradical ^ to close fits an

already commented upon series wherein for biradicals of this type

coupling of two secondary radicals is considerably more facile than

hydrogen abstraction, which is in turn considerably more facile than

the coupling of two tertiary radicals.®^ Evidently, the reason for this

is that methyl-methyl and methyl-axial hydrogen steric interactions

generated in the transition state greatly retard the rate of closure.

Since the transition states leading to disproportionation, 3^ and

reversion ^ are relatively insensitive to the additional steric inter action, olefinic products result, and a larger fraction of the biradicals 45

revert to starting material. The larger percentage of reversion

accounts for the dominance of products derived from the head-to-head

b ira d ic a l.

It is now revealing to use all of these concepts to account for the

relative insensitivity of the uracil ring to beta methyl substitution.

hv r H H

Since no axial hydrogens are present, there should not be a substantial

steric barrier to closure of the head-to-tail biradical. Even if such a barrier were to be present, no olefinic products would be anticipated since the transition state for disproportionation cannot be attained. At

most, if steric interactions could be introduced at both A and B, one would anticipate an increased proportion of biradical reversion and the dominance of the head-to-head cycloadduct. This is indeed precisely what is observed, as is evident in Table 5. 46

Table 5. Steric Effects on Product Orientation in the Phôto- addition of Isobutylene to Methyl Substituted Uracils

Head-to-Tail/ Head-to-Head Cycloadducts

3. 2 1

2 .2

1 H H

1.2

CHj

H . 88

‘ Ç- -H H 47

Effect of an Alpha Methyl Group

An alpha methyl substituent on cyclohexenone causes a marked

decrease in reactivity and leads to a complex product mixture. Again

this probably reflects a sterically promoted decrease in the rates of

product formation and a consequent large increase in the proportion of

biradicals undergoing reversion.

Potentially, an alternate hypothesis derives from the work of

Agosta.®^ He found that alpha methylene ketones upon irradiation are

isomerized to cyclopropyl ketones as well as to the expected cyclobutyl

ketones. For example, ^ afforded ^ an d ^ in yields of 23^ and 31^, respectively. The suggested rjeaction pathway involved 0 hydrogen

H C f^ o ' ^ U

abstraction to afford a derivative of trimethylenemethane, a ground state

•A * species with a theoretically estimated delocalization energy of 34 kcal/

I Ij W «juw >> I I] 48 mole. Thus, alternatively, alpha methyl cyclohexenone excited states may be deactivated by this process. That thymine is not similarly deactivated may reflect a lower propensity toward hydrogen abstraction by an amido carbonyl. CHAPTER III

PHOTOCYCLOADDITIONS OF 5-FLUOROURACIL- A NOVEL FLUORINE SUBSTITUENT EFFECT

Introduction

The previous study on the parent uracil system showed that

photocycloadditions were excellent synthetic reactions. Methyl substi

tutions on the enone moiety were not at all deleterious to the reaction,

and in all cases only cycloadducts were afforded in high yields. Thus,

the potential existed to apply Hunter's synthetic scheme to the synthesis

hv acetone

Ac -CCH

H H of 5-substituted uracils. We felt the best approach was to incorporate the leaving group in the starting m aterial, and toward this end two important criteria had to be met: the leaving group had to be photo stable and it could not interfere with the basic photocycloaddition process. With regard to the latter prerequisite for the leaving group, molecular orbital studies by Pullman®®’ ®^ indicated the types of groups which would be deleterious to the cycloaddition process. He found that

49 50

the greater the concentration of uncoupled electrons at the Cg—C& bond

in the first excited state, the greater the dimerization efficiency.

0 ,.« p o “ ‘

i V ' ■ H »

uracil 5-amino uracil 5-nitrouracll

Substituents which diminish this spin density can slow down or eliminate

photoadditions. Therefore, conjugating substituents were especially

deleterious to the photochemistry, and 5-nitrouracil with most of the

spin density in the nitro group doesn't dimerize. Unfortunately, calcu lations were not performed on the halogenouracils because the authors believed the only observed photochemistry was dehalogenation. Indeed,

Hunter's finding that a-bromo substituents on the enone moiety were unsatisfactory in cycloadditions, and the known photochemistry of 5 - bromo uracils^® tended to support Pullman's conclusion about

H + other products 51

a-halogenouracils. Still we felt the greater C-x bond strength of * > chloro and fluoro substituents might circumvent this problem. While

initial studies^^ on 5-chlorouracil were unsatisfactory, the 5-fluoro

compound still seemed promising.

Five-fluorouracil was first synthesized in 1957*^ and was found to

be a potent anticancer agent. Its photochemistry was first investigated

seven years later^^"*® when it and its derivatives were found to form

stable photohydrates. Significantly, photodimers were not reported.

From my own studies it became evident that the intersystem crossing efficiency of 5-fluorouracil was quite poor; thus, these early studies were singlet reactions. Since these studies were done, the photo chemistry of the molecule lay dormant, and the interesting and useful photochemistry of its triplet state unexplored.

Results

Cycloaddition of 5-Fluorouracil to Isobutylene

To a reactor containing 3 mmol of 5-fluorouracil in 150 ml of acetone fitted with a dry ice condenser was added isobutylene until a 10 ml increase in the volume was noted. After 2 h of irradiation, TLC 52

hv acetone Corex

55, 56

indicated the disappearance of starting material. A VPC analysis of

the reaction mixture afforded the surprising result that only a single

product had formed. This was indeed unusual since in the prior study

the minor cycloadduct always comprised greater than 2 0 ^ of the cyclo

adduct mixture. Still I had to be mindful of the fact that this might, as

in the case of uracil, simply be a failure to resolve the mixture by

VPC. It had become clear that the most useful and unambiguous

approach to the analysis of the fluorouracil cycloaddition reaction

mixtures was nuclear magnetic resonance. Each cycloadduct con

tained a single fluorine nucleus which during the course of this work

was shown to vary over 30 ppm in chemical shift depending on the local

environment about the fluorine. Thus, when the FMR of the crude

reaction mixture showed only one eight-line multiplet (Appendix A), it was clear that the cycloaddition had been regiospecific. A simple

recrystallization from ethanol water afforded a 909^ yield of analytically pure The assigned orientation derives from an analysis of the NMR

(DMSO-dfe, 60 MHz): .90 (s, 3H), 1. 18 (s, 3H), 2.0-2. 5 (m, 2H 53

partially obscured by solvent), 3.79 (q, J = 23 Hz, J = 4 Hz, IH), 8.0

(b r. 8 , IH), and 10. 546 (s, IH).

3 %I

The demanding feature of the spectrum is the appearance of H^^j

as a quartet centered at 3.796, with the large coupling 23 Hz from the

adjacent fluorine, and the small coupling 4 Hz due to H^^y Upon addi

tion of DgO the 4 Hz coupling is erased and the quartet collapses to a

doublet with J = 23 Hz.

From a synthetic point of view this result was extremely valuable

because I had encountered great difficulty in the separation of the iso

meric photoproducts in the uracil series. At best chromatographic and

recrystallization techniques afforded pure materials in poor isolated yield, when the separation could be accomplished at all. When I found

that ^ underwent a valuable synthetic reaction (discussed in the next chapter) the complete regioselectivity of the addition became of synthe tic as well as mechanistic interest. I, therfore, extended this reaction to olefins of similar symmetry. 54

Cycloaddition of 5-Fluorouracil to Methylene Cyclohexane Methylene Cyclopentane _58, and Methylene Cycloheptane 59

To a solution of 3 mmol of 5-fluorouracil in 150 ml of acetone

was added 45 mmol of methylene cyclohexane. After 2 h of irradiation

V A ... wO

through Corex, TLC showed that no further 5-fluorouracil was present.

VPC analysis, as in the isobutylene reaction, showed only a single product, This material could be isolated in 72^ yield by a simple

recrystallization of the reaction mixture. Again, the demanding evi dence for the indicated orientation derived from the appearance of in the NMR (DMSO-d^, 60 MHz) where it appeared as a quartet centered at 3.726, J = 4 Hz and J = 23 Hz.

The addition of methylene cyclopentane, 58, and methylene cyclo heptane, proceeded analogously, affording^ and in 7 6^ and

7 8 ^ isolated yields, respectively.

V ‘ à N I H 58 61 55

H 62

Having found that 5-fluorouracil was regioselective with olefins

possessing I® vs. 3® termini, a legitimate question arose as to

whether this regioselectivity was maintained with olefins possessing1 ®

vs. 2®, and 2® vs. 3® termini. Unfortunately, answering this question

necessitated the use of olefins, propene ^ and methyl cyclopentene

H M

CH X

7 63 â i which no longer possessed a symmetry element capable of reducing the number of isomers.

Photocycloaddition of Propene to 5-Fluorouracil

hv CH) acetone I CH Corex H H 66 55 56

At -5*C a steady stream of propylene was bubbled into a solution

of 3 mmol of 5-fluorouracil dissolved in 150 ml of acetone. After

2 h the irradiation was completed. The solvent was removed in vacuo

and the resultant solid recrystallized and sublimed, affording in 7 5 ^

yield a mixture of cycloadducts. As I was subsequently to learn, none

of the techniques I had been using, including VPC, TLC, FMR, and

FMR would have at this point sufficed to fully characterize this mix

ture. Thus, VPC, NMR, and FMR all Indicated a two-component mix

ture, while TLC on silica gel with benzene-acetone or chloroform-

methanol showed only a single spot. Finally, by employing diethyl-

amine-petroleum ether, I was able to resolve two bands on silica gel.

VPC analysis of the separated bands showed that I had separated the

two VPC components. A sublimed sample of the material isolated from

the top band showed a single methyl doublet in the PMR (DMSO-d^, 60 » MHz) and was thus a single cycloadduct. It was further characterized

65 by the appearance of initially as a doublet of two broad peaks centered at 3. 616, J = 20 Hz, which upon addition of D^O appeared as a quartet, J = 7 Hz and J = 20 Hz. The appearance of H^^^ as a quartet 57

with a J = 20 Hz ascribed to the F and the J = 7 Hz to H,,. established (4 this material as the head-to-tail cycloadduct, The exo orientation

of the methyl group was tentatively assigned on the basis of the low

field 1.16 position of the methyl doublet, since an endo methyl would be

in the shielding region of the ring.

The PMR spectrum of sublimed m aterial from the bottom band

had two methyl doublets, so despite its appearance as a single peak by

VPC, it was clearly a mixture. The FMR spectrum showed two multi

plets, one at 82 ppm and the other at 97 ppm from benzotrifluoride in

the ratio 2. 3:1. Cycloadduct ^ isolated from the upper band also

showed a single multiplet at 82 ppm in its FMR spectrum. Thus, in

analyzing the crude FMR spectrum of the reaction mixture, it had now

become clear that the multiplet at 82 ppm resulted from coincident ab

sorptions. The most reasonable interpretation of this was that the

coincident resonances arose from the two head-to-tail isomers, wherein each the immediate environment of the fluorine is identical; v iz

CHa

H 65, 66

It was, therefore, reasonable to assume that the major component in the unresolved mixture was 6 6 . Further analysis of this mixture by 58

^^CMR proved even more enlightening.

H 66 67

It was possible to assign the other component as a head-to-head

cycloadduct, ^ in the following manner. The coupling of fluorine to

carbon decreases rapidly with an increase in the number of intervening

carbon nuclei. It is thus reported that for an alkane, ^ J = -l6 6. 6

= 19. 9 Hz, = 5.25 Hz, with no value reported for

Indeed, for ^ the methyls appear as singlets, establishing ^J^p = 0.

f (4)CH3 H 56

CMR of the mixture showed a sharp methyl singlet at 13. 542 ppm from

TMS, consistent with the head-to-tail cycloadduct 6 6, and a doublet with resonances at 13. 8 6 6 and 14. 135 ppm (J = 6 . 1 Hz). The doublet is interpreted as arising from ^J^p coupling to the methyl carbon, establishing this m aterial as a head-to-head adduct. At this point it became possible to interpret the FMR of the crude reaction mixture and thereby analyze for the regioselectivity of the addition. The crude 59

FMR shows three multiplets at 82, 97, and 118 ppm in the ratio 76:18:6

7 6 : 1 8 :6 , the multiplet at 82 arising from the coincident absorptions of

the two head-to-tail cycloadducts ^ and 6 6, the multiplet at 97 ppm

arising from and the one at 118 ppm tentatively ascribed the

other head-to-head isomer. The ratio of head-to-tail to head-to-head

adducts is thus 76:24.

Cycloaddition of 1 -Methylcyclopentene, .64 . and 5-Fluorouracil

A 15:1 molar ratio of olefin to 5-fluorouracil was employed, and

after 2 h of irradiation through Corex the crude reaction mixture was

F CH)

hv acetone Corex

II 64 M 62. analyzed by ^“^FMR. Two major resonances were present in the ratio

84:7, one centered at 100 ppm and the other at 80 ppm from benzotri fluoride. This comprised 91^ of the total fluorine, the remainder being distributed among several lesser absorptions. The major pro duct was isolated by repeated fractional recrystallizations from ethyl

H jC 60

acetate, affording 35^ of ^ 8 . The regio- and stereochemical structural

assignments of this m aterial were made by a combination of analyses

of its PMR and FMR spectra. In the PMR (DMSO-d^, 60 MHz) it had a

sharp 3H singlet of 1.026 and was thus confidently a singlet material.

Significantly, appeared as a quartet at 3.666(J = 4 Hz, J = 22 Hz)

and on this basis was assigned as a head-to-tail adduct. The stereo

chemistry as to syn or anti was readily determined from the fluorine

spectrum (DMSO-d^) which appeared as four lines 100.715, 100.773,

100.975, and 101.033 ppm from benzotrifluoride, with J = 5 Hz, J =

22 Hz. This clearly established that the fluorine was coupled to two

hydrogens, H, . with a dihedral = 0°; J = 22 Hz, and H. . with a di-

h ed ral ^ = 1 2 0 °, J = 5 Hz. Thus, the major adduct was the trans-

anti 6 8 . (Note; A full discussion of the dihedral angle dependence of

Jyp follows in the enol acetate cycloaddition section.)

Cycloadduct ^ was not isolated but its structure tentatively

assigned from its ^^FMR (DMSO-d^) four lines: 80.394, 80.654,

80.726, and 80. 985 and J = 22 Hz, J = 28 Hz. Thus, both dihedral

angles are equal to 0“ and the structural assignment was made. Based on the above arguments, the regioselectivity in this addition was at le a s t 9 1: 9.

Enol Acetate Cycloadditions

Chronologically, the enol acetates were the first olefins I added to 5-fluorouracil; thus, it was at this stage that FMR first proved itself 61

extremely valuable in analyzing crude reaction mixtures and in

assigning structures to the adducts.

Cycloaddition of Cyclohexenyl Acetate, JO . and 5-Fluorouracil

To 3 mmol of 5-fluorouracil in 150 ml acetone was added 30

mmol cyclohexenyl acetate. This solution was irradiated for 2 h, after

¥ ? hv acetone C orex

A cQ ' 70 72 73

which TLC on silica gel showed no further starting material. An ali

quot was removed from the reaction mixture, and solvent and residual

cyclohexenyl acetate were removed in vacuo. The resulting white solid was taken up in DMSO-d^ and its fluorine spectrum recorded. As can be seen (Appendix A), the spectrum consists essentially of four m ulti plets; a triplet at 79.7, 80.0, and 80.3 ppm with 12.5# of the total integrated area; a triplet centered at 90.8 ppm, 2. 5#; a doublet with resonances at 101.8 and 102. 1 ppm, 69.8#; and a multiplet at 113. 1,

113.4 ppm, 15. 1#. Since it was felt that dimerization could well be a competing process and that some of these resonances might therefore be attributable to dimers, the reaction was run without cyclohexenyl 62

hv acetone Corex H

acetate. Again, after 2 h the starting material had completely reacted

and TLC followed by irradiation of the silica plate at 2537Â for visuali

zation showed a single spot which had not migrated in the 6 ^ CH3OH in

chloroform solvent system. The visualization of the material by a

presumed reverse 2+2, its lack of mobility on thin layer, and an NMR

of the crude product were all consistent with a mixture of dimers. The

fluorine spectrum validated our initial assumption that dimerization

was indeed a competing process. The dimer mixture consisted of four

multiplets: a triplet at 91.4, 91.6, and 91.8 ppm comprising 22.4# of

the integrated area; a multiplet centered at 109 ppm, 7#; a multiplet at

110 ppm, 6 . 3#; and a multiplet with resonances at 113.8 , 113.9, and

114. 1 ppm with 64. 3# of the integrated area. It was then possible to

return to the spectrum of crude reaction and confidently assign

the triplet at 91 ppm and the multiplet at 113 ppm to dimers. Thus,

dimerization accounted for about 18# of the 5-fluorouracil consumed.

