Hückel and Möbius Aromaticity in Bicyclic Systems

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Hückel and Möbius aromaticity in bicyclic systems

Citation for published version (APA): Gillissen, H. M. J. (1982). Hückel and Möbius aromaticity in bicyclic systems. Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR69545

DOI: 10.6100/IR69545

Document status and date: Published: 01/01/1982

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Hückel and Möbius aromaticity in bicyclic systems HUCKEL AND MÖBIUS AROMATICITY IN BICYCLIC SYSTEMS

Proefschrift

ter verkrijging van de graad van doctor in de technische wetenschappen aan de Technische Hogeschool Eindhoven, op gezag van de Rector Magnificus, Prof. Ir. J. Erkelens, voor een commissie aangewezen door het college van dekanen in het openbaar te verdedigen· op vrijdag 15 januari 1982 te 16.00 uur

door

HUBERT MARIA JOZEF GILLISSEN

geboren te Kerkrade DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR

DE PROMOTOREN

PROF. DR. H.M. BUCK

PROF. DR. H. CERFONTAIN

CONTENTS

Chapter I General Introduetion 7 Heferences and Notea 11

Chapter 11 Intramolecular electron transfer in 9-(arylseleno)bicyclo[4.2.1]nona-2,4,7- trien-9-yl and -bicyclo [4.2.1]nona-2,4- dien-9-yl carbanions promoted via the aryl ligands 13 11.1 Introduetion 13 I I. 2 Quench reeulte of 9-arylaeleno eubetituted carbanione 15 I I. 3 Structural aaeignment of the quenah produate 23 II.4 Direct 1 H NMR obeervation of anionio eolutione 27 I I. 5 Discussion 28 II.6 E:r:perimental 35 Referenaee and No tee 49

Chapter 111 Reductive eliminatien and skeletal re arrangement of S-hydroxy selenide deri vatives of bicyclo ~.2.1]nona-2,4,7- triene in a super acid medium 51 III.l Introduetion 51 III. 2 Rearrangement of S-hydro:cy eele- nides 54 III.3 Diecuesion 56 III.4 E:cperimental 58 Referenaee and Notes 62 Chapter IV Cationic derivatives of bicyclo[4.2.1J nona-2,4,7-triene as modelsystems for ground-state Möbius aromaticity 64 IV.1 Synthetia aonsidePations 64 IV.2 StePeoahemistPy of pPotonation 68 IV.3 NMR speatPosaopia investigations of aaPboaations undeP ~ong ~ife aonditions 10 IV.4 Disaussion 18 IV. 5 ExpePimental 81 RefePenaes and Notes 94

Sun:unary 97

Samenvatting 99

Curriculum vitae 101

Dankwoord 102 CHAPTER I

GENERAL INTRODUCTION

A concept, which has been of special interest for or 1 ganic chemists, is the Hückel rule , which involves that for ground-state molecules with a cyclic array of atomie orbitals, 4n+2 electrens result in aromaticity and thermo dynamica! stability. Fundamental in Hückel's reasoning is the large energy difference between ground-state and excited state(s) in a ring with 4n+2 electrons, whereas 4n electrens result in a smal! energy separation. This aspect has been nicely demonstrated in a quantitative way for the cycliza tion of butsdiene using complete VB and MO calculations by van der Lugt and Oosterhoff2 , The same is also true fora cyclic array of orbitals with 4n and 4n+Z electrons, respec tively, when this interchange is accompanied with an odd number of sign inversions for the orbitals in the ring. In the latter case, we are generally speaking of Möbius aroma ticity: 4n electrens result in aromaticity. Using simple MO calculations, the Möbius aromaticity concept has been explored for a variety of reactions, which are commonly 3 4 known as Woodward-Hoffmann reactions ' • It attracks attention that energy lowering of transi tion states and stabilization of intermediates has been 5 hardly explained with the concept of Möbius aromaticity , although the thermal conrotatory conversions and the thermal sigmatropie shifts with inversion of the migrating carbon are distinct examples for 4n electron aromaticity (Figure I).

7 b

Figure I: Transition state for a thermal aonrotatory con version (~) and a thermal sigmatropie shift with

inversion of the migrating carbon (~).

Of course, ground-state Möbius aromaticity has never been observed in consequence of the steric strain, which imposes a sign inversion on a small cyclic polyene. One possible way to generate ground-state 4n electron aromaticity is the preparation of bishomocyclic systems l· Sign inversion may then be realized by a simple orientation of the carbon p-orbital, which is homoconjugated with the two neighbouring carbons.

1 In fact, this resembles the transition state for the ther mal [1 ,3] C and [1 ,4] C sigmatropie shifts. In spite of the fact that the extended VB theory as was ~utlined by Oosterhoff et al. 6 is a direct tool in the search for the fundamentals determining aromaticity in the general sense, Möbius molecules seem to be exceptious or in other words their existence looks rare, whereas molecules possessing Hückel aromaticity are present in an overwhelming

8 quantity. A similar situation is encountered in antiaroma ticity7, i.e. 4n electrans in a Hückel arrangement or 4n+2 electrans in a Möbius cycle. From the work of Schipper and Buak 8 it appeared that if geometrical restrictions are di minished, the system escapes the 4n electron Hückel anti aramaticity via 4n-2 electron Hückel aromaticity and the simultaneous formation of a localized double bond (~).

Befare this fascinating observation Buak et aZ. 9 investiga ted the thermal D,j]shifts in cyclic systems with a pertu bation approach and INDO calculations. It was clearly shown that the concept of Hückel aromaticity controls the supra facial shift. Unfortunately, the antarafacial shift was not discussed in a quantitative way. We may expect that the an tarafacial shift results in Möbius aromaticity for the transition state. Hückel vs. Möbius aromaticity is then re flected in the electron density on the migrating hydrogen. The value of this concept is clearly demonstrated when the shift occurs between non-bonding carbons e.g. in the supra fadal [1, s] H shift in cycloheptatr.iene the hydragen carries one electron, whereas in the suprafacial [1, 7] H shift, which is only of theoretica! interest, the electron density on hydragen increases. In this thesis the concept of aromaticity is fully explored with a number of experimental ex~mples. The systems derived are cations and anions which demonstrate bishomo conjugation resulting in Hückel and Möbius aromaticity. The various structures were established by 1 H and 13C NMR mea surements. Generally, the ions are derivatives of bicyclo- ~.2.1]nona-2,4,7-triene. Chapter II deals with the chemistry of the bicyclo ~.2.1] nona-2,4,7-trien-9-yl carbanion. According to GoLd 10 stein's theoretica! model , this carbanion should besta-

