PHOTOCHEMISTRY OF 3,s-DIMETHOXYBENZYL ACETATE

Richard S. Smith

Submitted in @al fulfillment of the requirements

for the degree of Master of Science

Dalhousie University

Halifw Nova Scotia

December, 1999

@ Copyright by Richard S. Smith, 1999

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TABLE OF CONTENTS

LIST OF FIGURES

LIST OF SCHEMES

LIST OF TABLES

ABSTRACT

LIST OF ABBREVIATIONS

ACKNOWEDGEMENTS

vii

viii

xii

1. INTRODUCTION

1.1 . General Introduction 1

1.2. HistoricalBackground 2

1 2 . 1 The Frics Reamngement 2

1 2.2 The Photo-Fries Reanangement for X=C 4

1.2.3 The Photochemistry of 1 and the meta Effect 10

1.2.4 Electron TratlSfer Conversion of Radical Pairs to Ion Pairs 1 5

1.2.5 Photolysis of 3J-Dimethoxybeoyl Acetate in Methaool 16

2. EXPERIMENTAL

2.1 General Procedure

2.2 Synthesis of 3,s-Dimethoxybenyl Alcohol

2.3 Syuthesis of 3,5-Dimethoxybenzyl Acetate

2.4 LaserFlashPhotolysis

2.5 Photochemistry

3. RESüLTS AND DISCUSSION

3.1 Preparative Photolysis of 1 in Hexanes 25

3.2 'H NMR Spectra and Assignrnent of Chemical Shi& 27

3.3 "C NMR Specüa and Assignment of Chemical Shifts 29

3.4 Laser Flash Photolysis of 3,s-Dimethoxybenyl Acetate 36

APPENDICES

1. 'H NMR Spectrum of Bicyclic Isomer, 24 38

2. I3c NMR of the Specmmi of Bicyclic Isomer, 24 39

3. 'H / "C Correlated Spectnun of Bicyclic Isomer, 24 40

4. 'H NMR Spec~tnim of the 5 deshielded Protons in 2 41

5. ' H / I3c Comiated Spectnun of 2 42

NFERENCES 43

LIST OF FIGURES

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Important 'H NMR Chernical Shih of Cmpds 2,24,25 amd 26.

t 3 C NMR Spectral Assignment of Methoxy Gmups on 24 vs 2.

I3c NMR Spectral Assignments of 24 Relative to 25.

UV Spectra of DMBA Photolysis Products Over The.

Plot Indicaîing First Order Conversion of 24 to 2.

Plot lndicatiog First Order Conversion of 2 to 22 in Methmol.

LIST OF SCHEMES

Scheme 1. Product Distribution Summary of Jeegers Photolysis of I . 8

Scheme 2. Cornpetitive Pathways, Hetero/Holomo-lytic Cleavage, and Sequelae. 15

Scheme 3. Betuylic Ester Mechanistic Product Distribution 17

vii

LIST OF TABLES

Table 1. Product Distribution of Acetate vs Pivaiate Esters, Pincock & Wedge. 18

Photolysis of 3,54inietboxybeay1 acetate in hexanes gave a 10% yield of a bicyclic

isomer. 24, previously reporteci by D.A. Jaeger to be a trienyl isomer, 2. The bicyclic

isomer then ceananges t h d y , tin = 89 min @ 50 OC, to the îriene. The triene has a

maximum W absorbtion @ 3 15 nm with an estimated E = 5500 M" cm-' which accounts

for the gradua1 yellowing of the initially clear solution, p s t photolysis. The conversion

was shown to be first order in both hexanes and methanol, The conversion of the triene

to 3.5-dimethoxybenzyl rnethyl ether in methaaol was determined to have a half life of

2.7 min @ 25 OC. Monitoring the products of laser flash pbotolysis (266 nm) of DMBA

in both hexanes and methanol resulted in W absorbtion which rernained constant in

intensity with time at 320 nm, at the longest t h e scaies, approxllnately 10 ms, of the

laser system.

a

P

6

AGET

8

Ln*,

G+

CIDNP

cm

cm"

DAC

DMBA

D m

DM

DNA

ED

EW

FTIR

GC/FID

GCiMS

pnmary

secondaq

chernical shift

change in Gibbs fiee energy due to electmn transfer

molar absorbtivity

wavelength of maximum absorbance

Hammet substituent parameter

chemically induced dynamic nuclear polzuization

centimeter

inverse centimeter

dimethyl acetylenedicarboxylate

3.5-dimethoxylbenzyl acetate

dimethy lbeny 1

dimethy l

deoxyiboneucleic acid

electron donating

electron withdrawing

Fourier transform infked

gas chrornatography/ flame ionisition deîectot

gas chromatographyl mass spectroscopy

hv

HOMO

IR

h o 2

khi

kbt t

kbom

LCAO

LFP

LUMO

M-'

min

MO

nm

NMR

Nu

NuH

tm

TCE

UV

v h

energy of light at that wave-length

highest occupied rnolecular orbital

Infi.ared

decarboxylation rate constant

electron transfer rate constant

heterolytic cleavage rate coIlStatit

homolytic cleavage rate constant

linear combination of atomic orbitais

laser flash photolysis

lowest unoccupied molecular orbi ta1

reciprocal molarity

minute

molecular orbital

nanometer

nuclear magnetic monance

nuc leophile

nucleophile with proton

half li fe

tetracyanoethy lene

ultra violet

volume per volume

versus

I thank Dr. J. A. Pincock for al1 his patience. guidence, support and laboratory assistance

in helping me complete this thesis. 1 am al90 greatiy indebted to Alex Pincock for her

carefùl laboratory work which has enabled me to overcome a great hurdle in my research.