This was in good agreement with an 80# yield of cycloadducts deter mined by VPC against an internal standard.

The major cycloadduct, ^ i, the 6 9. 8 # material by FMR, could be isolated directly by recrystallization of the crude reaction mixture. 63

A cO

The appearance of in the PMR (DMSO-d^, 100 MHz) as a quartet at

4.406, J = 19 Hz, J = 4 Hz establishes the orientation as head-to-tail.

However, the syn or anti stereochemical assignment cannot be made

without an examination of the FMR spectrum. The dihedral angle

dependence of Jpjj. lor a series of conformationally rigid molecules had

been determined by Williamson. He concluded that the dihedral angle

dependence of (vie) was very similar to (vie) and was not a

linear function of dihedral angle as had been previously and erroneously

reported. Indeed, a plot of his values, augmented with some of my

values (Figure 2) for these rigid cycloadducts, showed a striking

resemblance to the Karplus curve for (vie), with a trough at 90° which was roughly three times deeper. The deepness of this well allowed for stereochemical assignments without any ambiguity. The

FMR of pure 7^ at good resolution showed four lines at 106. 515,

106. 573, 106. 746, and 196. 804 ppm from benzotrifluoride with J =

5 Hz, J = 19 Hz. Molecular models showed that the anti compound, JJi, had = 0 ° and $H^^^F = 1 2 0 °, and with predicted coupling constants in agreement with those observed. Note also that 64 30

20i

byC

0 30 60 90 120 150 180

O WILLIAMSON et.al.JACS ^,5678(1966) □ BOVEY pg. 225

A ' \ - f ° g 0“< J„p = 25.5,23.0Hz, e~0“

b J^F = 19Hz ( 0 = O'*) 5 Hz (8 = 120"*)

J = 2OHz(0»O®) J^P« 5H2(0«I20®)

AcO —

Figure 2. The dihedral angle dependence of vicinal J. HF 65

in the PMR showed J = 19 Hz, eliminating the possibility that

= 0 ° and that this might be a trans-fused cycloadduct.

The F MR of the minor adduct very nicely complemented the above

assignment. Again, models suggested that 0H^^jF and would

OAc

both be approximately 0®. Thus, the anticipated spectrum of the syn

adduct was a triplet or quartet with closely spaced center resonances.

The FMR of TZ isolated by column chromatography showed four lines:

80.414, 80.688, 80.716, and 80. 990 ppm, J = 23 Hz, J = 5 1Hz. This

readily allowed the assignment of 7^ as the syn cycloadduct.

Cycloaddition of Cyclopentenyl Acetate, TA , and 5-Fluorouracil

The reaction was run employing a ten-to-one molar ratio of olefin to 5-fluorouracil. The major cycloadduct could be obtained pure by simple recrystallization of the crude reaction mixture, which gave 64^

H N hv + acetone A c Corex H 74 75 66

of 75. Again, this material was distinguished by its FMR spectrum

(DMSO-d^) which appeared as four lines: 106.488, 106,498, 106.666,

and 106.733 ppm from benzotrifluoride, J = 5 Hz, 20 Hz.

Discussion

The smooth addition of olefins to triplet 5-fluorouracil indicates

that fluorine is not significantly diminishing the uncoupled Cg-C* spin

density. A simple Huckel calculation on 5-fluorouracil (Appendix B)

shows negligible uncoupled spin density (S.) on the fluorine and, there

fore, the efficient cycloaddition is in agreement with Pullman's

argum ents. Sj = C.'(HOMO) + C '(LUMO)

.0 7 5 .180

While fluorine is not deleterious to the cycloaddition process, a

major finding of this work is that it can significantly enhance regio-

selectivity of mildly polarized olefins. The observed regioselectivity

(T ab le 6) was greatest for olefins having primary and tertiary termini and decreased in the order X.,

From a synthetic point of view this was tremendously advantageous. As a kind of unfortunate but nonetheless amusing illustration of this, 67

Table 6 . Regioselectivity in the Photoaddition of Simple Alkenes to 5-Fluorouracil

Head to Tail Enone Olefin Head to Head

A > 30

A ~ 3 . 3 H

~ 3 . 3 A

II f >30 A N' 68

Table 6 (continued)

Head to Tail Enone Olefin Head to Head

c r 9 CH)

H3- N Il „ J L „ . 5.7

N '

HT ^ C H ,

) X 69

consider the difficulties encountered by Lange®^ in the following reaction;

.OAc CH3CN 30h

pA c CHO CHO

(76+27 = 20^)

where, in addition to product photolability, he encountered olefin forma

tion and a total lack of regioselectivity.

Mechanistic Rationale for Regioselectivity in Enone Cycloadditions. Origin of the Fluorine Substituent Effect

Several different approaches have evolved in the literature to account for regioselectivity in enone photocycloadditions. At this point,

I would like to develop each of these mechanistic approaches and consi der how they might account for the fluorine promoted regioselectivity.

The development of these approaches is in some instances rather involved; therefore, I w ill briefly state the conclusions I have drawn.

1) The PMO approach fails to account for the effect of

the fluorine because molecular orbital theory predicts 70

that fluorine only minimally perturbs the uracil pi

system .

2) While I have endeavored to rationalize the effect of

the fluorine within the framework of the "oriented TT

complex" mechanism by postulating an enhanced Cg-C*

bond moment in fluorouracil's excited state, at best

this can now be viewed as only a very tentative hypothesis.

3) The overall dipole approach predicts the incorrect

orientation.

4) The biradical reversion mechanism appears to offer the

most reasonable explanation for the observed effect.

Evidence from other fluorinated systems strongly

supports this approach.

% The PMO Approach

Herndon*^ has proposed to account regioselectivity in photocyclo additions by perturbation molecular orbital theory. Consider the intermolecular perturbation energy change upon interaction of the excited enone and olefin,A., to be given by

A = Q + Ai +Az f C T + P, where Q is a coulombic energy term, and Ag are molecular orbital interaction terms, and CT is a charge transfer term. The A i term arises from a degenerate, or nearly so, interaction between orbitals 71 and the A 2 term from nondegenerate interaction. N is an orbital

Ai = NCrCsyRS

A _ (NCrCsVRS) 2 ^ F - E occupancy number and corresponds to the numbers of electrons involved in the interaction, and the perturbation integral is assigned a value ^ where p is the fam iliar Huckel resonance energy, the rationale for this assigned value being that the bonds are half formed in the transition state. Generally, no contributions from the Q, CT, and P terms are considered.

Let me illustrate the method employed with a fam iliar example.

Dewar and Longuet-Higgens have developed a procedure*® for the approximate calculation of E^ of an alternate hydrocarbon by consid ering the molecule as arising from the union of two odd alternate systems. Anthracene and phenanthrene arise from a head-to-tail and head-to-head union, respectively, of two benzyl fragments, and the E^ of the product hydrocarbon is given by perturbation theory as

^n= 2P(Z CrCs) +E^^ +E^g.

(w here 1 >s)

Anthracene: Phenanthrene: head-to-tail oriented head-to-head oriented 72

Since = ^nS ® “ benzyl) it is seen that depends only on

orbital coefficients and orientation. It is seen that 1* + > 218 (Shwarz

AE^ = 2p[S(CrCs) - Z (C rC s ) head-to-tail head-to-hea 2 inequality); thus, phenanthrene is predicted stabler, i.e., having the greater E^. Herndon argues that the preferred product orientation in photocycloadditions is as above, determined by the larger TT energy stabilization, in this case, of the transition state. One need only identify the most significant orbital interaction and the orientation is then determined by the Shwarz inequality.

Herndon gives many examples of this approach; for instance, consider the addition of dimethoxyethene to styrene. An orbital corre lation diagram is constructed with orbital energies assigned from

CH,

E(P) / V . 60 -.70 -1 . 35p

. 6 0 -.39 -. 6 6p

.75 .41 . 60p H2C=C(0CH3)2'‘- . 6 0 .3 9 . 6 6p H 2C = CH }6

(from ref. 6?) 73

either HMO calculations or preferably from spectroscopy. The dashed

line connects the dominant interaction, and product orientation is as

depicted. As applied to the photochemistry of cyclic enones, Herndon

Et O E t 0

provides the following orbital correlation diagram (Figure 3) wherein

the dominant interaction is seen to arise between enone and olefin TT

1.9 ----- 2 .9 ------4.00 -----3.8

1 r TT * le v e ls TT le v e ls 1 s 8.7 It 1 s — -9.7 10. V 1 ------10. 5 1 0 . 9

, y H2C=CH2 HgCzzCHCN H2C=C(CH3)2 H2C=C(CI)2 (K) (O)

Figure 3. Interaction diagram for olefin additions to cyclopentenone (1 and s stand for large and small, respectively) orbitals. Although it is stated that this predicts correct product orien tation, it is clear from the HMO TT^ orbital of acrolein (Appendix B) that all olefins are predicted to give 50/50 product mixtures. This accounts successfully for observed orientation with isobutylene but not for polar 74 0-.577

-0 . 000— @.577 C) TT2 of acrolein

577 C4

olefins such as ketene dimethyl acetal. If C3>C 4 the theory would

predict correctly in all cases.

In the oxaenone system where Margaretha^^ has observed reglo-

specific addition of isobutylene to oxaenones, as shown below, PMO

theory does predict enhanced regioselectivity. If the dominant orbital

interaction remains the same as for simple enones, a Huckel calcula

tion shows an increase in the C 3/C 4 coefficient ratio in the HOMO

orbital and therefore predicts enhanced regioselectivity.

.626

,446<

Application of the PMO approach to uracil follows straightfor wardly (Figure 4). Huckel calculations give the coefficients for the

HOMO and LUMO orbitals. The energy of the HOMO orbital is set equal to the ionization potential, and the LUMO orbital lies 3. 26 e.v. above the HOMO orbital from emission spectroscopy.^® The isobutylene values are directly from Herndon's paper. The dominant interaction is again HOMO uracil HOMO isobutylene and the preferred orientation is predicted as head-to-tail in agreement with experiment. 75

E (e. V. ) U ra c il Isobutylene

1 . 9 e. V.

I s . ? e. v . ' ^

9. 43 e. V. 10.0

Figure 4. Interaction diagram for the photoaddition of uracil and isobutylene 76

Assuming the same dominant orbital interaction for 5-fluoro

uracil, the observed regioselective cycloadditions would indicate a

dramatic increase in the HOMO (uracil) orbital coefficient ratio.

This, however, is where a real deficiency in the PMO method mani

fests itself because molecular orbital theory predicts that the fluorine

does not significantly perturb the TT orbital system^* (Figure 5).

Orbital interaction is greatest between those orbitals closest in energy;

therefore, if the interacting p orbital is on a very electronegative atom,

it is far lower in energy than the TT system and does not significantly

interact. Note that Yi is essentially a p orbital on fluorine whereas

Y), and Sg constitute a virtually unperturbed acrolein TT system.

Strong support of this qualitative MO picture derives from photoelectron

spectroscopy of vinyl halides. Vinyl fluoride shows a first ionization

potential of 10. 58 e.v. , nearly identical to that of ethylene 10. 51 e.v. ,

showing that the TT orbital is virtually unperturbed by the fluoro substi

tuent. It was therefore not at all surprising that the Huckel calculations

on 5-fluorouracil (Appendix B) showed essentially the same coefficient

N 1^592 N

HOMO o rb itals ^ A = . 33 ratio Cg/Cg as uracil itself. If one introduces an auxilliary inductive parameter as described by Streitweiser^^ to introduce a degree of 77

0 F A Ü

. . 228 1 217 .20 102 . 577 657 f s - 1 .5 8 0 -1 . 530- . 428

-P . 429 . 436 jja47 577 3540 -.3 4 7 0 228 % 1 226

. 638 0=0 QBC ...... 657

577 - . 5 2 4

.1 8 9 . 000 041

1.000 - 41— . 577 . 610 . 697 . 657 201 577 u/ 570 . 429 l2 . 33 9 1 . 880 2 0 . 228 . 186

30 'ti 3.199 4 ■ f - 083

Figure 5. Molecular orbital diagram showing the absence of any significant perturbation of an enone TT system by an alpha fluoro substituent (see Appendix B) 78

polarization of the carbon bonded to fluorine, the ratio of the coeffi

cients Cg/Cô can be somewhat enhanced. Nonetheless, it appears quite

evident that the fluorine promoted regioselectivity is not readily

explained by the molecular orbital approach of Herndon.

The Oriented TT Complex

The concept of an oriented TT complex was first developed by

Corey. He found that MO calculations indicated that the enone excited state was electron defipient in the alpha position. Calculations by

Zimmerman^'* show on excitation to the TT -TT * triplet the alpha position

- . 3 3 h + .23

loses .23 electrons. Based on this finding Corey depicted the enone excited state as a dipolar species. Orientation in the rapidly formed exiplex was then determined by alignment of the olefinic dipole and excited enone dipole.

r CN (+) « (-) II or ■ 5(-) ''&(-) 6 (+ )" 79

The direction of the olefinic dipole is readily discerned by *^CMR

chemical shift. Resonance donating groups increase electron density

at the terminal methylene, and resonance withdrawing groups reverse

« » IR; ©

the polarity of the double bond. This is strongly reflected in the carbon

shifts (Figure 6 ) and is also evident in MO calculations.^^

Cl Cg X (ppm downfield from TMS) -a lk y l 139 114 -O C H j 153 84

• o i:CH . 3 142 96

-CN 108 137

F ig u re 6 . The effect of substitution on the chemical shift of olefinic carbons

This concept is readily applied to the uracil system via simple

Huckel calculations. Figure 7 depicts the net TT charges in the ground and first excited state (Appendix B). As in the simple enone system, the uracil excited state is again characterized by an electron deficient alpha carbon and a Cg-C& bond moment in a direction opposite to that of 80

N n -.H 4 hv + .2 1 4 q = 1 .0 53 + .2 3 6 Tocc A

F ig u re 7. TT Electron charges on uracil and its excited state

the ground state.

If we now turn our attention to 5-fluorouracil, as anticipated, we

see very little change in TT charge relative to uracil. It is now,

- . 0 8 2 hv + .228

+ .1 9 4 - .0 4 6

. k however, important to recognize that TT electron distribution alone does not adequately reflect electron densities in fluorinated systems.

Fluorine exerts a profound cr inductive effect which substantially diminishes

CNDO/^ calculations'^^on vinyl fluoride shows that the substantial positive charge on the carbon to which the fluorine is bonded arises via a reduc tion in

TT electron density is plotted against shift, the a-carbons bearing the substituents are grossly off the line. On the other hand, a strong rela tionship is found between the total (cf+TT) electron density and shifts

(Figure 9). This indicates that the carbon to which the fluorine is o o

♦o •* # % » ••05

-.101------1------1------1____ L_ -.10. 20 30 -40 -30 -20 -10 O 20 30 &*exp.(ppffl9—

n F ig u re 8 . q values vs. '13 Figure 9. ^ q ° vs. chemical chemical shifts: 1 , fluorobenzene; shifts. Numbering and circle 2, benzaldehyde; 3, nitrobenzene; designations as in Figure 8 . 4, toluene; 5, phenol; 6 , aniline; (from ref. 78) ®, a-carbon atom; O, o-carbon atom; ©, m-carbon atom; • , p- carbon atom ;^, benzene. 00 (from ref. 78) 82

bonded is far more electron deficient than indicated by consideration of

only TT electron densities. This analysis carries over to 5-fluorouracil

whose spectrum^^ differs markedly from the parent uracil. These

X C -5 C - 6 'H -lO i; 1 T 4 T .-2 F 140.8 127.3

authors found that the shift of carbon 5 for a series of halogenoura-

cils was a strong function of substituent electronegativity, decreasing with Increasing electronegativity of the substituent. In agreement with the finding of Bloor, they found that the shift of carbon 5 correlated linearly with total (cr+TT) electron density at that position (Figure 10),

IM '

m •

n '

M ,

Figure 10. The linear relationship between the chemical shift of C-5 and total (cr+TT) charge of C-5 substituted uracils (from ref. 7 9) 83

If one looks specifically at 5-fluorouracil electron densities, it can be * 3 seen that TT densities predict C -5 more electron rich than C- 6 , c le a r ly

showing that the cr densities cannot be ignored.