9 11 bilized by longicyclic interactions • The carbanions are generated by the cleavage of arylselenoketals. This strate gy leads to the introduetion of an arylseleno-group at the charge center. It is shown that the chemistry of the carb anions is dominated by the stereospecific transposition of the negative charge from the anti-Cg carbanion to the aryl ring of the introduced substituent via proton transfer. Electrophiles tend to react with the èyn-Cg carbanion. This result is compatible with the notion of a bishomoaromatic interaction12 between Cg and the diene moiety. In Chapter III the syn-c10 carbocation derivatives of bicyclo[4.2.1]nona-2,4,7-triene are introducedas possible model systems for the investigation of ground-state Möbius aromaticity. 6-Hydroxy selenide derivatives of bicyclo~.2.1] nona-2,4,7-triene were investigated in super acid media. It is demonstrated that neighbouring group participation13 by selenium preelucles the formation of free c,o-carbocations. Instead, exocyclic olefins and selenenyl cations are produced in a solvent cage. This initiates a rearrangement reaction for which a mechanism is given. Chapter IV describes the generation and investigation 13 1 of a-hetero-substituted c10 -cations. C and H NMR spec troscopy suggest that the empty orbital at c1 0 is o.rienta ted perpendicularly with respect to the mirror plane of the cations. The saturated analogues of these cations also adopt this configuration. The chemica! shift differences between the unsaturated cations and the saturated derivatives may suggest a certain degree of charge delocalization via Möbius aromaticity.

10 References and Notes

1. E. Hückel, z. Phys., 1931 , ?0, 204. 2. a. W.Th.A.M. van der Lugt, L.J. Oosterhoff, Chem. Com- mun., 1968, 1235. b. W.Th.A.M. van der Lugt, Thesis, Leiden, 1968. c. W.Th.A.M. van der Lugt, L.J. Oosterhoff, J. Am. Chem. Soc., 1969, 91, 6042. 3. a. R.B. Woodward, R. Hoffmann, J. Am. Chem. Soc., 1965, B?, 359, 2045, 2046, 2511 • 4511. b. R.B. Woodward, R. Hoffmann, Angew. Chem., 1969, 81, 797. 4. a. H.E. Zimmermann, J. Am. Chem. Soc., 1966, BB, 1564. b. H.E. Zimmermann, Accts. Chem. Res., 1971, 4, 272. c. M.J.S. Dewar, Angew. Chem., 1971, 83, 859. 5. E. Parenhorst postulated a Möbius-type intermediate in the photochemistry of benzene: E. Farenhorst, Tetrahe-. dron Lett., 1966, 6465. 6. W.J. van der Hart, J.J.C. Mulder, L.J. Oosterhoff, J. Am. Chem. Soc,, 1972, 94, 5724. 7. a. R. Breslow, J. Brown, J.J. Gajewski, J. Am. Chem. Soc., 1966, BB, 1564. b. M.J.S. Dewar, G.J. Gleich, J. Am. Chem. Soc., 1965, B7, 685. 8. a. P. Schipper, H.M. Buck, J. Am. Chem. Soc., 1978, 100, 5507. b. P. Schipper, Thesis, Eindhoven, 1977. 9. a. J.R. de Dobbelaere, J.M.F. van Dijk, J.W. de Haan, H.M. Buck, J. Am. Chem. Soc., 1977, 99, 392. b. J.R. de Dobbelaere, Thesis, Eindhoven, 1976. c. W.A.M. Castenmiller, Thesis, Eindhoven, 1978. 10. a. M.J. Goldstein, J. Am. Chem. Soc., 1967, B9, 6357. b. M.J. Goldstein, R. Hoffmann, J. Am. Chem. Soc., 1971, 93, 6193. 11. A longicyclic interaction is an interaction between three formally isolated n-systems in a longicyclic to pology10. The building bleeks of an unsaturated com pound are intact conjugated polyene segments, the so-

11 called ribbons. These are designated as unbroken lines. The mode of interaction is depicted by broken lines. A typical example of a bicyclic system with longicyclic topology is the 7-norbornadienyl cation 3: +

LongicyaLia topoLogy

12. For reviews on the subject of homoaromaticity see a. S, Winstein, Chem. Soc. Spec. Publ., 1967, 21, ~. b. S. Winstein, Quart. Revs. Chem. Soc., 1969, 23, 141. c. P.D. Bartlett, Non Classical !ons, New York, 1965. d. P.M. Warner, Topics Nonbenzenoid Chem., 1976, 2. e. L.A. Paquette, Angew. Chem., 1978, 90, 114. 13. For reviews on neighbouring group participation see a. B.C. Capon, Quart. Revs. Chem. Soc., 1964, 18, 45. b. B.C. Capon, S. Mc.Manus, Neighbouring Group Partici pation, New York, 1976.

12 CHAPTER 11

INTRAMOLECULAR ELECTRON TRANSFER IN 9-(ARYLSELENO)BICYCLO [4. Z.1) NONA-Z ,4, 7-TRIEN-9-YL AND -BICYCLO (4. Z.1) NONA-Z ,4- DIEN-9-YL CAREANIONS PROMOTED VIA THE ARYL LIGANDS 1

II.l Introduetion

In recent years a number of studies have been reported concerning the homo- and bicycloaromatic properties 2 of the 3 bicyclo [4. 2 .1] nona-2,4, 7-trien-9-yl cation .! • In disagree ment with the prediction4 this cation turned out to be de stabilized • The corresponding carbanion l is expected to be stabilized according to GoZdstein's prerequisite for 2 longicyclic stabilization • However, until now reports con-

cerning the preparatien and properties of. the unsubstituted carbanion 2 are almast completely lacking~ Photoelectron spectroscopit evidence 5 and 13 C NMR data 6 suggest bicycloaromatic interactions in the azabicycle l• which is isoelectronic with carbanion l· In this mole cule, the lone pair is positioned syn to the diene segment. According to CND0/2 calculations, this isomer is 5.4 kcal more stable than its invertomer. The 9-phospha~bicyclo- [4.2.1]nona-2,4,7-triene ~shows the samekind of behaviour:

13 • Ph Ph 'P_,",... ib-~ 4so•c~d::J 4 .§_

7 it is thermally generated from its epimer 4 • The base catalyzed decomposition of the pyrazoline 6 gave bicyclo~.Z.l]nona-2,4,7-triene z, presumably via 8 the intermediacy of carbanion 2 • When the reaction was run

8: ------2 ----

in a deuterated solvent, deuterium was incorporated prefe rentially from the syn-direction (ratio>l.6). This result is consistent with the proposition of favourable syn bis homoaromatic interactions in 2. Carbanion l could not be prepared by the classica! 9 ether cleavage method , using the syn-9-methoxy ether and sodium-potassium alloy~. This reluctance for generating l is further exemplified by hydracarbon z, which does not incorporate deuterium at c9 upon reaction with lithium cy 10 clohexylamide in cyclohexylamine-d?. , Recently, the 9-carbonitrile substituted bicyclo ~.2.1] nona-2,4,7-trien-9-yl carbanion g was generated in an indi rect manner by the rearrangement of 9-carbonitrile-ais 11 bicyclo[6.1.0]nona-2,4,6-trien-9-yl carbanion §_ • Carb anion g reacted with HCl in a nonstereospecific way to pro duce the protic epimers syn- and anti~lQ. Quenching with methyl iodide gave 9-methylbicyclo~.2.1]nona-2,4,7-trien- syn-9-carbonitrile !!·

14 CN

CN ~

NC H ~ syn-10 onti-10 11

Direct generation of negative charge at c9 can be achieved by the introduetion of heteroatoms, which can be cleaved from carbon readily. From organoselenium chemistry it is known that seleneketals are excellent precursors for 12 13 the generation of a-seleno substituted carbanions ' , Therefore, seleneketals of the bicyclo[4.2.1]nonane series were investigated. In the studies documented below, the properties of the carbanions generated from these seleno ketals are described. In the intermolecular reactions of these carbanions with various electrophiles, homoaromatic interactions play a smal! role. Much more important is the intramolecular transfer of negative charge from c9 to the aryl ligands via proton transfer. This process proceeds with 100% stereospecificity.