It is truly an honor to know these two people.

Thanks ever so muc h to Dr. Stephens, Gai1 Power and Dr. Burford for enabling me to

continue with my thesis despite the setback 1 encounted.

Thank you Dr. N.Schepp for your assistance with the laser flash photolysis.

My gratitude is great for the use of h. D.A. Jaegers' otigid laboratory notes. Until I

saw them I was doubtful the task could be accomplished.

Thanks Betty, for your support durhg this long venture.

INTRODUCTION

1.1 General inîroduction

oiss son as'^ f'irst reporteci the utility of photolabile protecting groups in peptide

synthesis and 3,s-dimethoxyknzy loxycarbony l moieties were shown to be very practical

for such purposes.3 The basic idea of this concept is that absorption of a photon by the

chromophore P in a molecule X-P cm lead to a very rapid release (micro or nanoseconds)

of the active molecule X. Using high intensity lasers, both spatial and temporal release of

X can be controlled by suitable choice of P.

In vivo site activation of toxic h g s by laser inâuced photolysis is a usehi bio-

application of photolabile adducts. Pirrung et al have made aàvances in the use of

photolabile protecting groups for biosynthetic purposes.' They have improved the

biocompatibility of the technique by uîilizing 3,S-dimethoxybenzoin to protect the 5'-

hydroxyl groups of nucleosides in the generation of DNA probes via phosphotamidite-

based DNA synthesis. These compouuds and the fesultant photolysis products are much

less injurious to cells than the commonly used nitrobenyl derivatives?-' Cameron et al

have explored the use of photolytically generated amines h m a-keto carhumtes, again

relying on the 3,5-dimethoxybenzoin moiety and its substituted analoggs.6 These

carbarnates are reported to give war quantitative photocleavage to yield free amine dong

with the corresponding substituted benzo[b]furan photocyciization product. A usefiil

review of work on benylic photochemistry published up to the 1980's is referenced

hemin' and a new ow has been published in 1999.'

The focus of this thesis is the photochemistry of 3,5dimethoxybenzyl

acetate (DMBA), 1, in both non-polar and polar (methanol) solvents to assess the

importance of the isomeric triene, 2, eq. 1, as a nactive intermediate.

1.2. Historical background

1.2.1 The Friea Reamngement.

The intramolecular photo-Fries reamgement of aryl esters is the most directly

pertinent exarnple of the many variations ascnbed to the Fnes-Claisen class of reactions.

The hdamental (thermal) Fries reanangement is the conversion of phenolic esters to

ortho and paru phenolic ketones under the influence of Lewis acids, eq. 2.

6 H C-R

If O

The finai products obtsined are known to be fonned by tautomerization of the tirst

fomed enones. The initial acyl transfer to the ortho and pcao positions is d s e d to be

via a contact ion pair, hence a heterolytic tramfer tbet favors the ortho-para product

orientation.

The analogous photo-Fnes reaction is known for a number of aromatic

derivatives,

(3)

X=O,NH,NR. Y = COR, CO2& SGR, etc.

In contrast to the thermal reaction and the attendant acyliurn ion, the photo-Fries miction

proceeds via radical pair intermediates that cm either rearrange in cage to give the classic

ortho-paru "Fries" pducts, or they can diffuse out of cage and abstnrt hydrogen to

fom typical radical reaction products. Cotlsequently, the "photo-Fries" products of a

photoreaction have becorne synonymous with 'ortho-para' rearrangement products as

opposed to the many other possible products available in photochernical reactions. The

photo-Fries intermediate ewnes have recently been observecl by laser flash photolysis

(LFP) at 266 nm , eq. 4."

(not detected)

Confirmation of the enone formeâ by LFP at 266 nm is verified by observing the

disappearance (bleaching) of the comsponding transient when a second pulse of laser

light at a longer wavelength (308 nrn) is applied shortly thereafler and the difference

spectnim clearly shows the presence of an absorption matching that of a ringspened

ketene. The radical pair and the mone intermediates have also been extensively studied

by other techniques, pnor to LFP, such as chemically induced dynamic nuclear

polarization (CIDNP) 12*" Raman spectroscopy l4 as well as studies on both magnetic

field and magnetic isotope effects." The suitability of any one method is limited by the

time h m e of the reactive intemiediates. LFP, in the presently achievable sub-

nanosecond range, is very useful for elucidation of hitherto unobservable reaction

pathways.

1.22 The Photo-Frk Reamngement for X=C.

The best known example of the photo-Fries rerrction for X=Carbon, eq. 3, is that

reported by Jaeger for the photolysis of 1 in hexane, eq. 5. l6

+ hu - He

(hexane) cH30&1 P

OAc cH30TH3 7, (yield not reported)

It is this photolysis that formed the basis for this thesis.

According to his labotatory notebook, the &y after rotovaping the hexanes and

transfemng the yellowish oil to the refngerator, Jaeger chromatographed the resultant

photolysis mixture on silica gel and eluted with hexanddiethyl ether. He analyzed each

fraction by IR, W and 'H NMR spectroscopy and ieported the isolation of 2

contaminated with 7.9% of 1 and 3 -4% of 7, the apparent photo-Fries pduct. This

mixture displayed IR bands at 2830 (CH30), 1740 (C=O) and 161 5 cm*' (C=C) in

agreement with the assignment of 2. However, the reported üV spectm in hexane, &

3 16 nm and E - 400 M-' cm-', was inconsistent with the highly conjugated triene which

would be expected to have a molar abûorbtivity measured in the thousands by analogy to

the unsubstituted iso-toluene which has a reported value of E = 4400 hî' cm-'." By

utilizing the Woodward-Fieser d e s for polyenes, '' a theoretical a l o f 300 nm can be

calcuiated. I9 The discrepancy with the molar absorbtivity for this cornpurid was the first

indication the assignment of the stnichue of 2 might be incorrect. A second difficulty

was the 'H NMR assignment by Jaeger for both the two methoxy groups and the lone H.

resonances as outlined below.