TT cr+TT '' ^ TT *r+n

1.0484 3.3887 . 8590 3.7598

I'd now like to return to Corey's orientedTT complex mechanism

and refine it somewhat. Let pg & equal the Cg-Cg bond moment. Then

hv % X r

N I H

M-5 ,6 ~ M’ 5 , 6 + 5 , 6* where for simple enones and uracils p'®“~0. Thus,

for both ground and excited states fxg^g is determined by For

fluorinated systems cannot ^e ignored, and to a first approximation

hv N

N I H

its direction and magnitude are unaffected on TT-TT excitation. The

enhanced regioselectivity would then arise because in the excited state of 5-fluorouracil, p^ g and p^g^ g are reinforcing and the larger excited state bond moment increases the rate of formation of the head-to-tail

oriented complex relative to the rate of formation of the head-to-head 84

com plex.

X ± F N > %»

In an attempt to confirm this hypothesis we sought a substituent

which would be as strong an inductive withdrawing group as fluorine but

which would be incapable of stabilizing an adjacent radical by delocali

zation. A trifluoromethyl group, cr^ = . 42 (for .34) was chosen.

Photoaddition of isobutylene and analysis of the crude mixture by FMR

CF CF, CH; CH

CH, U H H ratio by ‘’FMR, 9 5 ; 5

showed two products in the ratio 95;5. An NMR of the isolated major

cycloadduct shows a 2H singlet for the methylene proton resonances, and a IH doublet, H^^, which collapses to a singlet on adding D^O. The m aterial was thus assigned as the head-to-tail oriented cycloadduct.

The observed regioselectivity is greater than would be anticipated for a simple steric effect and this can then be interpreted as supporting this hypothesis. 85

The Overall Dipole Mechanism ' T DeMayo®® has shown that the photocycloadditon of 7^ to 22. p ro

ceeds regiospecifically in hydrocarbon solvents to afford cycloadduct 80.

P o

+ DCH, •Ac AcO 18 80 81

A ^®CMR spectrum of the ketal shows two nearly equivalent vinyl carbon resonances; thus, the double bond of2 2 , has very little polar character.

DeMayo argues that the observed regioselectivity cannot then be accounted for by an oriented TT complex. With increasing solvent polar ity the ratio 80^: 8 J^ changes from 98:2 in hydrocarbon solvents to 45:55 in methanol. This indicates that the transition state leading to which

% has a larger dipole moment than the one leading to _80, becomes less disfavored with increasing solvent polarity. Similar arguments have been presented to explain product ratios in cyclopentenone dimerizations®* and other photocycloadditions, ®*

A critique of this mechanism has already appeared, ** but at issue here is whether or not it can account for the fluorine effect. On the

H, c r ^ N : H , 86

basis of overall molecular dipole moment, this mechanism predicts the * ^ wrong orientation in the isobutylene addition.

The Biradical Reversion M echanism

Bauslaugh^^ has proposed to account for product orientation on the

basis of a pure radical mechanism where the relative rates of radical

ring closure and reversion to starting materials are determinate. For

the isobutylene addition he considers the likelihood that four possible

biradicals are formed;

82 83 84 85

where the rate of formation of ^ is greatest and that of8 ^ is least.

At this point either reversion to starting material or closure to cycloadducts can take place as was shown in this work by Bartlett:®’

reve rs io n

cycloaddition >[i:

Furthermore, Bartlett showed that the greater the stability of the diradical intermediate, the greater the ratio of reversion to 87

cycloaddition. Thus, Bauslaugh accounted for product orientation by

the following kinetic scheme:

83 o r 84 A

Y 82 or 85

k,'

where the most stable biradical £ 2 reverts to starting material more than it closes to product. So in terms of rate constants even when k^’ > kx, if k2'/ k3 ' > kg/kg, then the head-to-tail product may well predomi nate. Olefins having polar substituents at one end, dimethoxyethene, would require the superimposing polar groups for cyclobutane closure.

This would dim inish kg' and now kg'/itg'X^tg/kg and only h e a d -to -ta il product is observed. 88

A sim ilar argument was employed by Wagner and Buchek*’ to

account for ^ uracil being three times greater than fp thymine. These

authors argue that secondary radicals (i.e. , from uracil) couple more

d im er efficiently than do tertiary ones (from thymine). So, clearly, the prece dent for employing Bauslaugh’s biradical reversion theory of regio selectivity to uracils has been set.

Straightforwardly from Bauslaugh's arguments biradical ^ , because of its greater stability, reverts to starting materials more often than biradical thus, with kj."/kj,"> /k^ ', the head-to-tail adduct dominates. Similarly, polar olefins are more regioselective.

N‘ I H 86

A, 89

In terms of this mechanism the effect of the fluorine may be to

significantly enhance the closure to cleavage ratio for 8 9 relative to 8 8 .

rt-

We have been very recently informed by Wagner®^ of enhanced photocyclization of alpha fluoro ketone s. A ll three ketones, 90^, 21» and %

OH o

C -C x y GH 2CHCH; + CH2= C H -C H 3

Cxy CH2CH2CH;

5 0 (x = y = H )

92 (x=y=F) 90

^2, underwent only type II photoelimination and cyclization; however,

the cyclization/cleavage ratio increased from l / 5 for to l/l for 2 1 ,

and to 6o/l for 9,2. For y-fluorobutyrphenone 23 the ratio remained

1/ 5 .

'CH2CH2CHFCH3

Comparison of the biradicals 2^ and 2,5 derived from 2 i and 23

with the fluorouracil derived biradicals, 29 and 8 8 , reveals them to be

94 H h

8 8 structurally analogous. These results strongly imply that our observed enhancement in regioselectivity arises due to enhanced closure relative to fragmentation of the head-to-tail oriented biradical. The enhanced regioselectivity is greatest for olefins which have 1® vs. 3® termini wherein the difference in energy between the head-to-tail biradicals2 2 91

and 1® greatest. Diminished regioselectivity occurs for olefins

having 2“ vs. 3“ or 1“ vs. 2® termini because the energy difference

between the head-to-tail biradicals, 51, ^.nd5 8 or 99, and 100^ is

lessened.

Î-K »

H 100

Wagner has proposed to account for this effect on the basis of fluorine hyper conjugation. Biradical 94 because of the adjacent oxygen probably exists with a large degree of zwitterionic character®® as in 101, having a carbanionic and sp® hybridized carbon. It has been proposed that such species are stablest with the fluorine and the electron pair in the same plane as in conformer 102, with a proposed barrier to rotation of about 9 kcal. ®* While four-membered ring closure from this 92

H-O H- » H - CH,

i9 .L

c r

1 0 ^

conformer is possible, fragmentation which requires the sp^ orbital

and the cr bond to be in the same plane®^ jp3 is not. Analogous argu

ments would apply to our system wherein stabilized conformer

could only close to product.

104

An alternative to Wagner's proposal is the possibility that increased fluorine substitution leads to increasedcTg 3 bond strength.

F > ^ * ' 7 ^ Reversion then would clearly be more difficult, independent of confor mational preferences. At least one example of this kind of marked increase in cr bond strength on fluorine substitution is known.®® A clear 93

CF 3-CH 3 > C H j-C H j 0=117 kcal 0=83 kcal

distinction between these alternatives is possible since Wagner's mechanism demands the presence of an adjacent heteroatom x at C -l.

- — • ’ “ * 0

The regioselectivity observed in photoadditions to alpha fluorocyclohex- enone should then establish whether or not enhanced cyclization will occur when there is no adjacent heteroatom. C H A P T E R IV

FRAGMENTATION REACTIONS--RESULTS

Introduction

In this section I w ill describe the synthesis of a wide variety of

5-substituted uracils. Since these products were characterized pri m arily on the basis of spectral data, it is appropriate here to discuss in detail the spectral properties common to all uracils. This discus sion w ill then be referred back to when the structural assignments for the new compounds are presented.

The Spectral Properties of U ra c ils

Perhaps the diagnostic feature of the uracil nucleus is its pro nounced ultraviolet absorption maximum \ = 264 nm, e = 7900 (Figure

1 1 ). In base this spectrum is very characteristically shifted to X =

280 nm with a diminished e. The UV properties of the starting cycloadducts parallel those of dihydrouracil (Figure 12). At neutral pH the absence of a conjugating double bond erases the characteristic absorp tion. At alkaline pH a double bond in conjugation is generated, leading

94 95

5-METHYLURACIL (THYMINE) 5-MeUra (Thy)

M.W. 126.11 HN‘ CH, ' ' ■ #pH 120

220 840 8«0 260 300 MO 840

F ig u re 11. Ultraviolet absorption spectrum of thymine (from The Modified Nucleosides In Nucleic Acids by R. H. Hall (Columbia Press, 1971).

Ù H N f “H N ^ H '9 WM A A ii u ra c il dihydrouracil dihydrouracil p H -7 p H -7 pH -7 2100 2300 2500 2 X(X) (a) Absorption spectra of uracil at neutral pH (------) and of dihydruuracil at neutral and alkaline ( * )(') pH (Batt et al., 1934 and Janion and Shugar, I960;.

Figure 12. Ultraviolet absorption spectrum of dihydrouracil and uracil (from Photochemistry of Proteins and Nucleic Acids by A. D. McLaren and D. Shugar (Pergamon Press, 1964) 96

to an absorption maximum at X = 230 nm.

The infrared spectrum of thymine is characterized by a strong

well resolved doublet at 17 30 cm"* and 1670 cm"* (Figure 13). The

00 WAVELENGTH (MICRONS)

: ... 1 ,

2000 1800 1600 UOO WAVENUMBER (CM')

Figure 13. Carbonyl region of the infrared spectrum of thymine (from Stadtler Index No. 9740)

assignment of the Cg = 0 stretch to the higher frequency vibration, and the C4 = 0 to the lower frequency stretch follows straightforwardly from a discussion of the infrared spectra of nucleic acids.®’ These authors point out that the C2 = 0 bond length (1. 23Â) is shorter than C4 = 0 97

(1.26Â) and that on substituting C4 = fo r C4 = *^0 the lower frequency

peak shifts -5 cm”', with no shift for the higher frequency stretch.

Significantly the best resolved infrared spectra of the cycloadducts show

a very poorly resolved doublet 1730 and 1720 cm"'; thus, the removal of

the conjugated double bond raised the frequency of the C4 = 0 stretch

about 50 cm"'.

NMR

Most of the NMR's of the new uracils were recorded in DMSO-d^.

The NMR of thymine (Figure 14) shows a broadened singlet at 7. 216

assigned to H -6 , and characteristic of 5-substituted uracils. Uracil

itself exhibits (in DMSO-d^) two doublets, one centered at7 . 396 H - 6 and

the other at 5.486 H-5. Also evident in the spectrum, and appearing

often in my spectra, are a multiplet at 2. 525 assigned as DMSO-d^, and

a singlet at 3.356 (and concentration dependent) assigned to HgO.

*’ CM R

The CMR spectra for a variety of uracils have been published.

The shifts were reported relative to an external CSg capillary with

DMSO-d^ as solvent. I have converted these to TMS base shifts using

1 9 3 . 7 ppm as the TMS based shift of CSg. '

I k 152.4'X^ |]^108,5

H JJL

IT tt T#

Figure 14 . NMR spectrum of thymine (from Stadtler Index No. 9394M)

sO 00 99

The first fragmentation reactions which w ill be discussed are

those of the enol acetate-fluorouracil cycloadducts.

An Anticipated Fragmentation Reaction

Synthesis of 5-(Cyclopentano-2“Oxo)uracil _105

NN ? 0 + 3NaOH

105

To 408 mg (1.6 mmol) of 7_5 was added 4. 8 ml INNaOH in

methanol. After a 10 min reflux, the solvent was removed in vacuo,

and to an ice-cooled solution of the resultant orange glass was added

2.4 ml 2NHC1. This precipitated 105 in 73^ yield. A recrystallized

sample of the precipitated m aterial showed a single spot on TLC (silica

gel 6^ CH3OH in C H C I3). The mass spectrum showed a parent atm /e =

1 9 4, and the material gave a satisfactory analysis for C9H 10N2O3 .

Clearly, the starting cycloadduct, M. W. 256, CnHi 3 N 2 0 4 F, lost

C2H 3OF. The new product had an intense UV absorption (CH3OH) =

264 nm, e = 7700, which immediately indicated the presence of a uracil ring. Consistent with interpretation were two well resolved carbonyl stretches in the IR 5.75(s) and 6 . Ofx(s), and four of the lines in the 100

^*CMR at 163.6, 151.3, 140.0, and 111.1 ppm. These CMR resonances parallel quite closely the values for the C-4 and C-2 carbonyl carbons and the C- 6 and C-5 vinyl carbons, respectively, of the uracil nucleus in thymine. That the m aterial was a 5-substituted uracil was evident from the presence in the PMR of Hg a doublet at 7. 286 (J = 5 Hz), with no resonance at 5. 486 which corresponds to H-5. While ordinarily the presence of a cyclopentanone ring would receive support from a carbonyl band at 1751 cm“* (5.7 Ip) in the IR, this was here obscured by the higher frequency uracil carbonyl stretch. Nonetheless, the presence of a cyclopentanone ring was very evident from a ^^CMR resonance at 217.3 ppm, cyclopentanone itself absorbing at 213. 9 ppm. Note that in the cyclohexanone CMR, an alpha methyl substituent shifts the carbonyl resonance 1.5 ppm downfield from cyclohexanone. Thus, the anticipated

CMR position of the cyclopentanone carbonyl of 105 would be 213. 9 +

1.5= 215.4 in quite good agreement with the observed 217.3. Finally,

105 easily formed an orange DNPH derivative.

Synthesis of 5 - ( Cy clohexano - 2 - oxo) ur ac il 10^

CH3OH F + 3NaOH

106 101

The fragmentation of cycloadduct 7JI_ proceeded in much the same

fashion, affording 106 in 7 6 ^ yield. The assignment of structure again

derived straightforwardly from the spectral and analytical data which

appear in their entirety In the experimental section. The only special

feature to which I'd like to call attention is the shift in the carbonyl

resonance from 217.3 for the cyclopentanone carbonyl of IjDS to 208.2

in ^06 . A cyclohexanone carbonyl, in agreement with the above data,

is anticipated at about 5 ppm lower field.

The isolation of the minor cycloadduct ]72 allowed for a determina

tion of any stereochemical requirement for the reaction, When 72 was

V + 3NaOH i f H OAc

1 2 106 subjected to the same reaction conditions as 7^, a corresponding work up afforded material whose on TLC (silica gel 6 ^ CH3OH in chloro form) and whose IR spectrum were identical with those of from the cleavage of the major cycloadduct 71. 102

An Unanticipated Fragmentation

The regioselective addition of isobutylene to 5-fluorouracil was

an interesting reaction. The formation of a single cycloadduct in high

yield prompted a search for some synthetically useful chemistry for

this material. Anticipating a syn elimination of HF to give the strained

3KOtBu H Ô tB u CH -4F CH, H -j. 56 1 0 1 . uracil , I heated cycloadduct ^ at reflux with three equivalents of

KOtBu. The reaction took a much different course from the one antici

pated.

Synthesis of 5-(2-Methyl-2-propenyl)uracil 108^

To 235 mg K ( 6 mg-atoms) dissolved in 20 ml of tert butyl alcohol was added 372 mg (2 mmol) 56 . The stirred solution was brought to

CH H-QB u + 3 KOtBu CH, CH

56 108 reflux for . 5 h. Aliquots of the reaction diluted to INNaOH showed the appearance of a UV absorption at = 286 nm, which ceased in creasing after . 5 h at reflux. Solvent removal in vacuo was followed by 103

the addition of 5 ml of water. This ice-cooled solution was acidified to

pH-3 (red to hydrion paper) and the resultant precipitate collected.

TLC of this material, 8 ^ CH3 OH-CHCI3 on silica gel, showed a single

intensely fluorescence quenching spot which was isolated in analytical

purity by simply recrystallizing from ethanol-water.