II.2 Quenah results of 9-arylseleno substituted aarbanions'

The seleneketals 12a-c reacted with n-BuLi in THF at -78°C via C-Se bond cleavage to produce a-seleno substituted carbanions ~· Direct quenching after carbanion formation leads to c9-substituted derivatives (Table II). Deuterium oxide (or methanol-d4) afforded c9-deuterated epimers 18b and 19b in approximately equal amounts. Methyl iodide gave predominantly 9-methyl-anti-(p-tolylseleno)bicyclo~.2.1]-

15 R R @-se se-@ R'@-hse- n-Bu l1 ... d:J f -~ 12 Q- E ---35 o-e a R=H c R=o-CH - 3 nona-2,4,7-triene 19c together with the substituted aromatic compound 20c. The reaction with prenyl bromide produced the expected 9-(3-methyl-but-2-enyl)-anti-'9-(p-tolylselerio)bi cyclo [4.2.1] nona-2,4, 7-triene 1 Products like 20c, attri butable to electrophilic substitution in the aromatic ring, were formed in all reactions when electrophiles were added 0.5 hafter carbanion formation (Tables I and II). The phenyl selenoketal 12a then led predominantly to products ll• with substitution in the phenyl ring (Table I). The formation of c9-substituted products could be suppressed comple tely when the reaction was run in the presence of a crown ether. Complexation of the Li+-cation drastically increases the basicity of the initially formed c9-carbanions ~. which leads to the formation of aryllithium compounds 36 (vide infra). Thus, selenoketal 12b produced ayn-9-(p-tolyl seleno)bicyclo~.2.1]nona-2,4,7-triene 18a and ayn-9-(2,4-di methylphenylseleno)bicyclo 4.2.1 nona-2,4,7-triene 20c upon the reaction with methyl iodide in the presence of 18-crown-6.

CH3

n-BuLi H Se-@-CH3 12 b -=------1- 18-crown-6 + 2 CH 3I tb 18 a 20c

The o-tolyl selenoketal 12c afforded a third kind of product. Tetracyclic derivatives ~ and IZ were isolated

16 Tabte I: Products of the reaation of setenoketal 12a with n-BuLi and eteatrophiZea x

....1 -n Buli 2 E 12a .... ~ 0 -78°C T°C 26-©~ ©r:bf ~ 26-@~ ...-: f -- -- 8 x 11. 14 :!.§.. x 1§_ 11. y E x t~ T°C Products (%).2.

H20 H 30 -78 92.5 13a (81.4) 14a (18.6) 15a 16a 17a 60 20 76.4 16a (100) D20 D 30 -78 90.6 13b (30. 8)!. 14b ( 24. 1) 15b (45.1)!. 16b 17b CH 3I CH 3 30 -78 96 13c 14c (15) 1 Sc (85) 16c 17c 60 zo 84.4 16c (27)[. 17c (73).1Z. PhC(O)H PhC(OH)H 30 -78 87 13d 14d (48.1) 15d (51.9) 16d 17d PhzC(O) Ph 2C(OH) 30 -78 84.5 13e (16) 1 Se (84) 16e 17e DMF C(O)H 30 -78 81 13f (40)!. 15f (60)!. 16f 17f C0 C(O)OH 30 -78 d 2 90 11& ~ (17.6)- .!2..8. lZ8.

~ In minutes after the addition of n-BuLi. ~ Calculated from isolated n-butyl phenyl selenide. _ .2. Calculated from isolated products. !! Tot al yield. !. Calculated from •H NMR integrals. ~i Endo:exo ratio 7:3 • .IZ. Methyl substituent 100% endo...... Q) eZ.eatr>ophiZ.es H Se 0 CH3 CH H_..., X 3 li

E x t~ ".è. Products(%)~ H20 H 2 -78 80.4 -18a (56) -19a (44) -20a -21a -22a 30 -78 94.4 -18a (65) lli (35) 60 20 70 21a (100) D 20 D 2 -78 80.4 18b (56) 19b (44) 20b 21b 22b - d - d - - 30 -78 94.4 -18b (19.3)- -19b (35.8) -20b (44.9)- CH 3I CH3 2 -78 88.3 -18c 19c (85) 20c (15) -21c -22c 30 -78 98.4 19c (72.1) 20c (27.9) R e R1Br ,- 2 -78 84.9 -18d -19d ( 1 00) -20d -21d - 22d PhC(O)H PhC(OH)Hl 30 -78 84.4 18e (23) 19e (59) 20e (18) 21e 22e R2C(O)H R2C(OH)H.Il. 5 -78 100 18f (26) 19f (74) 20f 21f 22f R3C(O)H R3C(OH)H 5 -78 100 ~ (17) .:!28: (83) 12..& ~ § ~In minutes after the addition of n-BuLi • .è. Calculated from isolatèd n-butyl p-tolyl selenide. from isolated products. Calculated from 1 H NMR integrals. R (CH ) C=CHCH -. ~alculated ~ ~ 1= 3 2 2 lR2= (Ph)(Me)CH- • .ll. R3= (Et)(Me)CH-. Tab~e III: Produats of the reaation of se~enoketa~ 12a with n-BuLi and e~eatrophiZes

CH 3 CH3 1 n Bu Li ,._,2E . r-- _,...... 12c · ,.... @-s·x' 0 - -'78°C T°C ;!)~~ ;Elp~ . ...--: ;n d:::; x --- x 23 21. 25 26 n.