2 E =400

Whereas the remaining assignments are reasonable, the reported chemical shifi for the

doubly al1 y lic methine proton at an ester carbon as 6 3 .S8 is masonable when compared

to that of the CH2 in isotoluene at 6 3.32 plus the expected e&t of the added acetate

which gives an estimated value of 6 6.6. in structure 2 the two methoxy groups are in

very similar chemical environments so one would expect the chemical shih to be

likewise similar. The assigwd values of 6 3.24 and 6 3.66 would better correspond to

one rnethoxy group on sp3 hybridized carbon, 10, and one on an sp2, 11, rather than those

of 2.

Jaeger sought to trap the postuiated intermediate diene, 2, of DMBA photolysis in

hexane by Diels-Alder adduct formation. in g e n d , a Diels-Alder reaçtion is tht ground

state 2e4x cycloaddition and while this reaction would wrmally be used as a synthetic

tool it was clever of Jaeger to use it as a probe for dienes since tbe reaction is often

stereospecific and facile. 'EW' and 'ED', equation 6, =fer to electron withdrawing and

donating groups respectively. However, in practice a complementary electron

configuration berneen the diene and dieneophile should enable the desired cycloadditoa

to proceed. It should be noted that the reaction is not limited to carbon-carbon n systems

but to many other hetero-x systems as well which may complicate the products formed if

the Diels-Alder reaction is attempted in a mixture as cornplex as those of photolysis

products.

(6)

Specifically, Jaeger used dimethyl acetylewdicarboxylate @AC) and tetracyanoethylene

(TCE) as the trapping agents. Equation 7 shows the expected mechanisrn utilinng DAC

as the trapping agent; TCE would forrn analogous products to DAC except that the newly

formed bridge would be saturated as opposai to the rmsaturated bridge formed with

DAC. He was not successful with either Ragent and the reason for this faiiure is

unknown to us.

However, he was able to isolate a new and stable cornpouad, Rarnely 1J-dimethoxy-5-

methylphenyl acetate, 7. This cornpouad was used as additicmi evidence for the

formation of 2.

The mechanistic scheme as proposed by Jaeger is that 2 is formed by either

recombination of the 3 J-dimethoxybenzyl radical and acetoxy radical or by concerteci

process h m 1; i.e., photo-Fries reamuigement. He notes that photochernical [1,3]- and

[3,3 1-acetoxy shifts are symmetry allowed and forbidden respectively but M e r

mentions that both the shifh would be allowed thermaily. Jaeger summarizes the

product distribution as in Scherne 1 below.

Scheme 1 Product Distribution Summary of Jaegers Photolysis of 1.

Jaeger also photolysed ''0 labeied 3,s-DMBA but cüd not mention the formation

of the triene 2 because the photolysis was done in polar solvents where the triene muid

not be expected to be stable.20 The isotopic expecimeats did however nveal that in polar

solvents, aqueous methand and aqueous dioxane, the process of "0 scrambling of the

carbonyl oxygen is infrmolecular thus indicating interd rem of both the ionic anci

radical species as a possible ressoo for the low efficieacy, @, of the photolysis. More

importantly, in the same paper he reported that, in nonpolar aprotic solvents (hexane,

dioxane, cyclohexane), photolysis products h m the in-cage radical pairs were fonned to

a decidediy greater extent than in aqwous media, but the percent '*O scrambling

increased only slightly. He offered the suggestion that an alternative mechanism for

equilibration of the 180 starting material might involve concerted [1,3] suprafuciiai shift

of the 3Sdknethoxybenzyl group but M e r adds that: " Photochemically, the process

should proceed with retention of configuration at the benzyl carboa However, h m

photolysis of (-)-3,Sdimethoxybenyl-14 acetate in SOo! (vlv) aqueous methanol,

recovered starting material was - 85% racemized. Therefore, a concerted [1 ,3] shifi for

photoexcited Ir", (starting material), "is unlikely"?'

This indicates that even though we can deduce that there is considerable in-cage

recornbination of the acetste radical with the benyl radical, it can not be assumed that

there is no< a concerted mechanism (photo-Fries) respoasible for the migration and

subsequent reactions of the acetoxy group in the remaining 15% of the products.

CH, in-cage recombination

of ester group

DMB-methyl ether DMB-alcohol

1.2.3 The Photochemirhy of 1 rad the nu& effeet.

in a fundamental paper in 1963, Zhmerman and Sandel reported on the

photo1 ysis of 1, dong with the meta and para monosubstituted isomers, 13 aad 16, in

aqueous dioxane? The products of each, show in equations 9, 10 and I I were

rationaiized by the formation of both intemediate benzylic radicals and cations.

h l + 14 + Lesser amounts of radical derived product

(1 1)

The electron densities of monosubstituted benzene compounds with electron

donating or withdrawing substituents and those of methoxybenzene were calcuiated by

Zimmemian, using simple Huckel theory; the resuits indicated tbat excitation enhanced or

decreased, respectively, meta electrou deasity. He used valence bond structures, 19 and

20, to explain the reactivity of mono-substituted berizenes with el-n donating and

wi thdrawing groups, respective 'y.