That this material was a uracil was immediately apparent from its

UV spectrum^ \(CH J3 OH)/ X max = 265 nm, e = 7200, and in INNaOH X max = 286 nm, e= 6500. It also exhibited the well resolved carbonyl doublet

in the IR 1740 and I 6 6 O cm"^ and the characteristic uracil carbon

H 108

resonances 164. 181(s) C 4 , 151. 286(s) Cj, 138.768(d) C^, and 109.741(s)

C5 (with the off resonance decoupled appearance of the absorption in

parentheses). The mass spectrum showed a parent m/e = I 6 6 , and the material gave an acceptable analysis for CgHioNgOg, indicating that the reaction had proceeded with loss of HF. The appearance of the NMR

(DMSO-dg) was demanding for structure ^10^8 (60 MHz) 1.67 (s, 3H),

2.87 (br. s, 2H), 4.67 (br. s, 2H), and 7. 135 (s, IH). The singlet at

7. 136 H^^y and the absence of any resonance at 5.486, established that this was a 5-substituted uracil. The appearance of the rest of the spectrum is probably best discussed relative to the model compound, 104

2-P-methallyl-2-cyclohexenone, jOj2., whose NMR was recorded at

60 MHz in CCI4 . The relevant absorptions when converted to 5 units

it B . »

■1.666 %'

N' 109 4 .7 Ô H

are: 4.7 (zH, m, C= CHg), 2.85(2H, broad, -CCHzC^C), and 1.66

(3H, t, J = 1 Hz, C=CCH^ and are seen to compare almost identically with the PMR resonances of the isolated uracil. This firm ly estab lishes the nature of the side chain. Finally, the rest of the carbon

spectrum of_1^§_ was also consistent [22.06? (q) CH,, 33.343 (t)

111. 1 9 8 (t) and 143.355 (s) with the assigned structure.

Our initial feeling regarding the mechanism of the reaction was that the product was arising via a concerted 1,4 elimination of HF.

% However, experiments related to the mechanism were put in abeyance until the generality of the reaction was established.

Synthesis of 5-( 1- Cyclohexenylmethyl)uracil 111)

To a solution of 3 mg-atoms K in tert butanol was added 1 mmol of cycloadduct 60. After refluxing for 35 min, the reaction was worked

+ 3 KOtBu HO Bu

6 0 1 1 0 105

up exactly as in the previous fragmentation. TLC, silica gel 10^

CH 3OH in chloroform, showed a single intensely fluorescence quenching

spot.

I would like at this stage to discuss again in detail the structural

assignment of this material. The structural assignment of the homo

logues of jjjQ, follow straightforwardly from this discussion, and these

reactions w ill then only be discussed briefly.

A re crystallization of the precipitate from ethanol-water gave

material which satisfactorily analyzed for CnHi^NgOg. UV spectra

1 1 0 jjO

(CH 3OH) X = 266, s = 6000, and (INNaOH) X = 287, e= 6300, ^ ' m ax ' ' m ax and the characteristic IR doublet 1720 and 1665 cm"* are in agreement

with JJ[2_ having a uracil ring. In the PMR (DMSO-d^) appears as a

doublet at 7.056and collapses to a singlet on addition of D^O, H^^,^ the

vinyl proton appears as a broadened singlet at 5. 386 , the bis-allyl

protons appear again at 2.76, all of which is again consistent with

structure 110 . Most supportive of the structure, however, was probably the carbon spectrum (DMSO-d^), which showed six downfield resonances and five upfield resonances for a total of eleven carbons. 106

Downfield were: C4 164. 343(a), Cg 151. 286(a), C& 138. 337(d), C@

135.315(a), Cg 121.827(d), and C 5 110.011(a). Upfield were five lineas

2 1 . 9 0 5 , 22.444, 24.656, 27.678, and 33. 343 ppm. The off reaonance

appearance of the 33. 343 ppm peak waa a triplet and waa aaaigned to

Syntheaia of 5-( 1 -Cycloheptenylmethyl)uracll 111

H -O B u + 3 KOtBu

H H i Reaction and workup aa deacribed for HO precipitated 214. 5 mg

( 9 7^) of 111 . Thia material waa characterized by ita apectral and an alytical data in a fashion analogoua to 110 .

S/ntheaia of 5-( 1 - Cyclopentenylmethyl)uracil .11^

H -O B u + 3 KOtBu

112

Reaction and workup aa described for the prior homologues H O^ and ,1.11 afforded 112 in 86^ yield. Characterization followed straight forwardly from its spectral and analytical data. 107

Discussion

A wide variety of 5-substituted uracils are now available via thia

new synthetic route, Table 6 is a listing of the compounds already pre

pared. It is clear that a useful synthetic entry into a wide variety of

5-substituted uracils has been developed. The availability of 5-fluoro-

uridine and the mild conditions employed in the enol acetate fragmenta

tions suggests that this scheme is easily adaptable to preparing5 -sub

stituted uridines. Indeed, in a preliminary example, this has already

been realized.

Ha C ^ O A c HO OH

Mechanistic Considerations

Enol Acetate Cycloadducts

The enol acetate fragmentations, just as in Hunter's work, do not depend on the relative configuration of the fluorine and the acetate.

Thus, either configuration is capable of the orbital overlap required for ? 3NaOH 3NaOH cyNN-o

H - ^ H A c AcOr- b 108

Table 7. New 5-Substituted Uracils Synthesized by Employing 5-Fluorouracil as a Photochemical Synthon for the 5-Uracil Carbanion

Overall Yield fro m Starting 5-Fluorouracil 5 -F lu o ro uracil Olefin 5-Uracil (^ )

CH, Hs. N 22 H 3 CA.. OAc O ^ N

H If

% 47 O . OAc H H

29 Ac

75 A 109

Table 7 (continued)

Overall Yield fro m S tarting 5-Fluorouracil 5-Fluorouracil O lefin 5 -U ra c il (^ )

N 65

H . H

72 O H

X 78 H 110

the fragmentation to proceed. No doubt the reaction is facilitated by

relief of strain and the generation of aromatlcity, both of which serve

to overcome the high carbon-fluorine bond strength.

Q O

'Me

Cycloadducts of Simple Alkenes

To say the least, I was surprised by the course taken in the frag

mentation of the isobutylene adduct because if it proceeded as depicted

3 KOtBu CH H -O Bu

H a a.bove, an unactivated C-H bond would have been broken during the course of the reaction. To our knowledge this would be unprecedented.

We, therefore, considered alternative mechanistic possibilities. Ill

Mechanism I;

CH CH 108 CH

Mechanism II;

CH CH)

CH 108

Mechanism III:

CH CH CH CH)

108 112

Mechanistic Studies

Strong evidence against Mechanism II was obtained when the

tetramethylethylene cycloadduct 113 was found to undergo the

H ,C CH, CH, 3 KOtBu H -O B u

H H 113

fragmentation reaction. Mechanism III was also readily dismissed via

a deuterium labeling study. Photocycloaddition of isobutylene to

JL acetone JL ------CH, I CH, H H

5 -fluorouracil- 6 d^ gave the deuterated cycloadduct. PMR of this m aterial was identical to that of the protio compound with the exception that the H^^j resonance was completely erased. When this deuterated

Ha 3 KOtBu H -O B u CH, H cycloadduct was fragmented, 5-(2-methyl-2-propenyl)uracil-6d was obtained (m /e 167, NMR identical to that of the protio compound with the exception that H - 6 is erased).

At this point, therefore, the concerted Mechanism I is favored, where relief of strain and the gain of aromaticity may serve to facilitate 113

the fragmentation. The transition state is apparently one involving

extensive orbital overlap.

Experimental

General Procedures

Melting points were taken in open capillaries in a Thomas-Hoover

"Unimelt" apparatus and are corrected. Melting points greater than

2 6 0°C were taken on glass slides on a Nalge hot stage. Infrared spectra

were taken in the indicated phase on Perkin-Elm er Model 137 or 467

spectrophotometers. Nuclear magnetic resonance spectra were

recorded in the indicated solvent at 60 M H z on V a ria n H A - 100 and

Joelco M H -100 instruments; spectra are reported in ppm Ô units with reference to internal tetramethylsilane. FMR spectra were recorded on a Bruker Hx-90 at 84.7 MHz, and chemical shifts are reported in ppm upfield from internal benzotrifluoride. CMR spectra also taken on the Bruker Hx-90 at 22. 6 MHz are reported relative to TMS as an

Internal standard. Mass spectra were obtained with an AEI-MS9 spec trometer using an ionizing potential of 70 eV. All irradiations were carried out with Corex-filtered light from a 450-watt Hanovia medium- pressure source. VPC analyses were performed on a 14' x %" column of 5^ SE-30 on DMSO treated mesh Chromosorb G at 185°. Pre parative scale gas chromatography utilized either a 2 0 ' x %" column of

5^ S E-30 on DMSO trea ted ^ 0 mesh Chromosorb G (column A) at 220 °C 114

o r a 12’ X V4" column of 20^ Carbowax 20M on ^ 0 Chromosorb P at

220° (column B). Elemental analysis was performed by Scandinavian

Microanalytical Laboratory, Herlev, Denmark.

Photoadditions in Acetone-Water

General Procedure. The reaction vessel was immersed in an ice

isopropanol bath at -5°C and fitted with a dry ice condenser. Isobuty

lene was bubbled into the solution until a 10 ml increase in the volume

of the solution was noted.

Cycloaddition of Uracil, 1^, to Isobutylene. A solution of 200 ml

of acetone-water (4:1), 6 . 53 g (0. 116 mol) of isobutylene, and 0. 5 g

(4.46 mmol) of ^ was irradiated for 9 h, after which time UV analysis

at 2 6 0 nm indicated complete disappearance of uracil. VPC analysis of

the reaction mixture showed only one unresolved product formed in 9 2/È yield. Removal of the solvent afforded a white solid which was recrys tallized from hexane-ethyl acetate to afford a solid mixture of adducts which could not be separated by VPC. Thus, analysis was accomplished by méthylation of the reaction mixture followed by VPC analysis of the methylated adducts.

Méthylation of the Uracil Isobutylene Reaction Mixture. To 100 m g (0 . 5 9 mmol) of the above recrystallized mixture suspended in 2 ml of dry benzene was added 150 mg (3.12 mmol) of sodium hydride (50# emulsion in mineral oil). This was stirred until the evolution of 115

hydrogen ceased, then 0. 665 g (5. 27 mmol) of dimethyl sulfate was

added. The reaction mixture was stirred 4 h and quenched in water.

Workup afforded 153 mg of a yellow oil which showed two components by

VPC. Preparative VPC of this material showed the major component to

be ^ and the minor component to be ^ by comparison of the IR spectra

of the materials with authentic samples. The VPC yield of the methyla-

, tion reaction was 72^.

To determine the adduct ratio, the crude reaction mixture was

subjected to the méthylation procedure and the analysis performed by

VPC, giving a ratio of 7 5:25 for and 15. This ratio is in good agree

ment with that determined by NMR integration of the methyl resonances

in the crude unmethylated reaction mixture. Thus, the NMR (pyridine,

100 MHz) showed two methyl resonances of equal intensity at 0. 94 and

1.046 (assigned to the major adduct) and two methyl resonances of equal

intensity at 1 . 1 6 and 1 . 186 (assigned to the minor adduct) in the ratio

76:24.

Cycloaddition of Thymine, , to Isobutylene. A solution formed

fro m 150 m l of a c e to n e -w a te r (4; 1), 6 . 53 g (0. 12 mol) of isobutylene, and

400 mg (3. 17 mmol) of ^ was cooled to -7“C and irradiated for 8 h, after

which time UV analysis at 260 nm indicated the disappearance of starting material. Solvent removal in vacuo afforded 585 mg of white solid which by VPC analysis was a 72:27 mixture of photoadducts (92# VPC yield).

The major product was most readily obtained by fractional 116

recrystallization of the photolysis mixture from water. Thus, two care

ful recrystallizations afforded 101.5 mg (17.6^) of £: mp 240-241°; IR

(KBr) 5.82, 5.88, 7.25, 7.60, 7.96, 8.12, and 8 . 30p; NMR (CF 3CO2H,

100 MHz) 9.36 (br.s, IH), 7.46 (hr. s, IH), 3.72 (d, J = 4 Hz, IH),

2. 44 (center of AB, J = 14 Hz, IH), 2. 03 (center of AB, J= 14 Hz, IH),

1.62(s, 3H), 1.22 (s, 3H), and 1. 188 (s, 3H).

Anal, calcd. for C9H 14N 2O2: C, 59.31; H, 7.76; N, 15.37#.

Found; C, 59.01; H, 7.76; N, 15.10#.

The minor product, ^9 , was obtained by VPC separation of

the mother liquors and was recrystallized from ethyl acetate: mp 255-

256° C; IR (KBr) 5. 90, 7.78, 8 . 10, and 8.39p: NMR (CF 3CO2H, 100 M Hz)

9.47 (br. s, IH), 7.49 (br. s, IH), 3. 95 (m, IH), 2.36 (A of ABX, q of d, J = 8 Hz, J = 12 Hz, IH), 2.06 (B of ABX, q of d, J = 8 H z, J =

12 Hz, IH), 1 .4 9 (s, 3H), and 1.260 (s, 6H).

Cycloaddition of 6 - Me thy lu r a c il, to Isobutylene. A solution of

160 ml of acetone-water (4:1), 6 . 53 g (0. 116 m ol) of isobutylene, and 500 mg (3. 96 mmol) of jO^ was irradiated for 8 h after which time UV analysis indicated complete disappearance of starting material. Analysis of the crude reaction mixture by VPC revealed two products were produced in a ratio of 69:31 (VPC yield, 97#). The crude reaction was separated on column A. The major adduct, was recrystallized from ethyl acetate: m p 1 9 7- 1 9 8. 5°C; IR (KBr) 5.82, 5.89, 6.75, 6.89, 7.60, and 7.67p;

N M R (C F 3CO2H, 100 MHz) 9.50 (br. s, IH), 7.44 (br. s, IH), 3.32 (t. 117

J = 9 Hz, IH), 2.08-2.56 (m, 2H), 1.48 (s, 3H), and 1. 226 (s, 6 H).

Anal, calcd. for CgH^NgOg: C, 59.31; H, 7.76; N, 15.37#.

Found: C, 58.88; H, 7.85; N, 15.13#.

Establishment of Conditions for EpimerLzation and Attempted

Epimerization of Adducts 1^, lA, and 15. A solution of 15 mg (0.06

mmol) of ^ in G. 5 ml of pyridine containing 3# DMSO-d^ was trans-

, ferred to an NMR tube and its spectrum recorded. To this solution was

added 15 mg (0.4 mmol) of sodium arhide and after 5 min the NMR

spectrum rerun. This spectrum was identical to that of the cis-isomer,

21 . When this procedure was repeated for the mixtures of adducts

and and and no spectral changes were observed in the NMR.

Conversion of Adducts Jj6 and to Adducts ^ and 26.

Lithium diisopropyl amide was formed by addition of 0.7 5 ml (1. 5

mmol) of 2M butyllithium in hexane to 151.5 mg (1.5 mmol) of diiso

propyl amine in 1.5 ml of dry dioxane. To this solution was added 58. 8

mg (0. 3 mmol) of a mixture of jj 6 and 17^ and the mixture allowed to stir

for 5 min. Then 400 mg (3. 3 mmol) of dim ethyl sulfate was added and the

reaction stirred for 2 h. The reaction mixture was then quenched with

water and concentrated to yield an oil which was extracted with ether.

VPC analysis using bis[2-2(methoxyethoxy)-ethyl]ether as a standard

showed two components having retention times identical with ^ and .26

and present in 70# yield. Preparative VPC isolation of these two compo

nents (10' X SE-30 on ^/eo Chrom. G at 165*) and comparison of 118

their IR and NMR spectra with authentic ^ and ^ rigorously es tab -

* lished their structures.

Photoadditions of 5-Fluorouracil

General Procedure. The fluorouracil was dissolved in acetone with

stirring at reflux. The reaction vessel was fitted with a dry ice conden

ser and isobutylene was added till a 10 m l increase in volume was noted.

No external cooling of the reaction vessel was required.

Photocycloaddition of 5-Fluorouracil and Cyclopentenyl Acetate

74. To 390 mg (3 mmol) of 5-fluorouracil in 150 ml of acetone was V •F

added 3.78 g (30 mmol) of cyclopentenyl acetate. This stirred solution

was irradiated through Corex for 2 h, after which time TLC (10# CH3OH

in C H C I3) on silica gel showed no more starting material. Acetone was

removed in vacuo at 20 mm, and residual 74 was recovered at 0.4 mm with heating on a steam bath. The residue was taken up in hot methanol and filtered. The methanol was distilled off and replaced by ethyl ace tate, and 7^ was then precipitated by adding cyclohexane till the hot solution was saturated, the final volume being about 20 ml. Cooling 119

and filtration afforded 493 mg (64^) of 7^ as a white solid: mp 224-

226°C; IR (KBr) 3.05 m, 5. 8 s, 7.75, 8. 35, 8. 55, and 9- 50|i; NMR

(DMSO-d^, 100 MHz) 1.84 (br. s, unresolved and not integrable), 1.97

(s, 3H), 2. 92 (br. s, IH), 4. 10 (q, J = 20 Hz, J = 4 Hz, IH), 7. 84 (d,

Ji= 4 Hz. IH), and 10.68Ô (s, IH); FMR (DMSO-d^) 4 lines: 106.448,

1 0 6 . 4 9 8, 1 0 6. 6 6 6, and 1 0 6 . 7 3 3 ppm from benzotrifluoride, J = 5, 20 Hz.