'_:_J x t!! T°C tk products (%)~ H20 H 30 -78 86.4 -23a (68.5) -24a (14) -25a (17.5) -2.7a 60 20 95 26a (100) d (12.8)d D20 D 30 -50 92.4 --23b (9. 2)- 24b --25b 26b (78)!. -27b CH 3I CH 3 30 -78 92 --23c 24c (39.4) --25c (9. 9) 26c (13.7)t -27c (37)i-

!! In minutes after the addition of n-BuLi. É. Calculated from isolated n-butyl o-tolyl selenide. ~ Calculated from isolated products. ~ Calculated from 1 H NMR integrals. !. Predominantly (90-95%) endo deuterium. i Endo:ereo ratio 7:3. i. Methyl substituent endo. CD- ~ Table IV: Produate of the reaation of selenoketal 28 ~ith n-BuLi and eleatrophiles x x 'L_ -@-eH, H s,-@-cH3 a;:J CH3-@-~sex ;}) ê6Hse-@-cH 3 x 30 ~ ":: 33 _...", -- 30a

b E x t~ %- products (%)~

33a H2 0 H 2 56.2 -30a (20) -31a (80) -32a - 30 84 -30a (70) -31a (30) 60 81 30a (30.1)-d 33a (7)~ o o D 2 56.2 30b (8) 31b (80) · 32b+30a ( 12) 33b 2 - - -- - 30 70 -30b (6.2) 1b (38.4) --32b+30a (55.4) CH 3I CH 3 30 64.3 -30c -31c (42) -32c (20) -30a (38) -33c

~ In minutes after the addition of n-BuLi. ~ Calculated from isolated n-butyl p-tolyl selenide. ~ Calculated from isolated products. ~ Total yield of isolated product. together with c9-substituted compounds ~ and 24 and sub stituted aromatic products ~ (Table III). Deuterium oxide (and methanol-d4) gave predominantly the c5-substituted tetracyclic compound 26b. Methyl iodide produced predomi nantly the c3-endo substituted derivative 27c. All triene selenoketals 12a-~ gave exclusively tetra cyclic products when the electrophile was added to the carb anionic solution at room temperature. The isolation of electrophilic aromatic substitution products indicated that the initially formed Cg-carbanions 35 isomerize stereospecifically to aryllithium cempounds 36 (vide infra). H se-@RLi tb 36

So, the intermediate aryllithium cómpound 36 plays a crucial role in the reactions of the triene selenoketals. This raised the question about the origin of the proton at Cg in intermediate 36. Therefore, the deuterium-labeled selenoketal 12d was synthesized. This selenoketal was reacted D*S•D D Se*DD D ood:JÓ b f ~ _..,

12 d with n-BuLi and subsequently with water. A product 38 was isolated with deuterium at Cg and with protium in the aro matic ring (singlet at 7.2 ppm). In another experiment, the selenoketal 12e was reacted

21 with n-BuLi in the presence of furan. The benzyne-addition

n-Bu Li ,_78° c

12e 39 compound ~was the only product isolated. Thus, the proton at Cg resulted from a complete1y stereospecific electron transfer from Cg to the ortho-posi tien of the aromatic ring via proton exchange. In order to learn more about the possible homo- and bicycloaromatic properties in the arylseleno-substituted carbanions 35, the diene selenoketal 28 and the saturated selenoketal 2g were investigated.

CH3-@-:b -@-cH3 CH3-@-dj -@-cH3

28 29

The diene selenoketal 28 reacted somewhat slower with n-BuLi at -78°C than the triene selenoketal 12b. Reaction with an electrophile at this temperature gave three products: c9-substituted products, compounds formed via electrophilic aromatic substitution, and syn-9-(p-tolylseleno)bicyclo ~.2.1]nona-2,4-diene 30a (Table IV).Deuterium oxide and methanol-d4 afforded directly after carbanion formation mainly syn-C9 deuterated product 31b. This contrasts with the behaviour of the selenoketal 12b, which produced both Cg deuterated epimers in approximately equal amounts (vide su pra). The dienyl carbanions gavewith deuterium oxide at a

22 later point in time predominantly syn-9-p-tolylseleno deri vatives 30a,~ and 32b (Table IV). At room temperature the main product of the reaction of the anionic salution with water was 22!• Tetracyclic compound 33a was isolated in very low yield (less than 7%), A remarkable difference be tween diene selenoketal 28 and triene seleneketals 12 was the formation of 30a in all the quench reactions with ~· Apparently, anti-C9 dienyl carbanions are more basic than anti-Cg trienyl carbanions ~· In all likelihood, the dienyl carbanions react partly with n-butyl p-tolyl selenide. The saturated selenoketal ~ reacted very sluggishly with n-BuLi. After 1.5 h at 0°C, quenching with water afforded a product mixture which still contained 40% starting compound. Therefore, no further experiments were performed.

II.3 StruaturaZ assignment of the quenah produats

The stereochemistry of the bicyclic protic products is assigned on the basis of the 1 H NMR spectra which exhibit a triplet for H9 of the syn compounds (13a, 18a, 23a and 30a), whereas a singlet is observed for the anti compounds 3 (14a, 19a, 24a and 31a) , The stereochemistry of the deute rated products follows from a compàrison of their 1 H NMR spectra with those of the c9-protonated products (Table V). The syn disposition of the seleno moiety in the aro matic substitution products (11, ~, ~ and ~) is esta 3 blished on the basis of the triplets for H9 • Ovtho substi tution is evident from 1 H and 13 C NMR speetral data (Tables VI and VIII). The configuration of the methylated derivatives is ten tatively assigned on the basis of product formation similar to that in other quench reactions (vide infra). NOE experi ments did not provide further structural informations. The same arguments hold true for the product 19d. The stereochemistry of the benzylic alcohols 14d, 18e and 19e can be established on the basis of their speetral properties (Tables V and VII). The diastereotopic ring car bons all absorb at different field positions. The compounds

23 14d and ~display large 13C NMR shift differences between the diene carbons, whereas the chemica! shift differences between the monoene carbons are smal!. For the älcohol 18e the situatipn is reversed. The speetral data are consistent with a syn disposition of the benzylic alcohol, with res pect to the diene bridge, in 14d and 19e, whereas 18e has anti stereochemistry. Additional stuctural information on compounds 14d-f, 18e and 19e is obtained by using lanthanide shift reagents. Addition of Eu(fod) 3 to the benzylic alcohols causes marked nonequivalent downfield shifts of the bridgehead protons, the effect being the most pronounced for alcohol 18e (Figu re I). The results pointtoa time-averaged positioning of the hydroxyl function out of the plane bisecting the bridge head-bridge~ead axis. Dreiding models reveal that this mode of complexation can be realized. In 18e one bridgehead pro ton is pointing towards the hydroxyl group, whereas in 14d and 19e the corresponding proton is pointing away. This explains why the bridgehead proton in 18e is shifting faster than those in 14d and 19e and confirms the assigned stereo chemistry. In spite of the syn disposition of the alcohol function in 14d and 19e, the downfield shift of the monoene protons is larger than for the diene protons. This indicates that europium is located closer to the monoene bridge. In spection of the Dreiding models indicates that this mode of complexation is realized. The downfield shift of the monoene protons of 18e is, as expected, significantly larger than that of the diene protons. For the diphenyl carbinol 14e europium-induced shifts are very small, due to the crowded position of the hydroxyl function. Therefore, no extra structural information could be obtained. The application of Eu(fod) 3 is more success ful with 14f, which has a more approachable aldehyde ' -- functionality. The downfield shift of the diene protons is larger than for the monoene protons, which confirms the syn configuration of the aldehyde group with respect to the diene bridge (Figure I). In the syn benzylic compounds 14d and 19e, the monoene

24 N N :x: 14 f :x:,. 14d <:] 160

120 120 He

80 80

80 120 80 120 Eu(fodJ tmg) Eu lfod 1 ( mgl 3 3

N :x: :x:N ,. ,. <:J 18e <:] 19e 300 300

200 200

100 100

100 150 100 150 Eu(fodJ 1mg) 3 Eu Ifo d 13 I mg l

Figure I: Plot of the induaed chemiaal shift. Av. versus the amount of added shift reagent for protons of 14d. lil• 18e and 19e.