He found that Cmethoxybwzyl acetate gave exclusively products expected fiom benzyl

and acetoxyl radicals while those of 3-methoxybenzyl acetate, dong with radical derived

products, gave products denved fiom the 3-methoxybeayl cation and acetate anion. He

considered it most strüllng that a similar photolysis of 3,s-dhethoxybenyl acetate

yielded only the ion derived isolate, 3,5dimethoxybenyl alcobol. No prducts of radical

fission were detected in the latter case. He noted that Huckel level LCAO MO

calculations of DMBA showed an even greater increase in electron density at the carbon

metu to both methoxy groupis versus the shgly methoxy substituted case. The valence

bond scheme. eq. 12, shows the swmised mechanism of DMB-alcohol generation.

Therefore, the enhanced formation of the benyl cation is surmised to be due to the

promotion of an electron h m the HOMO to the LUMO with highest density at a meta

carbon. The hetemlytic bond cleavage then leads direçtly to the ion pair intemediate.

These findings are in con- to ground state expectations and are precisely the

observations that lead to the term 'metu eEèctT ascribed to photochernical, vernis ground

state, reactions with enhanceci meta d v i t y . These obsemations by Zberman piqued

the interest of Pincock et al. Their more extensive results on benzyl ester photolysis

resulted in a mechanism of d y homolytic cleavage at the arylmethyl ester b o a with

ions king formed by subsequent electron tramder thereby dowing the 'ion denved'

products to ensue. Zhemran believes that the ionderived products are eatirely of

direct heterolytic cleavage from Si of the ester.

Results by Decosta and pincock with vzuiously substituted 1 -naphthyhethyl

esters, 21, were explaineci by Marcus theory of electron m e r for converting radical

pairs to ion pairs *'

Of the naphthyl compounds, the 3-methoxy moiety gave a lower yield (3 1%) of the ion-

denved product than did the Crnethoxy moiety (74%) and the unsubstituted compound

yielded the greatest amount (84%). A plot of log of the rate of elecûon transfer for

converting the radical pair formed during photolysis to the ion pair as a function of the

oxidation potential of the 1 -naphthylmethyl radical yields a parabolic curve with a

maximum near the Cmethyl subsîrate. Similarly, a plot of percent yield of the ion

derived product, the methyl ether in methanol, vs a*, yields a parabda with low yields for

both strongly electron donating and withdrawing groups. The original hypothesis by

Pincock and Decosta was that homolytic cleavage followed by electron transfer leading to

the ionic species was the dominant proces of shglet excited state photolysis: kbm » kk,

Scheme 2.

Scheme 2. Cornpetitive Pathways, Hetero / Homo-lytic, and Sequelae.

Pmduct yields are then controlled by cornpetition between the rate constants for electron

transfer and for decarboxylation; k, and k2. The assumption is that the stmchval

changes in the ester are acting in an orthogonal maMer with the ester substituent R

having an effect ody upon b2 and the aromatic ring and its' substituents effecting only

kui-

The concept of a radical dock mechanisnt was introduced by Ingold and ~r i l l e !?~

and was used by Pincock to cdcuiate the vdues of k, because, at the time, b2 was

known for one acyloxy radical. The value of k2 ûom the Pmethy l fluoreny 1 carboxy 1

radical allowed the determination of & values as a function of substituent on the aryl

ring. The newly gleaned & vatues were then used to expaud the table of k2 values for

wider range of radicals. From this data and the Marcus plot (vide supra) it was

demonstrateci that a charge separation (two neutrals giving an anion and a cation) reaction

hl ly exhibited Marcus behavior. ,

1.2.4 Electron Trader Conversion of Radml Pairs to Ion Pairs.

Subsequent investigations by Pincock et al have revealed that the monosubstituted

benzyl esters also exhibit a normal and an inverted M m u s region relative to the

substituent on the aryl ring. The parabolie plot of log( &) vs A& is shifted to the right

for benzyl compounds (AG more positive) relative to aaphthyl compounds indicating

electron transfer for the naphthyl compounds is more facile than those of the benzyl

compounds .

Hilborn, McKnight Pincock and Wedge 27 expanded upon the preceding work of

Decosta and examined photomethanolysis of six substituted beayl acetates and pivalates

with a range of a' from -0.65 for the Cmethoxy wmpound to 0.66 for the cyano one.

They re-examined the historically important 3-methoxy, Cmethoxy and 3,5dimethoxy

benzylacetates as a test of the 'meta effect'. They aiso chose both pivalate and acetate

esters in order to ascertain the importance of decarboxylation in the product distribution

of the photolysis of the various esters chosen. They found that the excited state behavior

of both pivalate and acetate esters was the same and that ciifferences in product

distribution for the same aryl substituent were due to ground state reactions that followed

the photochernical step. The product distribution reveded that the 3-methoxybenzyl

acetate gave a maximum yield of ion derived product It was determined that the major

pathway for excited state solvolysis was homolytic and that the direct heterolytic pathway

was actuaily the minor one.

1.2.5 Phototysis of 3J-DLiwthorybeayl Ace8ate in MethanoL

Wedge and Pincock photoIysd a series of varïously substituted benzyl acetate and

pivalate esters in methanol in order to furtber test the bounds of the meta effecr. They

also found that the product distribution of the photolysed benylic esters could be

explained by a pathway that involves homolysis and thea electron transfer to fonn ion

pairs. The ion pairs then reacted, as expected, to form methyl ethers as in Scheme 3.

Scheme 3. Benzylic Ester Mechanistic Ptoduct Distribution

The mechanism again involves initial homolytic cleavage of the excited state ester

fo llo wed by cornpetitive decarboxylation, bRI which results in radical-derived proâucts

and electron transfer, k d y which results in ionderived products.