Anal, calcd. for CnHuNgO^F: C, 51. 56; H, 5. 11; N, 10.93#.

Found: C, 51.44; H, 5. 12; N, 1 1 .0 1 # .

Photocycloaddition of 5-Fluorouracil 5^5 and Cyclohexenyl Acetate

70^. To 3 9 0 mg (3 mmol) of 5-fluorouracil in 150 ml of acetone was

Ac v r H

AcO '

55 70 ' 71 12 . added 4. 2 g (30 mmol) of cyclohexenyl acetate. This solution was irradiated through Corex for 2 h, after which time TLC on silica gel

(10# CH3OH in C HCI3) showed no further starting m aterial. Solvent was removed in vacuo and excess cyclohexenylacetate distilled at 55“ C and

1 mm. The residue was taken up in hot methanol and filtered. The methanol was removed and replaced with ethyl acetate, and finally cyclo hexane was added until precipitation ensued. The solution was cooled and filtered, affording 311 mg (38#) of T^: mp 26l-264“C; IR (KBr) 120

5.82 s, 7.20, 7.75, 7.85, 8.20, 8.50, 9.40, and 12. 22^; NMR

(DMSO-dô, 100 MHz) 1-2. 2 (br. absorbance with a sharp singlet ât O 1. 90 t-CHj), 4.4 (q, J = 19 Hz, J = 4 Hz, IH), 8.0 (d, J = 4 Hz, IH),

and 10.726 (s, IH); FMR (DMSO-d^) four Unes: 106.515, 106.573,

106.746, and 106. 804, J = 5 Hz, J = 19 Hz.

Anal, calcd. for CizHigNgO^F: C, 53.33; H, 5.60; N, 10.37#.

Found: C, 53.30; H, 5. 53; N, 10.14#.

Isolation of Minor Adduct, TLC of the crude reaction mixture

on silica gel (6# methanol in chloroform) followed by irradiation of the

plate at 2537^ in order to visualize the cycloadducts showed one major

spot R^ = .67 corresponding to 7J_, a minor spot R^ = .70 which corre

sponded to ^ , and a very faint spot at lower R^. Isolation oiTZ was

then accomplished by taking up the crude reaction mixture (after

removal of the excess cyclohexenylacetate) in methanol and absorbing it

onto 2 g of silica gel. Elution from an 80 x 2 cm silica gel column

slurry packed with ether-pet ether proceeded as follows: 425 ml

ether-pet ether, nil; 310 ml ether, nil; 200 ml ethei; 113 mg (14#)

as an orange oil which crystallized on addition of ether. The column

was then eluted with 10# methanol in chloroform, affording an additional

6 9 1 mg (85#) of white solid composed prim arily of TJ^. Cycloadduct 72

had: mp 188-190*C; IR (KBr) 5. 80 s , 6.85, 7. 15, 7.30, 8.05, 8.70,

8 . 9 5 , 9.80 (br. s), and 10. 30fx; NMR (DMSO-d^, 100 MHz) 1-2.2 (br. O absorption with a sharp singlet at 2. 04 —C-CHs), 4. 28 (q, J = 24 Hz, 121

J = 4 Hz, IH), 8.02 (d, J - 4 Hz, IH), and 10.906 (s, IH); FMR

(DMSO-dt) four lines 8.445, 8 . 6 8 8 , 80.716, and 80.990 ppm, J = È3 Hz,

J = 25. 5 Hz (internal standard benzotrifluoride).

Synthesis of 5-Cyclopentyl-2-oxo)uracil, To 408 mg (1,6

+ 3NaOH F "I AcO" 105

mmol) of 7_5 was added 4. 8 m l of 4N sodium hydroxide in CH 3OH. This

immediately dissolved with stirring, and after 2 min a white precipitate

formed. The reaction mixture was then refluxed for 10 min. The sol

vent was removed at RT in vacuo, and to the resultant orange glass

cooled in an ice bath was added 2.4 ml 2N hydrochloric acid with

stirring. The precipitate was filtered, affording 223 mg (73^) of

The m aterial which was faintly yellow was taken up in hot methanol and

decolorized with charcoal. Recrystallization afforded a white solid from toluene-methanol: mp 252-253® C w. decomp. ; UV (CH)OH)X^^ =

264 nm, 0 = 7700; IR (KBr) [(5.75, 6.0) (s) doublet], 6 . 9, 7 .0 , 7. 15,

7.85, 8.10, 12.4, and 12. 9|x; NMR (DMSO-dfi, 100 MHz) 1. 6-2.4 (br. m), 3.0 (m), and 7.286 (d, J = 5 Hz); CMR (DMSO-d&) 217.3, 163.6,

151.3, 140.0, 111.1, 4 7 . 9, 37. 5 (overlapped with DMSO-d^), 29.1, and

2 0 .7 ppm. 122

Anal, calcd. for C^HigNjOj: C, 55.66; H, 5. 19; N, 14.43^.

Found: C, 55.47; H, 5. 20; N, 14.41#.

Synthesis of 5-(Cyclohexenyl-2-oxo)uracil, Kl 6 . To 211 mg (.78

f 0 ^ - CH) OH 3NaOH

A cO - -

II 106 mmol) of cycloadduct, was added 2,4 ml of IN sodium hydroxide in

methanol (3 x equivalents of base). The cycloadduct immediately dis

solved and after 2 min of stirring a white solid precipitated. The

stirred solution was refluxed for 10 min, after which TLC analysis on

silica gel (6# methanol in chloroform) of a neutralized aliquot showed no

remaining starting material. The solvent was removed in vacuo and to

the ice-cooled residue was added 2.4 ml of IN hydrochloric acid. The

product was filtered and dried in vacuo, affording 124 mg of 106 (7 6#).

Re crystallization from methanol benzene gave white solid: mp 280-

283“C; UV (CH 3OH) X = 264 nm, e= 7700; IR (KBr) [(5.80, 5. 95)

(s) doublet], 6 . 9 0, 7.02, 7.16, 8.01, 8.15, 8.35, 8 . 91, and 11.60p (br);

NMR (DMSO-d^, 60 MHz) 1. 5-2. 5 [br. absorption with following charac

teristics; 1.8 (br. s, 2.32 (smaller br. s with overlapping with solvent and nonintegrable)], 3.2-3.7(b r. s), and 7. 126 (sharp s); CMR

(DMSO-d^) 208.2, 163.7,151.1, 138.6, 110.8, 47.6, 41.4 (overlapped 123

with DMSO-d^), 31.67, 26. 8 , and 24. 7 ppm from internal TMS.

A nal, calcd. fo r CioHigO^Nz: C, 57.68; H, 5 .8 1 ; N, 1 3 .4 6 # .

Found: C, 57.44; H, 5.95; N, 13.24#.

Demonstration that Fragmentation Proceeds without Regard to the Relative Stereochemistry of the Fluorine and Acetate

CH3OH ^ , + 3NaOH ^

O -C C H j 106

To 34 mg (.13 mmol) of 7_2 was added . 41 m l of sodium hydroxide in methanol. The reaction mixture was refluxed for 10 min and worked up as in the case of the anti-adduct. This afforded material whose R^ on TLC (silica gel 6 # CH3OH in C H C I3) and whose IR spectrum were identical with those of 1^06 from the cleavage of cycloadduct JJ..

Cycloaddition of 5-Fluorouracil, 55, and 5-Fluorouracil-6-d ,

55-6d. to Isobutylene. A solution of 390 mg (3 mmol) of 5-fluorouracil

F H ,D hv CH.

55, 55-6d 56, 56-Id 123

in 150 ml of acetone was fitted with a dry ice condensor, and isobuty

lene was bubbled into the solution till a 10 ml increase in volume was

observed. After 2 h of irradiation through Corex, TLC on silica gel

(10^ CH3OH-CHCI3) indicated complete disappearance of starting

material. VPC analysis on a 14' 5^ SE-30 on silyl treated Chrom. G

column at T = 190°C, showed a single major product. The acetone was

removed in vacuo and the resulting white solid recrystallized from

ethanol-water. With one recovery from the mother liquor, this afforded 500 mg (90^) of cycloadduct 56: mp 244-245° C; IR (KBr)

[3220, 3040 (m, doublet)], 1710, 1730 (s, wk res doublet), 1475, 1305,

1270, 1215, 1180, 1070, and 860 cm -‘ (w. br. singlet); NMR (DMSO-dg,

60 M H z) . 9 0 (s, 3H), 1. 18 (s, 3H), 2.0-2. 5 (m, 2H partially obscured by solvent), 3.79 (q, J = 23 Hz, J = 4 Hz, IH) collapses to a doublet

J = 23 Hz with added DgO, 8.0 (br. s, IH), and 10. 546 (s, IH); FMR

(DMSO-d^, benzotrifluoride int. std. ) eight lines 81. 65, 81.76, 81.85,

81. 9 2, 81. 97, 82.02, 82.13, and 82. 24 ppm from IS, with apparent J =

9 Hz, J = 17 Hz, J = 23 Hz.

Anal, calcd. for CaH^NzOzF: C, 51.61; H, 5. 9 6; N, 15.05#.

Found: C, 51. 63; H, 5.97; N, 14.89#.

The deuterated cycloadduct 56-ld was prepared similarly from 5- fluorouracil-6 -d and had: mp 247-248® C; NMR (DMSO-d^, 60 MHz) .90

(s, 3H), l.l9 (s , 3H), 1.7-2.3 (m, 2H), and 7.976 (s, IH). 124

Synthesis of 5-Fluorouracil~6-d, 55-6d. To 12 ml of . 5 N

Q Hs

cXX ^

sodium douterohydroxide (138 mg, 6 mmol, of sodium in 12 ml of

deuterium oxide) stirred under nitrogen was added 390 mg (3 mmol) of

5 -fluorouracil. This solution was stirred at 60“ C for 4 h. The solution

was then cooled in an ice bath and acidified (pH~3, red to hydrlon paper)

by dropwise addition of concentrated hydrochloric acid. The precipita

ted white solid was collected by suction filtration and washed with ice

cold deionized water, affording 262 mg (6 6^) of .55-6d. Analysis for

percentage of deuterium incorporation was accomplished by NMR (in

DMSO-d^) against 1, 3, 6 -trimethyluracil as an internal standard. No

observable 6 -H was present and on this basis the product was analyzed

as greater than 95^ isotopically pure.

Photocyloaddition of 5-Fluorouracil 55 and Methylene Cyclohexane

57. To a solution of 390 mg (3 mmol) of 5-fluorouracil in 150 ml of acetone was added 4. 32 g (45 mmol) of methylene cyclohexane. After

F hV D : y •

55 57 60 125

2 h of irradiation through Corex, VPC analysis at T = 205°C showed a

single major product. The solvent was removed in vacuo and the

resulting white solid recrystallized from ethyl acetate. With one

recovery from the mother liquor, 448 mg (72^) of cycloadduct ^ was

obtained: mp 263-265°C; IR (KBr) [3220, 3080 (m, doublet)], 2920.

[1730, 1720 (s, poorly resolved d)], 1485, 1450, 1385, 1332, 1310,

1280, 1192, 1060, and 860 cm-i (w. bal s); NMR (DMSO-d^, 60 MHz)

1.0-1. 7 (br, m, lOH), 1.9-2. 4 (br. m partially obscured by solvent,

2H), 3.72 (q, J = 4 Hz, J = 23 Hz, IH), 8.02 (d, J = 4Hz, IH), and

10.486 (s, IH); *^FMR (DMSO-d^, benzotrifluoride internal standard)

eight lines 81.45, 81.54, 81.68, 81.71, 81.77, 81.80, 81.94, and

82.05 ppm from int. std. apparent J = 7. 5 Hz, J = 20 Hz, J = 22 Hz.

AnaL calcd. for CnHigNzOzF: C, 58. 38; H, 6.70; N, 12.38#.

Found: C, 58. 23; H, 6 . 69; N, 12.22#.

Photocycloaddition of Methylene Cycloheptane 59. and 5-Fluoro- uracil 55. To a solution of 520 mg (4 mmol) of 5-fluorouracil in 150 ml acetone was added 5. 28 g (48 mmol) methylene cycloheptane. After

55 59 62 126

2.25 h irradiation through Corex, TLC analysis indicated no starting

m aterial and the presence of a single product. Solvent was removed in

vacuo, and finally, excess olefin was recovered by distillation at 0 . 2

mm on a steam bath with the receiver cooled in dry ice-isopropanol.

The residual white solid was recrystallized from ethyl acetate, and with

one recovery from the mother liquor, afforded 7 52 mg (78^) of 6J,: mp

259-260° C; IR (KBr) [3220, 3080 (m doublet)], 2920, [1730, 1710 (s,

poorly resolved doublet)], 1390, 1290, and 870 cm"‘ (w. br. s); NMR

(DMSO-dg, 60 MHz) 1.50 (br. s, 12H), 1.82-2.4 (m, partially obscured

by solvent, 2H), 3.78 (q, J = 4 Hz, J = 23 Hz, IH), 8.02 (s, IH), and

10.46 (s, IH).

Anal, calcd. for CigH^NzOzE: C, 59. 99; H, 7. 13; N, 11.66#.

Found: C, 59. 93; H, 7. 12; N, 1 1 .7 0 # .

Synthesis of Methylene Cycloheptane 59. In a 1-liter three-neck

flask fitted with a mechanical stirrer was added 300 ml of anhydrous

ether. The flask was fitted with a condensor and maintained under a dry nitrogen atmosphere. There was then added via syringe 55 ml

(0. 1 mol) of 1.8 M methyllithium in ether, and this solution was allowed to stir for 5 min. While maintaining a positive pressure of nitrogen,

35.7 g (0.1 mol) of methyl triphenyl phosphonium bromide’^ was added. 127

The reaction mixture turned a deep yellow orange and was stirred for

1. 5 h, after which time the evolution of methane ceased. Then 12. 3 g

(0 . 1 mol) of cycloheptanone was added dropwise with stirring and the

reaction stirred at RT for 5. 5 h and finally re fluxed for 1 h. The flask was cooled in an ice bath and the precipitated triphenyIphosphine oxide removed by suction filtration. The cake was washed with ether (100 ml).

The combined ether filtrates were washed with water (3 x 100 ml) until neutral to pH paper and dried over calcium chloride. The solution was concentrated by carefully distilling off the ether through a 24 x 1.5 cm column packed with glass beads. The residue was distilled through a

6 5 x 0 .9 cm spinning band column, the product distilling at 135-137 ®C, affording 5. 5 g (50^) of methylene cycloheptane pure by VPC. The reaction and the distillation were monitored by VPC on a 5’ x

Porapak Q column at 200 “C. The NMR (60 MHz) of the product exhibi ted the following resonances in CDCI3: 4.65 (br. s, 2H), 2.26 (br. s,

4H ), and 1. 556 (b r. s, 8 H).

Photocycloaddition of Methylene Cyclopentane ^ 8 and 5-Fluoroura- cil 55. To 3 9 0 mg (3 mmol) of 5-fluorouracil in 150 ml of acetone was

55 58 61 128

added 4 ml of methylene cy clo p en tan e.A fter 2 h of irradiation

through Corex, a single product spot was visible by TLC. VPC

analysis at T = 20 5“C also revealed one major product. Solvent was

removed in vacuo and the resultant white solid recrystallized from

ethyl acetate, affording 470 mg (?6^) of mp 265-266°C (sealed

capillary); IR (KBr) [32.40, 30.80 (m doublet)], 1700 (s, br. singlet),

1315, 1300, 1265, 12ü0, and 880 cm“^ (w. br. singlet); NMR (DMSO-d^,

60 MHz) 1. 55 (br. m, 8 H), 2-2. 5 (m partially obscured by solvent),

3.95(d, J = 21 Hz, IH), 8.02 (s, IH), and 10.446 (s, IH).

Anal, calcd. for CioHi^NzCgF: C, 56. 59; H, 6.17; N, 13.20#.