25 N N J: J: :::. :::. <:l 18g <:l 19g 150 ISO ...,

100 "" 100

1 He

50 "1' 50

H2.5T

0 50 100 50 100 Eu(fod) (mg) Eu(fodl (mgl 3 3

N J: :::. <:l 18f 300

200

100

50 100 Eu I tod 1 I mg l 3 Eu(fod 13 (mg) Figur>e II: Plot of the induaed ahemiaat shift~ 6v~ ver>sus the amount of added shift r>eagent for> pr>otons of 2!!.1.. and ll~ 1J..t. :md ilj T= thr>eo~ E= er>ythr>o.

26 protons are respectively shifted 0,6 and 0.4 ppm upfield with respect to the corresponding seleneketals 12a and 12b, whereas in 18e the monoene protons are shifted slightly downfield (Table V). Due to the large steric interactions between the benzylic alcohol function and the seleno moiety, the latter is positioned time-averaged above the monoene protons of 14d and 19e, causing a shielding of these protons. In 18e these large steric interactions do not occur. The monoene protons of the diphenyl carbinol 1 display a 0.9 ppm upfield shift. Thus, the alcohol function of 14e is assigned the syn configuration with respect to the diene bridge. The stereochemistry of the alcohols 18f,~ and 19f,~ follows straightforward from their NMR data (Tables V and VII) and from LIS measurements (Figure II). Both .:!!.& and ~ are mixtures of the threo and erythro compounds. In the 13C NMR spectra two sets of resonances appear. Further more, the diastereoisomers interact differently with the europium shift reagent (Figure II). The smal! vicinal coupling constants (J approximately 3 Hz) indicate that the threo compounds are produced predominantly (.:!!.&: 62% threo; ~: 65% threo). The alcohols 18f and 19f consist of only one diastereoisomer. Again, the coupling constants (1 appro ximately 6 Hz) point to the threo configuration., Thus, the 1 arylseleno carbanions l§. fellow Cram s rule " upon reaction with ebiral aldehydes. The structure and stereochemistry of the tetracyclic products are obtained from 90 MHz 1 H NMR decoupling experi ments. 1 H NMR speetral data for these compounds are dis played in Table IX.

II.4 Direct 1 H NMR observation of anionic soLutions

The reaction of the triene selenoketal 12a with n-BuLi 1 in THF-d8 was investigated with the aid of H NMR spectros copy. The structure of one intermediate could be elucidated by 90 MHz decoupling experiments. This intermediate was formed at approximately -45°C. It was stable for several

27 J 1,2 2,3 3,4 4,5 5,6 6,7 Hz 4.0 5.0 10.5 8.5 4.5 3.0

J 7,8 1,8 1,9 6,9 1,7 1,3 Hz 5.5 2.5 8D 7.3 1.0 1.5 .

37o

6 5 4 3 Figure III: Part of the 1 H NMR spectrum of allylic anion 37a. 1 H NMR speetral data for 37a. days at room temperature. Quenching with water afforded the tetracyclic derivative 16a as the sole product. The interme diate had the tetracyclic stucture 37a (Figure III), At temperatures below -45°C other intermediates were present. However, we were unable to identify these because of fast intramolecular reactions (vide infra). No interme diate of the reaction of selenoketal 28 with n-BuLi in THF-d 8 could be identified. An allylic carbanion iQ, com parable with 37 was not observed.

II. 5 Discussion

The reaction of 9,9-bis(arylseleno)bicyclo~.2.1]nona- 2,4,7-triene with n-Buli in THF proved to be an efficient

28 metbod to generate seleno-substituted carbanions. High yields of products were isolated after quenching with elec trophiles. Three different products were isolated: c9-sub stituted products, substituted aromatic compounds and tetra cyclic derivatives (vide supra), The composition of the product mixture appeared to be dependent on time, tempera ture and electrophile. An acceptable mechanism for the product formation is affered in Figure IV. The seleneketals 12a-e react with n-BuLi to produce the equilibrating anions syn- and anti-35. "(Q>-se Se -

R n ' 36 Figure IV: Meahanism for the reaation of n-BuLi with seZe noketaZs 12 The latter are unstable and rearrange to aryllithium com pound ~· This intermediate reacts intramolecularly with the diene bridge to generate the stable allylic carbanion 37. The carbanion 37 was characterized with the aid of 1 H NMR spectroscopy. The other intermediatas are proposed on

29 the basis of the stucture of the isolated products. Seleno- and thio-substituted enolates undergo signifi 15 cant or even predominant alkylation at the heteroatom • The carbanions 35, however, alkylate exclusively at c9 .When prenyl bromide is used as the electrophile, only compound 19d is formed. Alkylation at selenium would lead to the ylid !l; a subsequent [2 ,3] sigmatropie shift would yield compound ,il (Scheme I).

H;,c-@-se

41 Saheme I

The hard electrophiles water and methanol react in a non-stereospecific way with bath c9-carbanions. Other elec trophiles, even bulky ones like benzaldehyde, prefer to attack syn-35, although this carbanion is sterically the most hindered one. The carbonitrile ~ubstituted anion ! reacts with methyl iodide at the sterically least hindered side (vide sup~a) 11 , 2 However, c9 of carbanion ! is sp hybridized, due to the strong electron-withdrawing effect of the substituent. There is no need for homo- or bicycloaromatic stabilization. The

30 stereochemistry of the reaction of ~ with electrophiles is 3 16 controlled by steric interactions ' • In the g-seleno substituted carbanions 2i• Cg is sp 3 hybridized. Soft electrophiles attack predominantly syn-2i because of the preferred localization of electron density at the diene side of the carbanion. This can be attributed to a small bishomoaromatic stahilizing 6 w-electron inter action in this intermediate. This stahilizing interaction is not possible in anti-35. Presumably, the latter carbanion is a contact ion pair with the lithium cation associated very closely to the lone pair at Cg• The importance of this cation complexation is underlined in the experiments run in the presence of crown ether: no Cg-substituted derivatives are formed because of the enhanced basicity of anti-2i in this medium (vide supra), To the anti-carbanions an alternative reaction path is available, which leads tomare stable intermediates. Via a stereospecific process, the anti-carbanions isomerize to aryllithium compounds 36. These react with electrophiles to produce substituted aromatic compounds. Substituted aromatic compounds have already been 12 17 reported ' • When phenyl vinyl selenide was reacted with n-BuLi in ether at room temperature and subsequently quenched with methyl iodide, a mixture of hexyl tolyl selenides was 17 isolated • Transposition of negative charge on the phenyl ring also occurs when carbanion generation is performed in 12 the presence of HMPT • Again, a mixture of substituted aromatic compounds is formed. Evidently, selenium substi tuted aryllithium compounds are more stable than a-seleno substituted carbanions. In our experiments only ortho-substituted products are formed, implying that the negative charge is generated ex clusively at the ortho-position. Dreiding models show that in the carbanions anti-2i the ortho-proton approaches the negative charge at Cg very closely. Intramolecular electron transfer via proton exchange leads to the aryllithium com pounds ~· This was established by the use of the perdeute ro selenoketal 12d and the m-chloro-phenyl selenoketal 12e.