The evidence h m their investigations indicated that the ion-derived product

yields increased for each additional meta methoxy group: 32% for 3-rnethoxybenyl

acetate, and 56% for 3,5dimethoxybenyl acetate. As expected, the 3,4,5-trimethoxy

compound had an even higher yield of ion-derived ether, 66%. This was in agreement

with the meia effect as proposed by Zimmeman, however the yield of the ether h m the

18

photolysis of the acetate esters was much higher than those of the pivalate esters which

was not predicted by the meta effect. The ion-deriveci product, benyhethyl etber, yields

as found by Pincock and Wedge are shown in Table 1

Table 1. Product Distribution of Acetate vs Pivalate Esters, Pincock & Wedge.

Aryl substitution Acctate ester Pivriate attr

Ether ykiâ, ./. Ether yieid, ./.

Pincock and Wedge noted that if the meta effet was entirely responsible for the product

distri bution then there should have been litîle difference between the ether yields for

pivaiate and acetate esters since the meta effect is an aryl substitution effect. If the

altemate pathway to ionderiveâ ether involved competition between decarboxylation of

the primary radical product and direct hetomlysis of the ester, kh, and khek then the ester

substituent would effect the product yields.

Attention was turned to the triene, 2, isolatcd by Jaeger in the nonpolar (hexanes)

photolysis of 1, DMBA. ifthe triene, 2, was also p m t in the polar (methmol)

photolysis of DMBA then it could serve as the mbstrate for the additional ion derived

product by thermal solvolysis of the ecetate. This is graphicaily illustrated in eq. 13.

Thermal pathway

The major products of hexanes photofysis have been outlined in eq 5.16

The major products of methaool photolysis of 3,S-DMBA are outlined in eq 1 4 . ~ ~

The questions which needed to be answered were: was the triene 2 fonned upon

photolysis in polar solvents and if so, did it play a d e in the formation of ion-derived

products? This thesis attempts to answer those questions.

2.1 General Procedure.

Proton ('I-I) and carbon (I3c) nuclear magnetic resoaance (NMR) spectra were

obtained in CDC l 3 on an AC 250 F NMR spectrometer in automation mode. Chernical

shifts are reported in parts per million relative to tetramethylsilane ( 0 . 0 ) as an intemal

standard. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q =

quartet, m = multiplet. lnfrared spectra were obtained on a Nicolet 205 FTiR

spectmmeter and the fkquencies are reprted in wavenurnbers (cm"). Tirne dependant

Ultraviolet (UV) experiments were done on a Hewlett-Packard diode array

spectrophotometer. Other W spectra were obtained in metban01 or hexane solution as

required in 1 cm quartz cuvettes on the same spectrometer. Wavelength maxima (Amax)

are reported in nanometea. GCEID analyses were p%onned using a Perkin-Elmer

Autosystem with an autosarnpler. the column was a 30 m x 0.2 mm. 5% phenyl methyl

silicone. GCMS analyses were done on a Hewlett-Packard 5890A GC and a 5970 mass

selective detector. n i e column used was a 25 m x 0.2 mm 5% phenyl methylsilicone on

fused silica with a film thickness of 0.25 pm. Masses are reported in d t s of m a s over

charge (m/z). Intensities are reported as a percent of the base peak intensity. The

molecular ion is indicated by W. KPLC analyses werp obtained with a Waters 6000

solvent delivery system and a Waters U6K injector under isofratic conditions with a flow

rate of 2 W m i n ushg a Waters Spherisorb Silica 5 pm column (4.6mrn x 250 mm) with

a Waters Mode1 450 variable wavelength detector. W detection for monitoring the

reaction was at 254 nm. Silica gel T-6145 plates h m Sigma were used for thin layer

chromatography (TLC). Silica gel, 60 A (70-230 mesh), was used for nomial column

chromatography. Column solvents were distilled prior to use. Tetrahyhfuran (THF )

was dried over sodium and benzophenone just prior to use. Reagents such as 3,s-

dllnethoxybenzoic acid was purchased h m the Aldrich Chernical Co.

2.2 Syntheses of 3,5-Dimdhorybenzyl Alcohol.

The preparation of the ester, 1, required 50 g (238 m o l ) of 3,5-dimethoxybenzyi

alcohol. The alcohol was synthesized by reducing 3,5-dimethoxybenzoic a d , 57g (240

mrnol) with 1 M boraae/THF solution in dry THF. A standard workup gave 33.4 g (198.6

mmol, 83 %) of the cmde alcohol. The alcohol was purified by bulb-to-bulb distillation.

The 'H NMR agreed with the literahve spectnun: 'H NMR 6 6.6 (d, 2H), 6.45 (t, lm,

4.72 (s, 2H), 3.85 (s, 6H), 2.0 (s, 1~):'

23 Syathesis of 3,5=Dimetboxybeiyl Acttate.

Acetyl chloride (0.022 mol) in 30 mL of dry benzene was added to a solution of 3,s-

dimethoxybenzyl alcohol(0.02 mol) and 1 mL of pyridiw Ui 50 ml, of dry benzene. The

solution was stirred overnight at room temperature. Water was added (50 mL) and the

two layea were separated. The bemne layer was washed hvice with 10% aqueous HC 1,

once with 5% aqueous NaOH, and finally with water. The organic layer was drid

(Nds2S<W)r filtered, and evaporated under reduced pressure to give the crude ester. The ester

was purified by either column chromatography or bulb-to-bulb distillation: 'H NMR 6

6.50(d,2H),6.41 (t, IH), 5.04(~,2H),3.79(~,6H),2.11 (s,3H); ' 3~NMR6 170.7,

160.9, 138.2, 106.0, 100.1,66.2,55.3,20.9; IR (mat) 2910,2904,2840, 1769, 1609,

1465, 1242,1154,1070,834 cm-'; GCMS m/z 210 (&, 49), 169 (1 1), 168 (Iûû), 167

(401, 15 1 (24), 139 (98). 124 (1 8), 1 O8 (12), 107 (12). 91 (24). 79 (19). 78 (21), 77 (39).