Found: C, 56. 6 6; H, 6 . 19; N, 1 3 .1 6 # .

Synthesis of 5-(2-Methyl-2-propenyl)uracil, 10 8 , and 5-(2-Methyl-

2-propenyl)uracil-6d, lp 8 _-6 d. To 235 mg of potassium (6 m m ol)

+ SKOtBu

o ^ n \, d '

l l 56-ld 108, l08-6d dissolved in 20 m l of tert butyl alcohol was added 372 mg (2 mmol) of cycloadduct The stirred solution was brought to reflux (bath tem perature 130“C) for 0. 5 h. After a 10-min reflux, the solution turned milky. The reaction was conveniently followed by diluting aliquots into IN sodium hydroxide and observing the appearance of a UV 129

absorption maximum at X = 286 nm. After 0. 5 h no further in- ^ m ax crease was noted. The solvent was removed in vacuo (0. 3 mm), and

the resultant glass taken up in 5 ml of water. The solution was cooled

in an ice bath and acidified till pH-3 (red to hydrion paper) by dropwise

addition of concentrated hydrochloric acid. The precipitate was filtered

and dried in vacuo, affording 277 mg (83^) of 108 . TLC showed one

major intensely fluorescence quenching spot. Analytically pure 108

from ethanol-water had: m/e parent 166; mp 272-274°C; UV (CH 3 OH)

X = 2 6 5 nm, e = 7 2 0 0 , in NaOH X = 286 nm, g= 6500; IR (KBr) m ax m ax » \ /

[ 3 180, 3040 (m doublet)], [1740, 1660 (s, well resolved doublet)], 1450,

1242, 1205, 900, 840 (br. singlet), 765, 585, 550, 463, and 440 cm“‘;

NMR (CMSO-dt, 60 MHz) 1.67 (s, 3H), 2.87 (br. s, 2H), 4.67 (br. s,

2H), and 7. 136 (s, IH); CMR eight lines 22.067 (q), 33.343 (t),

109.741 (s). 111. 198 (t), 138.768 (d), 143.355 (s), 151.286 (s), and

164. 181 (s).

A nal, calcd. fo r CaHioNzO^; C, 5 7 .8 2 ; H, 6 .0 7 ; N, 1 6 .8 6 # .

Found: C, 57.47; H, 6. 18; N, 16.57#.

The deuterated uracil, 108-6d, prepared analogously from 56-ld had mp > 270°C w. decomp, m/e parent 167; UV (CH3OH); X = 265 nm, e = 6 9OO; IR (KBr) [3200, 3020 (m doublet)], [1745, 1665 (s doublet)], 1450, 1217, 910, 840, 586, 552, 465, and 440 cm”*; NMR 1 (D M S O -d 6, 60 M H z) 167 (s, 3H), 2 .8 7 (b r. a, 2H), and 4.676 (br. s,

2H). 130

Synthesis of 5-(Cyclohexenylmethyl)uracil, j^lO. To a solution of

118 mg of potassium (3 mmol) in 10 m l of tert butyl alcohol was added

HOtBu 3KOtBu

226 mg (1 mmol) of cycloadduct The material dissolved, and after

5 min of stirring at RT, a white solid separated. The mixture was then

heated to reflux, pot temperature 130°C. The solid redissolved, and

after 10 min at reflux the solution turned milky. Again the reaction

was followed by UV as described previously. After refluxing for 35

min, no further increase at \ = 286 was observed and the reaction was

worked up. The solvent was removed in vacuo (0. 3 mm) and the

resultant glass taken up in 5 ml water. The solution was cooled in an

ice bath and acidified by dropwise addition of concentrated hydrochloric acid till pH-3 (red to hydrion paper). The precipitated solid was filtered and washed with water to afford 2 0 6 mg (quantitative) of 110 homogeneous by TLC (10# methanol in chloroform) on silica gel.

Analytically pure material from ethanol-water had; mp 277 -279“C;

UV (CH,OH) \ = 266, e = 6000, (IN NaOH) \ = 287, € = 6300; ■* ' max ' ' max IR (KBr) (3200, 3050 (m doublet)], 2920, [1720, 1665 (s. well resolved doublet)], 1450, 1400, 1245, 1205, and 860 cm"' (w. bal. singlet); NMR

(DMSO-dfi, 60 MHz) 1. 50 (br. m, 4H), 1.85 (br. m, 4H), 2.7 (br. s. 131

2H), 5.38 (br. s, IH), and 7.056 (d, J = 5 Hz); CMR (DMSO-d&)

eleven lines ppm from TMS; 21.905, 22.444, 24.656, 27.678,

33.343 (t), 110.011 (s), 121.827 (d), 135.315 (s), 138.337 (d),

151.286 (s), and 164.343 (s).

Anal, calcd. for CnHi^NgOg: C, 64.06; H, 6.84; N, 13.58#.

Found: G, 63.80; H, 7.02; N, 13.10#.

Synthesis of 5~(C ycloheptenylm ethyl)uracil, H_l_. To 118 mg

(3 mmol) of potassium dissolved in 10 ml of tert butyl alcohol was added

+ 3KOtBu HOBu^

62 111

240 mg (1 mmol) of cycloadduct 62. Reaction and workup as previously described precipitated 214. 5 mg (9^#) of 111 homogeneous by TLC.

Analytically pure material from ethanol-water had: mp 282-283®C w. decompl UV (CH3OH) = 266, e= 7 500; IR (KBr) [3180, 3060 (m doublet)], 2 9 1 0, [1715, 1660 (s. well resolved doublet)], 1450, 1240, and 860 cm"‘; NMR (DMSO-d&) 1. 5 (br. m, 6H), 2.01 (br. m, 4H), 2.75

(b r. s, 2H), 5. 54 (t, J = 6 Hz, IH), and 7.066 (s, IH).

Anal, calcd. for CigHi^NgOz: C, 65.43; H, 7.32; N, 12.72#.

Found; C, 65.22; H, 7. 25; N, 12.78#. 132

Synthesis of 5-(C yclopentenylm ethyl)uracilTo 118 mg (3

mmol) of potassium in 10 ml of tert butyl alcohol was added 2 1 2 mg (1

HOtBu

61 IIZ

mmol) of cycloadduct 6^. With stirring, ^ went into solution almost

immediately, and after 2 min a white precipitate formed. The reaction

mixture was then refluxed at a bath temperature of 130°C. Initially the

precipitated material went back into solution, and after 5 min the solu

tion became cloudy. After 15 min the reaction stopped and was worked

up as described. This precipitated 165 mg (8 6 ^) of analytically

pure from ethanol-water: mp 265-267°C w. decomp; UV (CH3OH) \

= 266, e = 7300; IR (KBr) [3180, 3040 (m doublet)], [1720, 1665 (s, well

resolved doublet)], 1450, 1420, 1400, 1240, 1210, and 8 6 O cm“* (br. w.

singlet); NMR (DMSO-d^, 60 MHz) 1. 4-2.4 (br. unstructured mult, 6H),

2.95(br. s, 2H), 5.29(br. s, IH), and 7. 136 (s, IH).

Exact mass calcd. for C1ÛH12N2O2: 192.08985

Obs; 1 9 2 . 0 9 0 0 9

Photocycloaddition of 5-Fluorouracil 5^ and Tetramethylethylene

115. To 520 mg (4 mmol) of 5-fluorouracil dissolved in 150 ml acetone was added 4 g (48 mmol) of tetramethylethylene. Irradiation through

Corex for 2. 25 h afforded a single product by TLC. The solvent was 133

k H 55 115 113

removed in vacuo and recrystallization from ethanol-water afforded 6 7 8 mg (7 9?^) of 113. The analytical m aterial recrystallized from ethyl ace tate, then ethanol-water, had: mp 267-268®C; IR (KBr) [3250, 3070 (m, doublet)], 1720 (s, br. singlet), 1300, 1195, 1130, 1060, and 870 cm"‘ w. br. singlet; NMR (DMSO-d^, 60 MHz) .82 (a, 3H), .94 (s, 3H), 1.03

(a, 3H), 1. 13 (d, J = 3 Hz, 3H), 3.70 (q, J = 23 Hz, J = 3. 5 Hz, IH),

7.9 (br. a, IH), and 10.46 (s, IH); ‘^FMR (DMSO-d^) two lines:

94. 247 and 94. 522 ppm from benzotrifluoride J = 23 Hz. At high reso lution the two lines are further split J = 3 Hz.

Anal, calcd. for CioHigNzOzF.- C, 56.06; H, 7.05; N, 13.08$.

Found: C, 56. 24; H, 7.08; N, 13.02$.

Synthesis of 2, 3-Dimethyl-3-(5-uracilyl)butene, 114. To 236 mg

(6 mmol) of potassium dissolved in 35 m l of tert butyl alcohol was added

428 mg (2 mmol) of cycloadduct 113. This m aterial appeared less

3KOtBu H -O B u I I

H 113 114 134

soluble under the reaction conditions and the heterogeneous mixture had

to be refluxed for 18 h at a bath temperature of 130 ®C. Occassionally,

the waxy solid was broken up with a glass rod. The standard workup

precipitated 387 mg (99^) of 1 lj4 homogeneous by TLC. Note, here 10/è

methanol in methylenechloride on silica gel separated starting material

and product: mp > 270“ w. decomp; UV (CH3OH) X = 260 nm, e =

6 6OO; IR (KBr) [1700, l660(s, well resolved doublet)], 1440, 1240, 1080w,

880, 6 9 0, 660, 560, and 540 cm”*; NMR (DMSO-d^, 60 MHz) 1.3 (s, 6H),

1.6 (s, 3H), 4.73 (s, 2H), and 7.036 (s, IH).

Exact mass calcdl for C^Q Hi^^NgOg: 194. 10550;

Obs: 1 9 4. 10578.

Cycloaddition of 5-Fluorouracil and 1-Methylcyclopentene

CH, H H,C

55 64 68 69

To 390 mg (3 mmol) of 5-fluorouracil dissolved in 150 ml of acetone was

added 3.7 g (45 mmol) of methyl cyclopentene. After 2 h of irradiation

through Corex, no starting material remained by TLC. VPC analysis at

210“C showed two major product peaks. *^FMR of the crude reaction mixture showed two major absorptions in the ratio 34:7, comprising 91^ 135

of total fluorine along with several lesser absorptions. Solvent was

removed in vacuo and the resulting white solid subjected to two frac tional re crystallizations from ethyl acetate, affording 221 mg (35^) of

as white needles: mp 232-234“C; IR (KBr) [3220, 3080 (doublet)],

1710 (s. br. singlet), 1390, 1375, 1300, 1282, 1250, 1220, 1160, 1080,

1048, 860, 790, and 440 cm”‘; NMR (DMSO-d^, 60 MHz) 1.02 (s, 3H),

1.4-2.0 (br. unstructured mult, 6H), 3.66 (q, J = 4 Hz, J = 22 Hz),

7.80 (s, IH), and 10.506 (s, IH); ‘’FMR (DMSO-dfi, benzotrifluoride) four lines: 100.715, 100.773, 100.97 5, and 101. 033 ppm from IS J =

5 H z, J = 22 H z.

Anal, calcd. for C10H 13N 2O2F: C, 56.60; H, 6 . 17; N, 1 3 .1 9 # .

Found; C, 56.46; H, 6 . 26; N, 13.14#.

Cycloadduct ^ was not isolated but its structure tentatively assigned from ‘’FMR (DMSO-d^) four lines: 80.394, 80,654, 80.726, and 80. 985 ppm from IS J = 22 Hz, J = 28 Hz.

Cycloaddition of 4-Fluorouracil and Propylene 63. To 390 mg (3

hv HI CH,

63 65 66

67 136

mmol) of 5-fluorouracil in 150 ml of acetone at -5®C (ice-isopropanol

bath) was added a steady stream of propylene. Propylene was allowed

to bubble steadily into the solution throughout the course of the reaction.

After 2 h, the irradiation was complete, the solvent was removed in

vacuo, and the residual white solid recrystallized from ethyl acetate-

cyclohexane. This afforded 480 mg of white solid which was then sub

limed at 150°C (0. 1 mm), affording 390 mg (75^) of a cycloadduct mix

ture. VPC analysis at T = 180“C showed two major but not completely

resolved peaks. Preparative TLC on silica gel with 20^ diethylamine

in petroleum ether as solvent, after two passes, resolved two bands.

The top band, corresponding to the shorter retention time peak on VPC,

afforded 140 mg (27^) of A sublimed sample of this material had:

mp 239-241 “C (sealed capillary); IR (KBr) [3240, 3080 (m doublet)],

[1730, 1710 (s, poorly resolved doublet)], 1490, 1395, 1300, 1215, and

1052 cm -‘; NMR (DMSO-d&, 60 MHz) 1.1 (d, J = 6 H z, 3H), 1. 5-2. 5 (b r. unstructured mult), 3.61 (d, 2 br. peaks, J = 20 Hz, IH; with added

DjO appeared as a quartet J = 7 Hz, J = 20 Hz), and 8.096 (br. s, IH);

*^FMR five lines 82. 234, 82.280, 82.501, 82.652, and 82. 699 ppni from internal standard.

Anal, calcd. for C^H^NjO^F: C, 48. 84; H, 5.27; N. 16.27#.

Found: C, 48. 93; H, 5. 36; N, 16.27#.

The bottom band afforded 228 mg (44#) which, while corresponding to a single VPC peak (longer retention time), was shown by PMR, FMR, 137

and CMR to be a two-component mixture. Thus, the PMR (DMSO-d^)

showed two methyl doublets in a 2:1 ratio, the larger doublet at .9 2 6

J = 7 Hz, and the smaller at 1. 166 J = 7 Hz. *^FMR showed two

multiplets, one centered at 82 ppm, the other at 97 ppm from internal

benzotrifluoride at a ratio of approximately 2. 3:1. CMR showed a

sharp singlet at 13. 542 ppm and a doublet at 13. 866 and 14. 135 ppm

from TMS (J = 6 . 1 Hz). The singlet would be consistent with the other

head-to-tail epimer while the doublet was consistent with a head-to-

head isomer 67 where ^ J = 6.1 Hz. OJ? At this point a discussion of the FMR spectrum of the crude

reaction mixture is justified. The crude mixture showed three multi

plets in the following ratios, centered at 82 ppm, 97 ppm, and 118 ppm:

7 6 : 18 :8 , respectively, the multiplet at 82 ppm arising from the coinci

dent absorptions of ^ and 6 6, the multiplet at 97 ppm arising fro m ^ ,

and the one at 118 also assigned to a head-to-head epimer. On this

basis, the relative regioselectivity is assigned;

II . Ti 'Tf ”’

H H 76 : 24

Cycloaddition of 5-Fluorouracil and 2-M ethyl-2-butene 116. This crude reaction mixture was analyzed quite readily by ‘^FMR, and two separate integrations afforded almost identical results for product 138

it 116

120

ratios. Thus, 390 mg (3 mmol) of 5-fluorouracil in 150 ml of acétone

with 3. 15 g (45 mmol) of 2 -me thy 1 - 2 - bute ne was irradiated 2 h through

Corex. The solvent was removed in vacuo and *^FMR spectra recorded

in DMSO-d^, and 20^ acetone-d^ in pyridine. In DMSO-d^ four multi

plets appeared at t: 78. 125, 78.371, and 78. 635 ppm; doublet 94.355

and 94.637; doublet 97. 239 and 97. 450; q; 103.042, 103. 130, 103.323,

and 103.411; in the ratio 20:10:5:65, respectively. The triplet centered

at 78. 371 ppm arose from two J's = 23 Hz and was assigned to ^ & The

doublets at 94 and 97 ppm were assigned to the head-to-head oriented

cycloadducts 119 and 1^20, and the quartet centered at 103. 2 ppm J =

7. 4 Hz, J = 23.8 Hz was assigned to ,H7..

On this basis, the relative regioselectivity is assigned 85/i5, head-to-tail/kead-to-head. A P P E N D IX A

*’FMR, ‘^CMR, and PMR SPECTRA

139 «900 4000 3000 Mi tm •m 1000 3000 1000 iM tm tsoe 1000 300

i i I I I ...