31 Intermolecular proton transfer can be ruled out on the basis of steric hindrance and the absence of compounds 13a, 18a and 23a in the quench reactions with the aprotic elec trophile methyl iodide. The isomerization of the c9-carb anions ~ to aryllithium compounds 36 is a 100~ stereospe cific process. No product attributable to a rearrangement of syn-~ to aryllithium compound 43 was observed. Apparent-

H se-@ d:J" anti-35 36

syn- 35

ly, the bishomoaromatic stabilization in syn-~ decreasas the basicity at c9 and disfavour intramolecular proton ex change. However, this bishomoaromatic interaction does not overcome the tendency to generate the more stable aryl-. lithium intermediatas 36 via prior equilibration of the c9- carbanions. Unfortunately, no data are available on the difference in basicity between syn- and anti-35. Hydragen deuterium exchange experiments, using 13a and 14a and various bases and solvents, failed completely. Thus, the degree of bishomoaromatic stabilization in syn-35 cannot be quantified.

32 The p-tolyl selenoketal 12b gives under identical experi mental conditions less substitution in the aromatic ring than the phenyl selenoketal 12a. The p-methyl substituent has no effect on the steric interactions at c9 • Therefore, the lower tendency to isomerize has to be attributed to the electron-donating effect of the methyl substituent. The o-methyl group in anti-~ exercises a similar electronic effect as the p-methyl group in anti-35b. Once proton transfer has occurred, the negative charge in 36c comes very close te the diene bridge because of the steric requirements of the o-methyl group. The allylic carbanion 37c is then formed via direct intramolecular electron trans fer. The other aryllithium compounds also produce allylic carbanions (vide supra).

CH3 dj~ V 36c

The allylic anions 37 are the most stable intermediatas in the reaction pathway. The carbon atom c5 has the highest electron density as is revealed by the high upfield shift 1 of the H5-resonance in the H NMR spectrum (vide supra). Water and deuterium oxide react exclusively at c5• Methyl iodide shows a preferenee to react at ·c 3• A possible ex planation for these results is that 37. exists in THF as a contact ion pair with the lithium cation asociated to endo c5. Water and deuterium oxide displace the metal cation to form deuterium and hydrogen-bonded carbanions, which rapid 18 19 ly collaps ' • On these precedents endo protonation and deuteration at c5 is to be expected. Conversely, it is pro babie that quenching with methyl iodide occurs without the involvement of hydragen bonding. The preferenee to attack c3 has to be explained by steric bindrance from the lithium

33 cation associated to c5. In the allylic carbanion 37 a bishomoaromatic interac tion is possible between the allylic anion part and the proximate double bond. This kind of interaction has been reported to occur for the bicyclo[3.2.1]octa-2,6-dienyl 20 21 anion ii • However, recent theoretica! investigations disclaim the bishomoaromatic character of anion 44. There fore, cyclic delocalization of negative charge in lZ is extremely unlikely. Direct 1 H NMR investigations of lZ did not provide evidence for stahilizing 6 TI-electron interac tions·. The mechanism for product formation out of the diene selenoketal 28 is almost the same as that encountered for the triene seleneketals 12. The selenoketal 28 reacts with n-BuLi via C-Se bond cleavage to produce syn-ii. The soft electrophile methyl iodide attacks exclusively this bisho moaromatic stabilized syn-carbanion. Equilibration affor~s anti-ii, which appears to be more unstable than the corres ponding trienyl carbanion anti-~. It reacts with n-butyl p-tolyl selenide to produce 9-(p-tolylseleno)bicyclo ~.2.1] nona-2,4-diene 30a. It partially isomerizes to the aryllithium

compound 46 via intramolecular proton transfer. Tetracyclic

34 carbanion 40 is formed in only minor amounts, as is evident from the low yield of isolated tetracyclic product ~· This low yield can be attributed to the side reaction of anti-45 with n-butyl p-tolyl selenide. From all these results it is evident that the chemistry of 9-arylseleno- substituted bicyclo ~.2.1]nona-2,4,7-trien- 9-yl and -bicyclo [4.2.1] nona-2,4-dien-9-yl carbanions ( 22, and 45, respectively) is dominated by the availability of an unique stereospecific reaction path in which electrens are transferred from c9 to the aryl ring via intramolecular proton exchange. The driving force for this isomerization is the formation of the more stabie aryllithium compounds out of the "hot" c9-carbanions. In the latter a small bis homoaromatic stabilization occurs in the syn-carbanions; bicycloaromatic stabilization seems to be absent. The aryl lithium compounds, finally, can transpose negative charge by intramolecular cyclization,which leads to stable allylic carbanions.

II,6 ExperimentaL

- Generat remarks

1 H NMR spectra were recorded with Varian EM-360A, Va rian T-60A, Bruker HX-90R and Bruker WM-250 instruments 13 using Me 4Si as internal standard. C NMR spectra were taken on Varian HA-100 and Bruker HX-90R instruments interfaced with a Digilab FTS-NMR-3 computer. Mass spectra were obtained with a Finnigan 4000 GS/MS instrument at an ionization po tential of 70 eV. Infrared spectra were recorded with Perkin Elmer 237 and Beekman Acculab 9 spectrometers. UV spectra were measured withaPerkin Elmer 123 Double Beam instrument. Preparative high-performance LC separations were accom plished on Jobin Yvon Chromatospac 100 and on Jobin Yvon Miniprep. All seperations were performed on silica H (type 60, Merck). Microanalyses were carried out in our labora ties by Messrs. P.v.d. Bosch and H. Eding. 3 Bicyclo [4. 2 .1] nona-.2 ,4, 7-trien-9-one C.i.Z) , bicyclo-

35 3 22 [4.2.1]nonan-9-one (48) , benzeneselenol (49a) , p-toluene 22 22 selenol (49b) , o-tolueneselenol (49c) , benzene-d5-sele 22 nol (49d) 22 , m-chlorobenzeneselenol (49e) were prepared according to literature.