65 (25), 63 (19); W (CH30H) k, 278 (E 2400).

2.4 Laser Flash Pbotofysh

The nanosecond laser flash system is of standard design ushg as the excitation

source, the fourth hamionic from a Continuum Nd: Yag NY-61 laser (266 am, < 8

ns/pulse, < IûmJ l pulse).

2.5 Photochemistry.

Photoreactions were carried out using a 450 W Hanovia@ medium pressure rnercury

larnp as the light source? R e d o n mixtures were prepated in a kshiy desiccated (oven

dried) 420 mL immersion well and flushed with dry nitrogen for % hour prior to, and

continuously during, photolysis. The immersion well and lamp were cooled with

circulating tap water to maintain a tempera- of 20" C or les. The photolysis mixture

was stirred continuously by Tefion@ coated magnetic stir bar. The progress of the

reaction was monitored by withdrawing aliquots through a rubber septum aml injecting 1

j.L directly into a GC/FID. The reaction was allowed to pmceed until approximately

75%. by peak ma, of the stanng matend 1 had been convexted. mer photolysis, the

solvent was irnmediately removed by rotory evaporation under vacuum in a water bath of

circulating water; ice water for the hexaaes solvent and tap water for the methanol

solvent. The photolysis products were then ûansferred in a mal1 quantity of solvent to a

high vacuum (IO-' torr) apparatus to prepare a neat sample for column chromatogaphy

and analysis by 'H NMR and GCIMS. Photolysis products to be stored were left in the

original solvent and stored under N2 at -4" C.

2.6 Preparitive Cbromatogiphy.

The neat sample, was dissolved in distilled hexanes and subjected to drycolumn

chromatography on a 4.5 cm x 5.0 cm bed of silica gel and eluted with 1 L each of:

1 0.20,30,50 and 100Y0 hexanedethy1 acetate.and.collected in 50 mL fractions.

3. Results and Diacussion

3.1 Preparntive Photoiy8b of 1 in Hexrne

Photolysis of3,S-dimethoxybenzyl acetate (DMBA), 1, in hexane, gave a 10.h

yield of the isomer 24, previously reported as 2 by Jaeger. Of the radical-derived

coupling products, 4 was the major one at over 50% yield, with the dimer 5, the solvent

adduct 6 and the remaining products forrning consecutively lesser Factions of the total

photolysis mixture. No attempt was made to isolate the low molecular weight

components, such as acetic acid.

1 (hexanes) CHî0Ac

DMBA is photolytically converted to more than 90 % product afler just 30 minutes as

indicated by the disappearance of DMBA. Aliquots of photolysis were withdrawn at five-

minute intervals and subjected to GCEm and the ha1 photolysis products subjected to

GCNS anal ysis utilipag similar chrornatographic parameters. Independentl y identified

sampled2 of 3,s-DMBA in addition to both 3,s-dimethoxybenyl methyl ether and the

3 .S-dimethoxy benzy l dimer were available for initial calibration of the chromatogram.

The spectra and methodology h m Professor Jaeger's photolysis of DMBA in 1974 were

invaluab le in establ i s h g the conditions necessary to isolate the unstable compound 2.

Once the photolysis and chrornatographic conditions were worked out so that 2 could

reliably be generated and isolatecl, as verified by 250 MHz 'H NMR spectroscopy, an

effort was made to isolate pure samples of 2 for experimentation in polar media In an

attempt to maximize the yield of 2 diquois of the photolysis mixture were withdrawn at

five minute intmals and examined by HPLC (since 2 is thennally labile and unsuitable

for GC/FID) for any evidence of 2 relative to the disappearance of 1. The HPLC was

done on a 5 pn silica gel column eluted with 5% ethyl acetate in hexanes monitored at

320 nm. In spite of dl the counter-checks available to us, the compound ihought to be 2

was not observed in the HPLC chromatogram but ail other photolysis products as denoted

in eq. 1 5 were. This caused considerable confusion w hen we isolated the compound

identified by Jaeger as 2, since the compound was reported to have E of 400 M' cm" at

3 I 5 nm. Utilising his methodology for gcavity column chromatography, the triene mis

isolated in quantities suficient to allow identification of the signa- 'H NMR of 2, as

assigned by Jaeger, but 2 was still not evident in the 320 am HPLC chromatogram.

Further to this ditficul&, the more carrfully and quickly the photolysis mixture and the

ûaction thought to contain this compound was manipulateci the less indication of its

presence was noted by 'H NMR spectroscopy. Al1 indications were tbat this compound

could not be 2, therefore a carefùi reassessment of the 'H NMR and "C NMR spectra

were initiated.

3.2 'H NMR Spectm and Assipmcnt of Chernical Shifta

The ' H NMR spectrum in CDCk of the chromatogaphed k t i o n contaïning the

suspected triene 2, (actually 24) is displayed in Appendix I ( 'H NMR, fraction 24). The

signals in the approximate range of 6 2 and 6 6 are fiom the suspected triene, the others

are impurities, p ~ c i p a l l y h m the solvent (CilCl,) and hexanes fiom the

chromatography.