Spectrum 1; '^FMR Spectrum of the 5-Fluorouracil Cyclohexenyl Acetate, 70, Reaction Mixture. H m f 9

S pectrum 2 : ^’FMR Spectrum of the Major Cydoadduct, from the fro m the Photocycloaddition of 5-Fluor our ac il and Cyclohexenyl Acetate. I

spectrum 3; ^^FMR Spectrum of the Minor Cydoadduct, 72, from the Photocycloaddition of 5-Fluorouracil and Cyclohexenyl Acetate. M CHg

«I

Spectrum 4: ^^FMR Spectrum of the 5-Fluorouracil 55 Isobutylene' 7 , Reaction Mixture Showing the Presence of only One Product, 56, Inset is a tiowup of the Multiplet of 56. w 1000 BOO 330 ZOO 100.

Spectrum 5; PMR Spectrum of the 5-Fluorouracil Isobutylene Cydoadduct 56. The upper trace shows the collapse of the vicinal N-H coupling to on addition of DgO. I»» IflOO MO 400 MO <00 100 0 CM *80

Spectrum 6 : PMR Spectrum of the 5-Fluorouracil Methylene Cyclohexane Cydoadduct 60. * ta se WM(T: ee 10

.too

#a ?a ## 00 Spectrum 7: PMR Spectrum of 5-(2-Methyl Isopropenyl)Uracü 108.

o •fe SM

\jY'W A&;(4VW f^

Spectrum 8 : Upper trace is the "CMR Spectrum of 5-(2-Methyl Isopropenyl)Uracil. 10l§ Lower Trace is the Off Resonance Decoupled ^^CMR Spectrum. 1000 KO too 100 340

Spectrum 9: PMR Spectrum of 5-(Cyclohexenyl Methyl) Uracil 110.

00 A P P E N D IX B

MOLECULAR ORBITAL CALCULATIONS

149 150

Compounds Calculated and Numbering System Used

Fa II. ac ro lein alpha-fluoro acrolein

F 3

H u ra c il 5-flucrouracU

oxaenone

Huckel Theory

H u - ES^ I H u -E S u • " H in -E S in

Hzi .E S u Hzz - ES22 • • H 2H “ES2n

Hm -ESni Hnz -ES „2 • Hfin -ESnn w here Hii = j ViH't’idT a for carbon P for carbon

Si. = ]y.*dT 1

Si2 = j^YiYzdT 0 151 for heteroatoms, H ii = a + hP

Hi 2 — kp

All of the values of h and k employed are evident in the diagram fo r 5 -fluorouracil shown below: h = l k = l

N k=1

t e ?8 N h= 1. 5 k= . 8

In two calculations on 5-fluorouracil an auxilliary inductive para meter (AIP) was used to increase the effective electronegativity of the carbon bonded to fluorine^®

hC(j^ ^ ^ w here 6 ’s of 0. 0, 0.1, and 0. 33 wore employed.

Input

The actual input is the m atrix of h and k values, shown here for

5-fluorouracil.

1 2 3 4 5 6 7 8 9

1 1 .0 1 .0 0 . 0 0 . 0 0 . 0 0 . 0 0 .0 0 . 0 0 . 0

2 0 . 0 1 .0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 8

3 0 . 0 0 .7 1.0 0 . 0 0 .0 0 . 0 0 . 0 4 3 .0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 5 0 . 0 0 . 8 0 . 0 0 . 0 0 . 0

6 1. 5 0 . 8 0 . 0 0 . 0 7 0 . 0 1 .0 0 . 8

8 1 .0 0 . 0 9 1 .5 152

Output

The output consists of:

T itle Description

A -M a tr ix The input m atrix of h and k values.

V -M a tr ix The eigenvector matrix, i. e ., orbital coefficients. Orbital I corresponds to energy 1, the orbital of greatest energy.

Energy 1-n Orbital energies, with orbital energies decreasing 1—>n

P -M a tr ix M atrix of bond orders.

Free valences,

Superdelocalizabilities

Results

Uncoupled Spin Density, S., in the Excited States of Uracil and 5-Fluorouracil

S. = C.‘ + 0 / I i (HOMO) i (LUMO) U ra c il:

LUMO-Ya, E = -. 589P

HOMO-Y 4, E = .799P

53 - 1(. 205)2 + 1(. 608)2 = .412 412

54 - I(. 662)2 4. 386)2 _ ^ 587 153

5-Fluorouracilî K Jl^F.039 N ^ . 2 0 1 LUMO-Y), E = 595p 648 à

HOMO-Y 4, E = .720P

429

= 1(.039)^ + !(-. 182)* = .034 H

Sc3 = !(-. 201)* + 1(. 5 9 2 )* = . 390

= 1(.64B)* + 1(.425)* = .6 0 1

TT-Charges, q,

Uracil-ground state

jth . q. = 1-S nC *.. i = 1^^ atom 1 -U j = j molecular orbital ^ r ° c c

J 2 0 93 = 1 lJŒ4 i t

q, = 1 - 2[(.215)* + (. 119)^ + (.357)* + (.019)' + (.608)*]

qj = -.1 1 4

q4 = 1 - 2[(. 227)* + (-. 186)* + (-. 376)* + (. 068)* + (. 386)*]

q4 = + .2 3 6 154

Uracil-excited state

q. = 1- [S 2C^. , + S C^j^g] d = doubly occupied ^ yd ^ Vs 8 = singly occupied

8 4 q^3 = 1 - [^ 2C^d

qc3 = 1 - [2[(. 215)2 + (. 119)^ +(.357)2 +(.019)^] + (. 608)2 + (.2 0 5)2]

qc3 = +.214

qc4« 1 - [2[(. 227)2 + (. 186)2 + (.375)2 + (.068)2] + (.386)* + (. 205)2]

9c4 = -.053

5-Fluorouracil-ground state

9 qc3 = 1 -jS 2C23j

qc3 = l-2 [(.276)2 + (. 136)2 + (.087)2 + (.298)2 + (.016)2 + (.592)2]

9c3 = - . 082

qc5 = 1 -2[(. 103)2 + (. 200)2 + (. 202)2 + (. 353)2 + (. 069)^ + (.425)2]

qc5 = + .1 9 4

5-Fluorouracil-excited state

9c3 = 1 - 4 ^ ^*3 9] d=5 S-3 qc3 = 1 - [2[(. 276)2 + (. 136)2 + (.087)2+ (.298)2 + (.016)2] + (. 592)2 + (. 2 0 1 )2]

qc3 = . 228

qc5 = 1 - [2[(. 103)2 +(.200)2 + (. 202)2 +(. 353)2 + (.069)^]+(.425)2 + (.6 4 9 )']

qc5 = -.046 V n DIAGCNALIZATION,REVISED, . CIS 10

~ i------iMsED'FORM‘’P ’ OCPE"tO^BY^B^klGlLSON'*ND J.Ë;SLOORr------:— C lÈ ' 40 C REVISED FOR IBM 1620I40KJ. CIS 50 Ç PROGRAM TO CALCULATE HUCKEL ORBITALS, ENERGIES, BOND ORDERS, CIS 60 \ KoiSûîFcsrajiîîj v a C «...CIS 40 C INPUT IS AS FOLLOWS CIS 100 2l“"THEN^THE''HATR^X^ÔF^HÂNB°K^VA?6iP l§ 'T h F EQUATION E)s " îlo C ALPHA!II = HAALPHA(C), BETA!I,J) = K*BETAiC-C>. CIS 130 C INPUT,!S IN FORMAT 2 1 3 ,P14.6 ,2 1 3 . THE LAST 2 FIELDS MARK THE CIS 140 E - HgÂE"2%awiN^^Sg6'G!îN&%AE&l2;uSg'"AAf$:]i'Et!l^^^^ Ell C 3 . GIVES ATOM INDEX OF EQUAL MATRIX ELEMENTS. ÇIS 170 C 4 . A CARD I N , 13 GIVING THE NUMBER OF OCCUPIED SPIN ORBITALS. CIS IBO

Ç 6. CARD IN II TO INDICATE NEW PROBLEM, I«YES, 2«N0. CIS 220 - g . ...c|s 230 1 ÔÎMÊNSÎÔN'Â(25^25KvÎ25;25);ir25>ÎFVÎ25»ÎÎÂ(25Î;ÎBf25>ÎÎCÎ(24r***CIS I» 2 22 READ 15,1) 3 WRITE 16,17) WRITE 1 6 ,1 ) ------

I--30- 2?i!3)^s!&» Hg B N=0 CIS 330 9 31 RFAO 15.2) I,J,AR,K,L . 11— ------1 \ \ - w t 13 32 READ 15,3) IICT!IMP),1HP>1,24) i# î^rIIl^VÎ HI I t î

I I I t m tig -19 ------HN*ICT(IRR) (IS 440 I? ' m t i î

______i l l

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SENTRY

ICROLEI' a-HAlRlX 1 1.00000000 I 2 1,00000000 1 3 0.00000000 1 4 0 .0 0 0 0 0 0 0 0 ? 1 .0 0 0 0 0 0 0 0 2 2 0 .0 0 0 0 0 0 0 0 2 3 1 .00000000 2 4 o.oooonono 3 0.00000000 3 ? 1.00000000 3 3 0.00000000 3 4 1 .0 0 0 0 0 0 0 0 4 0,00000000 4 2 0,00000000 4 3 1.00000000 4 4 0 ,0 0 0 0 0 0 0 0

V-NATRIX

-0.65653060 0,42052570 I I -S:S|E?liSS J I . I | -0,22801210 0 ,6565 3780 0,5773 4870 i i 0 ,57734940 I I - i l î î l l V â î I I I I 0,42852620 4 4 0.22801450

NERGY

1 -1.53207500 2 -0,34729530 3 0,99990flio 4 1.07934900 p-MATRIX

1 1 1,52875000 1 2 0,75810450 1 3 -0.10398010 1 4 -0,36726760 2 1 0.75810450 2 2 0,66666610 2 0 ,49481760 2 4 0 ,26328670 3 1 -0.10398010 3 2 0,49481760 3 1 1,03393100 3 4 0 ,86208430 4 1 -0.36726760 4 2 0.26326670 4 3 0.86208430 4 0 .77064600

Ln o FREF VALFNCFS 0.97394630 J 0.47912770 3 0.375147B0 4 0.86996550

SUPERDELOCALIZA81L 1TIE 5

ELECToQPHILIC FREE-RADICAL NUCLEOPHILIC 1 1.12537700 1.12537600 1.12537500 0.35472B30 1.35472900 7,35473700 I 0.R62085R0 0.86708690 0.PA2087P0 4 0.72199330 1.72199500 7.77199600

**AL^A. FLUORO ACROl^lN*

a -MATRIX

1 1 1 .ononnooo 1 2 I.00000000 1 3 0.00000000 1 4 0.0000 0000 1 5 o.ooonnopn 2 1.00000000 2 2 0.00000000 ? 3 iCoooooooo 2 4 o .ooon npoo 2 \ 0.00000000 ■a 1 0.00000000 3 7 1.00000000 3. 3 0.00000000 3 4 0.69999090 3 5 1 .0 0 0 0 0 0 0 0 4 0.00000000 4 2 0.00000000 4 3 0.69999990 4 4 3.00000000 4 I 0.00000000 5 0.00000000 5 2 0.00000000 5 3 1.00000000 5 4 0.00000000 5 I 0.00000000

V -MATRIX

1 -0.217^5260 1 2 0*56140360 1 3 -0.66900050 1 4 0.1027 6290 Î 5 0.42^59440 ? 0.43610040 7 2 -0.59085020 2 3 -0.22643610 ? 4 0.04774669 ? I 0.63P12600 3 -0.52426070 3 2 0.04096524 3 3 0.56204400 3 4 -0.18931860 3 I 0.60968420 4 0.69686510 4 2 0.56977620 4 3 0.33877430 4 4 -0.20056310 4 0.1P63833D 5 0.O4416R77 5 2 0.09693801 5 3 0.26552130 5 4 0.95458990 5 I 0.0831177?

O' O 161

o o O C a o m ir._ «n to g O' N *'* rt C N *0 » s te iT Z * S c a M « # # ?

N rt

«I«4 CO' Co O «0 e «0 N r> « w> ao * I» m m N « f O' cc c u\ m o «f c #4 «0 • • • • • o c M o o

~~m m m m m~~

~~f# N m '* «A~~

~~N C g ê 1-4 R § I m4 Sb K s 5. ; 5 h- «m *A m r-# 43 #i ®. n; O c c ^ o~~

~~«M Al N N Al~~

~~#« A, m * «A~~

oecof-iooeoe o < xf'»44«>r*o e o o o o <044*VCC CONiAmN 0 0 >>-i0 0 GCu.iNitni\iir.OfoaoN o-tr o o is i «t 4« •* r» N fo o •'4f- Z î P4 FREE VALENCES 0.97232700 0.48874910 I 0.23448640 1.57382300 i 0.87629100

~~SUPEROELOCALIZABILITIES~~

electrophilic FREE-RADICAL NUCLEOPHILIC 1.13190900 1.13191000 1.13191100 0.36674510 1.36675100 2.36675800 I 0.85575980 0.85576200 0.85576330 4 0.69249310 0.35915910 0.02582473 5 0.84899400 1.68566100 2.52233200 CORE USAGE OBJECT CODES 8288 BYTES,ARRAY AREA. 5496 BYTES,TOTAL AREA AVAILABLE* 28672 BYTES DIAGNOSTICS NUMBER OF ERRORS* 0 , NUMBER OF WARNINGS 0 , NUMBER OF EXTENSIONS" 0 COTPILE TIME: 0 .4 4 SECtEXECUTION TIME 0 .2 3 SEC, WATFIV - JUL 1973 V1L4 1 1 .1 4 .5 1 SATURDAY 28 JUN 75 / 206 Eim CIS 2400 SENTRY

~~•♦♦♦UR ACIL♦♦♦♦♦»♦♦♦♦•♦♦♦♦♦♦*♦ • 8 a-MATRIX~~

l.oooooono 1 2 l.ooonnooo 1 3 0.00000000 1 4 0.00000000 ! \ 0.00000000 1 6 0.00000000 1 7 2 1 1.00000000 o.oooooooo 1 n C.onoonnnn 2 2 0.00000000 2 3 1.00000000 2 4 0.00000000 2 5 0.00000000 ? 6 o.oooonoon 2 7 o.oooooono 0.00000000 2 R o.ponnnnno I 2 1,00000000 3 n.ooonnono 3 4 l.o o o o o o n o Ï 0.00000000 3 6 0.00000000 3 4 1' I o.oooooooo 3 P o.oooooono 0.00000000 4 2 0.00000000 4 3 1.00000000 4 4 5 0.80000000 4 4 o.oooooono 6 0.00000000 4 7 0.00000000 4 P 0.00000000 o.oooooono I 2 o.ononoonn 5 3 0.00000000 1.50000000 5 4 0.80000000 I 5 6 0.80000000 5 7 o.oooooono 5 8 o.oooooooo 6 0.00000000 6 2 0.00000000 6 6 3 0.00000000 6 4 o.oooooooo 1 0.80000000 6 6 0.00000000 6 7 1.00000000 0.00000000 6 8 o.eoooonoo 7 2 0.00000000 7 0.00000000 7 4 o.oooooono 7 I 0.00000000 7 6 1.00000000 8 7 I 1.00000000 7 8 0.00000000 1 0.00000000 8 2 o.sooonooo 8 3 0,00000000 8 5 0.00000000 8 4 0,00000000 8 6 0.80000000 8 7 0.00000000 8 8 1.50000000

~~V*MATRIX~~

-0 .20480240 1 2 0.56378170 1 2 -0.58465030 -0 1 4 0.42263310 I .16051240 1 6 0.21684860 1 7 -0.08064706 1 0 .09308640 1 8 -0.19504?io 2 2 -0.182139PO 2 3 0,24100830 2 4 -0.04841897 ! 5 -0 .24336050 2 6 0.79573010 2 7 -0.40666260 2 8 -0.19981460 3 0 .34062850 3 2 -0.54138230 3 3 3 -o -0.20474240 3 4 0 .6620 44^0 Ï .23180240 3 6 -0.05664977 3 7 0.03564353 3 8 0.22848140 4 1 -0 .44171340 4 2 0.04903908 4 4 4 5 -0 0,60740680 4 0.38642090 .37414890 4 6 -0.05837491 4 7 0.28980550 4 p 5 1 0 .50509140 -0.04637907 5 2 0.09081185 5 3 0.01925495' 5 4 -0.068097^5 5 5 -o .12449480 5 6 0,11792820 5 7 0,65593330 5 P -0.52150770 6 .33097120 6 2 -0.22098540 6 6 3 -0.35736950 6 4 -0.37499510 .33500490 6 6 0.30477590 7 0.45646740 6 8 7 .42633650 7 0.29975720 2 0.42388060 $ 3 0.11939220 7 4 -0.18578230 7 .61236010 7 6 -0.19252710 7 7 8 -0.19364390 7 A 0.37448450 .20755880 8 2 0.33062180 8 3 0.21514130 8 4 8 .46751990 8 0.22721910 6 0.41147110 8 7 0.2583 1590 e . 8 0,54321130