- 9 ~ 9-bis (pheny Lee Leno) biayalo [4. 2. 1] nona-2., 4.,?-triene (12a)

A stream of dry HCl gas was passed through a salution of ketone 47 (7.8g; 59 mmol) and benzeneselenol 49a (15.6g; 99 mmol) in dry Et2o (20 mL) at 0°C during 15 min. The re sulting mixture was poured onto a saturated sodium bicar bonate salution and extracted into Et 2o. The organic layers were washed with water, 7% aqueous KOH and water, dried (MgS04) and concentrated. High-performance LC with benzene 1 hexane (10/90) gave 11.3 g (53%) of 12a; H NMR (CC1 4) o 7.9-6.8 (m,tO); 6.1 (m,4); 5.3 (d,2); 3.1 (m,2); 13C NMR (CC1 4) o 56.02 (C 1 6); 134.22 (C 2 5); 128.01 (C 3 4); 122.23 ' ' J (C , ); 56.02 (C ); 134.22 and 131.28 (Ci); 129.60 (C ); 7 8 9 0 134.10 and 138.42 (Cm); 129.60 (CP).

- 9 .. 9-bis (p-to lylse 1-eno) biayal.o [4. 2, 1] nona-2 1 4 .. ?-triene ( 12b)

Selenoketal 12b was prepared in the same way as 12a, Trituration with n-hexane gave pure ketal in 55,7% yield: 1 mp 79-80°C; H NMR (CC1 4) 6 7.6-6.67 (m,8); 5.93 (m,4); 4.92 13 (d,2); 3.00 (m,2); 2.53 (s,3); 2.30 (s,3); C NMR (CC1 4) o 55.80 (C 1, 6); 134,01 (c 2, 5); 121.97 (c 7, 8); 127.97 (C 3, 4); 57.26 (C ); 127.84 and 128.94 (Ci)i 130.17 (C ); 138.77 and 9 0 139.09 (Cm); 138.47 and 137,98 (CP); 22,54 (CH 3); Anal. Calcd. for c23 H22 se2: C, 60.53; H, 4.86. Found: C, 60.72; H, 4.91.

- 9,9-bis(o-tol.yLsel.eno)biayalo 4.2.1 nona-2,4,?-triene ( 12c)

is prepared and isolatedas for 12b: yield 30,5%; mp

36 1 82-83°C; H NMR (CCI 4) 6 7.77 (m,8); 5.93 (m,4); 4.83 13 (d,Z); 3.37 (m,2); 2.40 (s,3); 2.27 (s,3); C NMR (CC1 4) 6 57.08 (c1, 6); 134.19 (Cz,sli 127.66 (C 3, 4); 121.62 (C 7, 8); 56.95 (C 9); 134.01 and 133.0 (Ci); 139.97, 136.48, 143.01 and 143.76 (C ); 130,97, 126.51 and 126.60 (Cm); 129.12 and 0 129.78 (CP); 24.57 and 24.66 (CH 3). Anal Calcd. for c23H22 se2: c, 60.53; H, 4.86. Found: c, 60.76; H, 4.91.

- 9~9-bis(phenyl-d 0 -seleno)biayalo[4.2.1]nona-2~4~?- tPiene (12d)

is prepared and isolated as for 12a: yield 45%; 1 H NMR (CC1 4) 6 5,9 (m,4); 4.87 (d,2); 3.03 (m,Z).

- 9i9-bis(m-ahloPophenylseleno)biayalo[4.2.1]nona-2~4i?- tPiene (12e)

is prepared and isolatedas for 12a: yield 42%; 1 H NMR (CDC1 3) 6 7.83-7.17 (m,8); 6.20 (m,4); 5.20 (d,Z); 3,23 (m,Z).

- Biayalo [4,2.1]nona-2i4-dien-9-one (50)

The nickel boride catalyst29 used was prepared under nitrogen in the hydragenation flask by adding dropwise a solution of sodium borohydride (0.033 g; 0.87 mmol) in 20 mL of EtOH to a stirred solution of nickel(II)acetate te trahydrate (0.23 g; 0.92 mmol) in 20 mL of EtOH. Ketone ±1,1 g, dissolved in 20 mL of EtOH, was introduced into the reaction flask and 169 mL of H2 was taken up under stirring. The resulting mixture was poured onto 50 mL of saturated aqueous sodium bicarbonate, filtered and extracted into Et 2o. The water phase was. stripped from EtOH and subsequently extracted with Et2o. The combined organic layers were dried (MgS04) and concentrated, yielding 0.87 g (861) of ketone 1 50: H NMR (CDCI 3) 6 5.44 (m,4); 2.42 (m,2); 2.00 (m,4); mass spectrum m/e 134.

37 - 9 ~ 9-bis (p-_to ly lse leno) biayalo [4. 2 .1] nona-2., 4-diene ( 28)

Toa solution of ketone SO (0.5 g; 3.7 mmol) and p-to lueneselenol 49b (1.09 g; 6.4 mmol) in 5 mL of dry Et2o 24 was added 0.2 mL of concentrated H2so4 • After being stirred for 1 h at room temperature under a nitrogen blanket, the reaction mixture was poured onto a saturated aqueous sodium bicarbonate solution.and extracted into Et2o. The organic layers were washed with water, saturated aqueous sodium bi carbonate solution and water, dried (MgS04) and concentra ted, High-performance LC with benzene-hexane (10/90), fol Iowed by recrystallization from n-hexane gave 0.47 g· (32%) of pure~. mp 95.2-95.7°C; 1 H NMR ö 7.72-6.63 (m,8); 5.73 13 (m,4); 2,38 (s,6); 2.4 (m,4); C NMR (CC1 4) ö 51,26 (C 1 6); ' 135.60 (C 2, 5); 127.13 (C 3 , 4); 41.55 (C 7, 8); 63.87 (C 9); 128.50 and 127.84 (Ci); 130.26 and 130.57 {C ); 137.81 (Cm); 0 139.26 and 139,88 (CP); 22.45 (CH 3), Anal. Calcd. for c23H24se2: c, 60.26; H, 5.28, Found: C, 60.07; H, 5,35.

- 9.,9-bis(p-tolylseZeno)biayaZo~.2.1]nonane (29)

is prepared in the same way as selenoketal ~. yield 25$; mp 93-94°C; 1 H NMR ö 7.67-6,9 (m,8); 2.6-1.23 (m,12); 2.3 (s,6). Anal. Calcd. for c23 H28 se2: C, 59,74; H, 6.10. Found: C, 59.95; H, 6.18.