Upoa critical analysis of the chernical shifts made by Jaeger for Ha it is apparent

that it shodd have a signal occurring much M e r downfeld than 6 3.58. Ha is doubly

allylic and geminal to acetate and, therefore, one would reasonably expect it to produce a

signal in the vicinity of 6 6. For instance, compare the chemical shifts of the then

poshilated compound 24 to those of the uasubstituted compound 25. The 'H NMR

spectral assignrnents are ihstrated for the uwubsti~ed compounds 25 and 26, as

provided by Hasselmann and Loosen, in addition to those for the equivalent protons as

assigned by Jaeger for 2 and those of the cumnt investigations for compounds 2 and 24

in Figure 1?3Y

6 5.19, 5.08 (S.O~,S.I~J~~)

2 24 (Not observed by Jaegar)

5 3.77

Figure 1. Important 'H NMR Shifts of Compounds 2,24,25 and 26

Although the endo and exo-hydrogens in 25 were not assigneci, the expected downfield

shift. of 6 3.43, for an ac~scetate substih>ent3' gives caiculated signais at S 6.48 (3.05 +

3.34) or 6 5.58 (2.1 5 + 3.43). The similarity between the 6 5.58 and observed 6 5.66 in

24 suggests that the ex01 e d o assignment in 25 is as shown. A fbrther difficulty with the

structural assivent of 2 is the chernical shift of the methoxy groups. They are in

similar chemical environments as depicteci in Figure 2 but the chemical shih Jaeger

ascribes to them wodd suggest that they are in two quite dissimilar enviroaments.

Examination of the two stnichires below indicates that the chernicd shifts observed in

laegers spectrum better fit 24 than that of 2. This is because methoxy on the sp2 carbon

would be expected to appear m e t dowafield tban that on the sp3 carbon.

The assignments of chernical shifts for 24: 'H NMR (CDC13 at 250 MHz) 6 5.66

(Ha, 5.24 (Hc or &), 5.16 (Hc or Hd), 4.74 Wb), 3.71 (3H, s), 3.66 (He), 3.33 (3H, s) and

2.09 (3H, s). Utilising a simulation pro- NMRSIM~~ gave the best fit of the

experimental spectnim with the foilowing coupling constants, J (Hz): eb (1.22), ec (0.9 l),

ed ( 1 33) . ca (2.44) and da (2.14). This represents the observed splining very well and

confimis that the spectra previously thought to belong to 2 is in fect 24

Figure 2. I3c CMR Spectral Assignment of Methoxy Groups on 24 vs 2

3.3 I3c S p c m and Assigimcit of chernid shifts

Our l3c NMR spectra, e.g. Appendix 2 ( ' 3 ~ NMR of Frac 38 f 9,40.>24) of the

fraction containing the suspected triene were not in agreement with the signai

assignments of structure 2. This sample also contains DMBA and chrornatographic

hexanes. Jaeger did not report a I3c NMR spectnmi.

Spectnim of 24, I3c NMR CDC13 at 250 MHz) 6 170.5 (C=O). 158.3 (<-OCW), 144.6

C=€H2), 1 12.3 (Cd<H2), 95.6 (C-Hb), 8 1.0 (ç-WH3), 76.6 GHd, 56.8 (CH30), 53.3 -

(c-&), 52.6 EH@) and 20.9 (CH3), as assigneci below in Figure 3.

The ' H-'~c correlateâ spectrum, Appendix 3, of 24 indicate that both Ha (6 5.66)

and H, (6 3.66) are on sp3 hybridid carbons at 6 76.6 (under the C X l 3 ) and 6 52.6,

respectively . The uasubstituted compound 25 has similar cbmiical sbift at quivalent

unsubstituted carbons as those of 24. The reàuction of shielding induceci by a strained

cyclobutane ring with added substitution is eviderit in both the signals of 24 and 25. Very

large a-âeshielding and P -shielcüng effects are observed for the akenyl carbons with

methoxy and acetate substituents. The net effect is to reduce shielding with consequential

increase the chemical shift on the alpha carbon, and to increase shielding with decreased

chemical shift on the beta carbon. This is observed in structure 24 relative to 25

25 24

Figure 3. I3c NMR Assignments of 24 Relative to 25

TLC of the pure hctions resulted in a senes of bands, most of which contallied

only s m d amounts of the sought after compound identifid as 2 by Jwger. It was

apparent that our compound was not thennally stable. AAer exhausting all reasomble

photolytic and chrornatographic methodological possibities, it appears that 2 is in fat

denved t h e d l y fiom 24 during solvent removal and chrornatography. Moreover, 24 is

likely formed photolyticaüy &er grneration of 2.

The fiactions of the pbotoisomer 24 were obtained with purity as hi& as W h on

silica gel dry- flash chromatography by elutiag with 5% ethyl acetate in hexaws but the

fmctions always contained some DMBA. This was likely because the CO-solubility of

DMBA and the photoisorner 24 is great s k they elute on silica in fiactions sequentially

adjacent. It is also possible that there is some themai conversion of 24 back to DMBA

on the silica gel.

Initiaily the photolysis mixture was colo~~less but developed a yellow colour and

a flocculent precipitate during solvent removal. GC/MS and GClFID anaiysis of the

precipitate indicated it to be dimenc. The formation of dimer is likely a cornpetitive

reaction related to the thermal conversion of 24 to 2 and, because the medium is

nonpolar, the mechanism cm be presumed to be a thermal cycloadditioo of some

unknown kind. Up to this point it was believeà that extreme care was necessary in order

to isolate any of the triene 2 but a relatively pure sample was le ft at room temperature in

hexane over the weekend. The sample was very yellow but was stiU largely cornprised of

what appeared to be the triene 2.