~~NERGY~~

~~-1.68715000 -0,95663450 i -0*58936020 w 164~~

~~c o c ocf c\i fc c c 6r* fva >» «MlNKf U,ff •i»■o i \(ih S ««*«««•••••••••• cococc CCOOCCOOO'4 I I I I I I I I I w «r cc sr cu c >f a't a: 4 a 4 K ni4 4W.ir <~~

~~c o c o c c C (^ 0 C C O O 0 4 0 p>»f•-••-fpirsiU. a *-CO p i"ip-rKP.C«Jr-f» •0(v.<\jO.orMi>< 4 p-ir fp'iP'P' <\.CPv^corN.o'U' ■cp-.p’,pii-ip>i«v>eo*f >04(nr> cr^u' u •cpi4~~

~~•H (V Cg m PT) 4 4 IT) ifi 4 ■« I* !>■ n CC~~

~~CNOP>C C OXOOh-COOOO P-fi Pg U". (X (Si IT Pm » < m r* » <\ 10 « o~~

~~04 IM 41 (<• 4S14 lO M >0 •Mi»)Oii\iinpi44toiOiCio«~~

CCCCCCOOOCO-OmCOOw CPmP-» P'l^PmISiOiC rPiCtO^NIO oceoc f“pM4)» t-<4*-'orOi4r>i»«HrPi4c P-CCCO 4 0 -» 4 •-•CO'Pir* 4 434l^04P«e f“i04oa4>4 4a<-> 4) 0.4iP'Cr »aiC>o4»ioPMeor^P>r44Ps4;p- rPI40iCriOU'4>tO|OOQ loo* 4)"-*m 4)mfp.lOir 4>4)i-«(P|PM»-<(i44iOi04KNrp«>« (X FREE VALENCES 1.04275200 I 0.17133600 3 0.41809210 4 0.57438810 5 0.88236150 0.18672480 % 1.04579500 8 0.90704570

~~SU8ERDEL0CAL1ZAB1L1TIES~~

CLECTROPHILIC FREE-RADICAL NUCLEORHILIC 1.38491800 0 .9 2 4 4 7 7 8 0 0 .4 6 4 0 3 6 4 0 0.36162690 0 .9 0 1 1 9 6 5 0 1 .4 4 0 7 6 6 0 0 1,17931400 0 .8 9 9 1 0 2 6 0 0 .6 6 8 8 8 0 6 0 0.67491440 1 .1 6 4 4 7 9 0 0 1 .7 0 4 0 4 7 0 0 1.05613400 0 .6 9 6 4 1 7 8 0 0 .3 3 6 7 0 1 7 0 0.31128070 0 .8 5 0 8 4 6 4 0 1 .3 9 0 4 1 0 0 0 1.77869100 0.81874970 0 .3 5 7 8 0 6 9 0 1.02635700 0.66663610 0.30691410 CORE USAGE OBJECT CODE' 8788 BYTES,A9RAY AREA* 5496 BY7ES,T07AL AREA AVAILABLE* 28672 BYTES DIAGNOSTICS NUMBER OF ERRORS* 0 * NUMBER OF WARNINGS* 0 , NUMBER OF FXTENSIONS* 0 COMPILE TIM E' 0 .5 0 SEC,EXECUTION TIME* 0 .4 2 SEC, HATFIV - JUL 1973 V1L4 1 3 .3 9 .2 6 MONDAY 30 JUN 75

~~O' 166~~

~~I w«/> u~~

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~~oo oc oc OC oo CO CO OO CO OO CO Of* ON e CO oo oc ac oo cc CO OO CO e«o *Tf«- me 90 o oc oo oc ac oo cc CO GO CO N w r-m~~

~~mr- mh* mr» mh- mh- mh- mh* mf^ ml»- mh- mr- r,i- mN m~~

~~#4 #4NN mm «!■««•IAV> «C«Û CCCD ao* WW CNiCM mm «r«r lA~~

OO oc oc oo CO oo OO OO OO oo CO oo oo O oo oc cc oo oc CO oo oo OO NC «r«r O'N 4 oo oo oo oo oo CO CO oo oo aw C*A «r m N«1 o OC OC oc oo cc CO CO CO oo NC &no h*e CIO o oo oo CO oo cc CO oc op CO a «r t^U\ ee wN •0 oo CO oc oo CO oo CO oo So m«r e&A eo (ON oo CO oo oo CO CO CO OO CO 4T>tA iTfO INil\ o oo oc oo oo ce cm OXj oo eo ew wN IAN pirn o • • • • e # # # # # • • • wo oc wC oO cc Ow CO OO oo CO o ?? ??

~~Me Ne NO Ne NO Ne NO Ne Ne Ne Ne N<0 N~~

~~ww NM mm «r«r mm ee f-r* ee aa ww NN mm •#•#~~

ocoococcooooccooocccococcoo COOCCirOOOCCOc >- OCC'CCOOCOOOOCOOOOCCCCCCCOOO ro-c-#o;ro>£frâO*-iO'ecN K OCCOOOOCCOOOCCOOOCOOOCOCCOOOCCOOOOCCOOOOCCOOCCOCOOCOOO r i o r> O 'm cccc. r~ oL r> 4 «V 9 0 10 5 OCCOCOOCCOOOOCOOOCOOOOCCiCOCO&irt• ••••••••••••••••••«•■••••• f\J••••••«•••••• «» •-> C O CM fr. < IN ^ s <~>0 c » »0 0 0 >-<0 0 0 0 0 0 0 0 0 0 c 0 0 0 0 0 0 0 o< COÔ^ÔCCÔÔ o «4inQ>>HnO'r4inO'r4ioo•Mtoff'Mirvo' M •Ml09»*l09r4l00 s IM H e « î-iMfNiNiNinrrim<9<#<9tn i . Î d > 5 5 -0,06879759 5 6 -0.12113260 5 7 0 .1 1 7 2 9 4 5 0 5 A 0 .6 5 2 7 1 2 5 0 5 9 -0.5?1790?0 6 1 -0,38000540 6 2 -0.23902410 6 3 -0.29806950 6 4 0 .1 5 2 1 8 6 0 0 6 5 -0.35106200 6 6 -0.34633430 6 7 0 ,2 9 7 2 1 5 7 0 6 8 0.47252560 6 9 0 .3 6 0 8 8 0 0 0 7 0,42202240 7 2 0.41747000 7 3 0.08695024 7 4 -0.06021443 7 I -0.20235810 7 6 -0.61184960 7 7 -0.17177500 7 A -0.17365420 7 9 0 .4 0 1 8 0 2 4 0 e 1 0 .1 9 0 8 1 7 2 0 8 2 0.29759000 A 3 0.13551050 8 4 -0.21536070 A 5 0 .2 0 0 0 1 0 5 0 e 6 0.47053340 8 7 0.42317870 8 8 0 .2 7 1 3 4 8 0 0 8 9 0 ,5 4 4 2 0 9 8 0 9 i 0 .0 5 5 6 0 2 8 2 9 2 0 .1 2 2 6 2 1 5 0 9 * 0 ,2 7 5 5 4 3 5 0 9 4 0.93944310 9 5 0 ,1 0 2 9 7 3 8 0 9 6 0 .0 6 8 1 5 2 8 4 9 7 0 .0 4 2 3 0 5 6 6 9 8 0 .0 1 9 1 8 3 4 5 9 9 0 .0 7 7 3 7 0 8 2

~~NFR6Y -1.72379500 i -0,96374150 ? -0.59697270 4 0 .7 1 9 7 9 2 3 0 5 1 .1 7 9 6 7 7 0 0 1 .6 2 8 9 6 2 0 0 $ 1 .9 8 9 1 5 0 0 0 A 2 .5 5 9 5 0 7 0 0 9 3 .2 0 5 2 8 6 0 0 p -M ATRIX~~

1 1 1 .6 6 1 7 8 0 0 0 1 2 0.63750450 1 3 -0.14269810 1 4 0 .0 1 5 7 1 3 3 3 1 5 -0.27339660 1 6 0 .1 3 7 1 1 5 7 0 1 7 -0.01512516 1 A 0.0157624 5 1 9 -0.20244330 2 1 0 .6 3 7 5 0 4 5 0 2 2 0.71962420 2 3 0 .5 1 7 8 0 1 6 0 2 4 -0.06846261 2 5 0 .2 4 0 3 9 0 9 0 2 6 -0.16225860 2 7 -0.02137548 2 8 -0,01512448 2 9 0 .3 9 6 6 8 6 0 0 3 1 -0.14269810 3 2 0 .5 1 7 8 0 1 6 0 3 3 1 .0 8 2 1 1 6 0 0 3 4 0 ,1 4 2 9 9 7 6 0 3 5 0 .7 8 6 9 7 1 7 0 3 6 -0.16148140 3 7 -0.15590440 3 A 0 ,1 1 5 9 2 8 1 0 3 9 -0.03415989 4 1 0 .0 1 5 7 1 3 3 3 4 2 -0.06646261 4 3 0.14299760 4 4 1 .9 7 7 4 9 9 0 0 4 5 -0.12931650 4 6 0.02491760 4 7 0 .0 3 4 7 4 3 4 9 4 8 -0.02320268 4 9 -0.00204325 5 1 -0.27339660 5 2 0 .2 4 0 3 9 0 9 0 5 3 0.78697170 5 4 -0.12931650 5 5 0 .8 0 3 0 6 1 6 0 5 6 0 .4 0 7 4 4 8 3 0 5 7 -0.04352815 5 A -0.00861233 5 0 -0.15697350 6 0 .1 3 7 1 1 5 7 0 6 2 -0.16225860 6 3 -0.16148140 6 4 0 ,0 2 4 9 1 7 6 0 6 0 .4 0 7 4 4 8 3 0 6 6 1.72535000 6 ? 0 .4 3 4 5 9 3 0 0 6 A -0.21008440 6 9 -0.05476230 7 -0.01512516 7 2 -0.02137548 7 3 -0,15590440 7 4 0.03474349 7 -0,04352815 7 6 0.43459300 7 7 0 .6 3 6 6 5 2 4 0 7 8 0.68315520 7 9 0 ,4 2 9 3 0 9 9 0 R 0 .0 1 5 7 6 2 4 5 8 2 -0.01512448 8 3 0 .1 1 5 9 2 A 1 0 A 4 -0.02320268 A 1 -0.00861233 8 6 -0.21008440 8 7 0.68315520 8 8 1 .6 5 6 0 6 4 0 0 8 9 -0.21023660 9 1 -0.20244330 9 2 0 .3 9 6 6 8 6 0 0 9 3 -0.03415989 9 4 -0.00204325 9 5 -0,15697350 9 6 -0.05476230 9 7 0 .4 2 9 3 0 9 9 0 9 8 •0.21023660 9 9 1 .7 3 7 7 8 2 0 0 5 MEE VALENCES 1 1.09454500 2 0 .1 8 0 0 5 7 7 0 0 .2 B 4 2 7 B 2 0 I 1 ,5 8 9 0 5 2 0 0 5 0 .5 3 7 6 2 9 8 0 0 .8 9 0 0 0 8 1 0 I 0 .1 8 4 9 * 1 5 0 -S—

~~SUPEROELOCALIZABILITIES~~

EtECTROPHlLlC fr e e - r a d ic a l NUCLEOPHILIC 1 .4 0 8 0 7 9 0 0 0 ,9 3 8 6 4 5 7 0 0 .4 6 9 2 1 0 3 0 \ 0 .3 8 3 7 8 5 9 0 0 .9 1 4 3 6 1 5 0 1 .4 4 4 * 3 5 0 0 3 1 .1 5 1 6 5 2 0 0 0 .9 1 2 4 4 7 2 0 0 .6 7 3 2 3 9 2 0 4 0 .7 1 0 7 5 2 0 0 0.364393 50 0 .0 1 8 0 3 4 8 2 5 0 .7 4 1 8 9 6 7 0 1 .1 8 0 8 9 3 0 0 1 .6 1 * 8 9 5 0 0 1 .0 7 9 1 3 3 0 0 0 .7 0 5 3 6 2 5 0 0 .3 3 1 5 9 1 0 0 f 0 .3 1 8 7 6 8 1 0 0 .8 4 9 3 3 8 4 0 1 .3 7 9 9 0 7 0 0 8 1 .2 9 1 6 9 4 0 0 0 .8 2 2 2 5 9 6 0 0 ,3 5 2 8 2 3 3 0 9 1 .0 2 6 7 4 7 0 0 0 .6 6 7 0 2 7 7 0 0 .3 0 7 3 0 6 5 0

~~-MATRIX -0.21440290 1 2 0 .5 5 0 6 4 3 3 0 1 3 -0.64914760 1 4 0 .4 6 7 3 6 4 9 0 I -0.10476710~~

O' 00 1 0.40440460 2 2 -0.59111890 2 3 -0.13148260 2 4 0 .6 5 1 8 2 3 8 0 5 - 0 . ;2 5 --0 0 .2 . ;2 1 1 8 2 8 8 0 3 I -0.65402260 3 2 0 .0 8 4 4 0 0 4 8 3 3 0 .6 2 5 5 6 3 8 0 3 4 0 .4 4 5 8 6 1 6 0 3 5 -0.30653340 * r— 0.68783370" "4 " 2 ~ o; 4 0 .0 6 3 3 3 4 9 4 4 5 -0,28735710 5 1 0.10212850 5 2 0 .1 3 8 7 5 4 3 0 5 3 0.22514020 5 0 .3 9 2 2 6 4 9 0 5 5 0,87507500

NERGY 1 -1.56823900 -0.46169940 I 0 .8 4 7 6 5 4 8 0 4 1.82 36 6 80 0 5 2 .3 5 8 5 9 6 0 0 p-MATRIX 1 1 .58 09 7 20 0 1 2 '0.71422260 1 3 -0.17201420 1 4 -0.32678410 5 0 .1 2 6 3 9 5 5 0 1 0 .7 1 4 2 2 2 6 0 2 2 0 .6 9 4 7 3 7 0 0 2 3 0 .5 5 9 4 5 2 3 0 2 4 0 .2 5 5 8 8 4 9 0 I -0.13503110 I 1 -0.17201420 3 2 0 .5 5 9 4 5 2 3 0 3 3 _1,12263400_ 3 4_ 0 .7 7 8 2 1 0 4 0 -V "5—=0 . 1917483a ------4 1 -0,32678410 4 2 0 .2 5 5 8 8 4 9 0 4 3 0 .7 7 8 2 1 0 4 0 4 4 0 .7 1 3 3 5 1 1 0 4 I 0.37410340 0.12639550 5 2 -0.13503110 5 3 -0.19174830 5 4 0 .3 7 4 1 0 3 4 0 I 1 .8 8 8 2 9 3 0 0 FREE VALENCES -IV0ITRZ70O 0 .« 5 8 3 7 A 6 0 0 .3 9 4 3 8 6 5 0 T4 9

~~SUFEROELOCALIZABILITIES~~

electrophilic FREE-RADICAL NUCLEOPHILIC 1 .2 5 1 9 1 6 0 0 1 .0 0 9 4 9 0 0 0 0 ,7 6 7 0 6 4 1 0 0.38516210 1 .1 4 2 7 3 9 0 0 1 .9 0 0 3 1 7 0 0 1 .0 9 7 1 3 9 0 0 0 ,8 5 4 7 1 7 9 0 0 .6 1 2 2 9 5 6 0 I 0 .6 0 3 9 1 7 7 0 1 .3 6 1 4 9 2 0 0 2 .1 1 9 0 6 9 0 0 5 0 .9 6 5 9 5 7 5 0 0 .5 8 7 1 6 8 0 0 0 .2 0 8 3 7 8 4 0 CORE USAGE OBJECT CODE# 8288 BYTES,ARRAY AREA# 5496 BYTES,TOTAL AREA AVAILABLE# 28672 BYTES OI.ACIWSTICS NUMBER OF,ERRORS# 0 , HJMBER OF WARNINGS# O , NUMBER OF EXTENSIONS# 0 COMPILE TIME# 0.4V SEC,EXECUTION TIME# 0.68 SEC, WATFIV - JUL 1973 V1L4 1 0 .1 9 .0 8 TUESDAY 25 NOV 75