The ' H NMR signais in the area of S 5.0-5.4 ppm were very much in evidence

which indicates that the development of colour cannot be xdated to the conversion of 2 to

some other product. Timed aliquots of photolysis product were checked for absorbtion at

320 nm and it was noticed tbat the initiaiiy mail shoulder at 320 nm increased in

intensity over the course of many hours as the samples stood in the dark. Figure 4 is of

the superllnposed W spectra of the photolysis products of DMBA over an eight hour

period rrialysed on a diode anay scanning spectmphotometer.

Figure 4. UV Spectra of DMBA Photoproducts Cher Tirne.

The development of the longer wavelength absorption and conversion of 24 to 2 couid be

venfied by 'H NMR. The infrease in absohce at 320 nm was ploned as in Figure 5

and indicaied the conversion of 24 to 2 was first order and had a half-life of

approximately 10 hrs at arnbient temperatures.

Figure 5. Plot Inâicating FUst Order Conversion of 24 to 2.

It was dso detennined that the conversion of 24 to 2 was first-order in hexanes at 50°C

with a balf-li fe of 89 min. For the uasubstituted compound, a half-life of 2 1 O min. in

THF c m be calculated h m the Arrhenius values reporteci by Haselman and ~oosen?

Sarnples of 2 chat were isolated for both 'H NMR and I3c NMR anaiysis changed when

rescanned at a later date in spite of the fact they were stored at -4' C. It was subsequently

determined that NMR sarnples of 2 in CDCb were relatively unstable and were shown to

rearrange to the toluene acetate derivative 7, another apparent photo-Fries product,

quantitatively after 2 hrs at 50° C. This observed themal instability also htrated

attempts to generate clan specûa of fiaçtions suspected of containing 2 since more scans

ovcrtly meant more conversion of analyte. Jaeger ' reported the same conversion in

benzene at 50' C but in fact, the process Jaeger observed was the thermal conversion of

24 to 2 then 2 to 6. It Uierefore appears that the compound p~viously reported as 2 by

Jaeger is, in fact, the bicyclic isomer 24.

The 'H NMR spectrum of 2 in CDCll could not be analysed becaw the signais

for Hb, He, & and H. were hast coincident at 250 MHz giving an unresolved multiplet.

niese sigials were well dispefted in acetonitrile-d3 though. In acetonitde, 2 rearranges

back to DMBA, presumably because this more polar solvent induces contact ion pair

formation, so that DMBA is present in the spectra of 2.

As shown on structure 2 (Figure 1) on page 28 , the five single hydrogens are in

the range of 6 5.08 to S 6.09, Appendix 4, (the signal at 6 5.04 is DMBA). The two

rnethoxy groups (unassigned) are at 6 3.68 and 6 3.65 as expected for their similar

chernical environment. An 'H-'~c correlated specmmi, Appendix 5, a h w s assignment

genenites 3,s-dimethoxyethylbenzene, 6. Therefore, 2 is fomied as a primary

photoproduct of DMBA in methanol but is repidly converted by ground suite solvolysis to

3,5-dimethoxybenyl methyl ether, 22. It is stiil uncertain what fraction of 22 is f o d

in the primary photochemistry of 3,s-DMBA and what portion is f o d in a secondary

thermal process fiom 2.

3.4 Laser Fhsh Photolysis of DMBA

Initially, laser flash photolysis of DMBA in hexane was perfomed with a YAG

laser at 266 m. The nonpolar solvent hexane was used in order to veriQ the

methodology since we knew that 2 was photolytically generated in hexanes

Once the signature absorption peak at 320 nm belonging to 2 was identified polar

solvents were substituted for hexane. Hexafluoroisopropmol, isopropanol and methanol

were used in order to examine the lifetime of 2 generated in this manner. The resultant

specmim indicated an absorbance maximum at 320 nm that remaineci constant on the

millisecond tirne scale. This is a reasonabIe indication that 2 is fonned in methmol,

albeit briefly, in a process similar to its formation in hexanes. Samples of DMBA were

then subjected to multiple 266 nm laser pulses and transferred to a diode anay

spectrorneter to monitor the decay of the photogenerated transient. The decay lifetime

was identical to that obtained h m the preparative sale NMR samples. This is m n g

evidence that 2 is also a primary photoproduct in methanol.

Examination of the structure of 24 shows that it could fom by secondary

photochemistq of 2 in an ailowed disrotatory butadiene to cyclobutene ring closure. This

means that two photons are absorbed for the conversion of DMBA to 24 in hexanes but in

methmol2 reacts by grouud state solvolysis before it cm be converted to 24. This is

because 2 will be converted to the ether 22 before a second photon can be absorbe4

because the energy necessary to form ionic species by soivolysis is low in methanol.

Having stated so, it appears that 2 is a primary photoproduct in polar, nucleophilic

solvents, like methanol, and may provide an alternative pathway for formation of ion-

derived products in the photolysis of 1,3,5-DMBA. This is Unportant because 3,5-

DMBA. and other multiple methoxy substituted benzyl acetates, have been show to give

a higher yield of ionderived products than direct heterolytic mechanisms predict?7J8

This ex plains the discrepancy in the yields of those same products when compared to the

theoretical yields expected h m direct heterolysis to e h . The yield of the ionderived

product, the methyl ether 22, is thereby increased by a ground state pathway for its

formation that is independent of the photocbernical pathway. The formation of 2 is

analogous to the photo-Fries reaction where dical pair intermediates, generated h m the

singlet excited state, fonn non-aromaîic isomers by recombinaîion at ortho (and para)

positions.

Appendis 1. 'H NMR Spechum of Bicyclic Isomer 24.

13 C NMR Spectnim of Bicyclic Isomer, 24.

'H MNR Specbimi of the 5 Deshieldeci Protons in 2.

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