- General procedure for the quench reactions

A salution of 1 g of triene selenoketal 12a-d in 10 mL of dry THF was treated with 2 mL of n-BuLi (15% in hexane, Merck) at -78°C under a nitrogen atmosphere. In the direct quenching experiments the electrophile was added 2 min af ter carbanion generation. In the other low temperature ex periments the anionic solution was stirred for 0,5 h prior to the addition of the electrophile. For the room tempera ture experiments the triene seleneketals were reacted 0.5

38 h with n-BuLi at -78°C and 0.5 h at room temperature. After being quenched, the reaction mixtures were allowed to warm to room temperature, poured onto water and extracted into Et2o or CHC1 3 • The organic layers were washed with water, dried {MgS04) and concentrated. The products were isolated with the aid of high-performance LC. Por 1 H and 13C NMR speetral data see Tables V-IX. Some products were solids: 12& (mp 213-214°C); 18e (mp 156-158°C); 19e (mp 122-123°C); 19f (mp 88-90°C); 21a (mp 113-114°C); 26a (mp 89-91°C); 27c (mp 115-119°C). All these compounds gave satisfactory microanalyses. The products of the reactions of ~-E with n-BuLi and water, deuterium oxide or methyl iodide were examined with the aid of GLC/MS. All derivatives gave the expected molecular ion.

• PPenyl bPomide quench e~periment

The procedure was as described under general procedures. The electrophile was added 2 min after carbanion generation. Yield after work-up 77% of 19d; mp 82-84°C. Anal. Calcd. for c21 H24se: C, 70.97; H, 6,81. Found: C, 70,91; H, 6.81.

• Furan-trapping e~periment

A salution of~ (0.15 g; 0.55 mmo!) in 8 mL of a mix ture of furan-THF (1:1) 25 was treated with 0.4 mL of n-BuLi at -78°C under a nitrogen atmosphere. After stirring for 5 h, the salution was allowed to warm to room temperature. The 1 usual work-up afforded 0.08 g (66%) of~; H NMR (CDC1 3) ö 7.37-6.73 (m,3); 6.15 (m,4); 5.82 (d,2,J= 7.5 Hz); 3.63 (t,l); 3.20 (m,4).

• Quenohing in the presence of 18-crown-6

A salution of 12b (0.5 g; 0,55 mmo!) and 50 mg 18-crown- 6 in 5 mL of dry THF was treated with 1.3 mL of n-BuLi at -78°C under N2• After 30 min the reaction was quenched with

39 methyl iodide. After the usual work-up, high-performance LC yielded 0.2 g (80.4%) n-butyl p-tolyl selenide, 0.13 g (3g,4%) of and 0.10 g (31.8%) of 18a.

- Reaations with diene selenoketaZ 28

The procedure was the same as described for the triene seleneketals 12a-c. Reaction with water afforded 30a and 31a. 1 -- - 30a: H NMR (CDC1 3) ó 7.50-6,73 (AB,4); 5.70 (m,4); 3,85 (t,1); 2.77 (m,2); 2.27 (s,3); 1.92 (m,4). 13C NMR (CDC1 3) 45,13 (C 1, 6); 136.31 (c2, 5); 126.60 (C 3, 4); 40.1g (C ); 46.00 (Cg); 129.42 (Ci); 130.44 (C ); 7 ' 8 0 135.16 (Cm); 137.10 (CP); 22.19 (CH 3). Mass spectrum m/e 290. 1 31a: H NMR (CDC1 3)ó 7.47-6.78 (m,4); 6.03-5.27 (m,4); 3,93 (s,1); 2.57 (d,2); 2.27 (s,3); 2.07 (m,4). 13C NMR (CDC1 3) ó 46.76 (C 1, 6); 137,85 (c2, 5); 124.93 (C 3 , 4); 39.52 (C , ); 50.86 (Cg); 128.19 (Ci); 130.66 (C ); 7 8 0 134.89 (Cm); 137.37 (CP); 22,19 (CH 3). Mass spectrum m/e~290. Reaction with deuterium oxide afforded 30a, 30b, 31b and 32b. 30b and 32b: mass spectra m/e 291; 1 H NMR and 13C NMR as for 30a. 1 31c: H NMR (CDC1 3) ó 7.47-6.73 (AB,4); 6,03-5.10 (m,4); 2.60 (m,2); 2.27 (s,3); 2.06 (m,4), 13 C NMR as for 30a. Mass spectrum m/e 291. Reaction with methyl iodide afforded 30a, 31c and 1 31c: H NMR (CDC1 3) ó 7.60-6,93 (AB,4); 5,87 (m,4); 2.50 (m,2); 2.43 (s,3); 2.13 (m,4); 1.43 (s,3), 13C NMR (CDC1 3) ó 22.78 and 29.73 (CH 3); 39,66 (C 7 , 8); 50.20 (C 9); 51.21 cc 1 ' 6); 126.47 cc 3 , 4); 136.3g cc 2 , 5), Mass spectrum.m/e 304. 1 32ci H NMR (CDC1 3) 6 7.60-6.70 (m,3); 5.74 (m,4); 3.54 (t,1); 2.70 (m,Z); 2.23 (s,6); 2.00 (m,4). Mass spec trum m/e 304.

40 .. Reaation of selenoketal 29 with n-BuLi and water

This reaction was performed at room temperature. Quenching and work-up afforded a mixture of n-butyl p-tolyl selenide (m/e 228), syn-9-(p-tolylseleno)bicyclo~.2.1]no nane (m/e 294; 3.5 ppm, t, H9) and anti-9-(p-tolylseleno) bicyclo[4.2.1]nonane (m/e 294; 3,6 ppm, s, H9), which could not be separatèd with high-performance LC.

41 1 ~ TabZe V: H NMR SpeatraZ data for c9-substituted produats

R1 Rz Hl, 6 Hz-s H7 , 8 Hg Har Hothers 13a H Ph Se 3.27(t) 6.03(m) 5.27(d) 3.77(t) 7.53-6.87(m) 14a Ph Se H 3.20(d) 5.90(m) 5.23(d) 3.47(s) 7.53-6.87(m) 13b D Ph Se 3.3(d) 6. 1 (m) 5,33(d) 7.53-6.87(m) 14b Ph Se D 3.20(d) 5.90(m) 5.23(d) 7.53-6.87(m) 7.67-6-87(m) 1.33(s) 14c Ph Se CH 3 2.87(m) 6.07(m) 5.07(d) -14d Ph Se PhC(OH)H 2.97(m) 6.07(m) 4.53(d) 7.70-6.70(m) 3,53(s) 3.43(m) 4.33{s) 7.70-6.70(m) 3.40(s) 14e Ph Se Ph 2C(OH) 3.93(m) 5.90(m) 4.23(d) -14f Ph Se C(O)H 3.30(m) 6.13(m) S.ZO(d) 7,60-6,70(m) 9.07(s) 1'8a H p-tolSe 3.17(t) 5.9(m) 5.13(d) 3.57(t) 7.36-6,73(AB) 2.33(s) 19a p-tolSe H 3,10(d) 5.78(m) 5,08(d) 3.27(s) 7.36-6.73(AB) 2.27(s) -18b D p-tolSe 3.2(d) 5.9(m) S.13(d) 7.37-6.7(AB) 2.33(s) -19b p-tolSe D 3.10(d) S.SO(m) S.lO(d) 7.4-6.77(AB) 2.27(s) Tab~e V ( Continued)

R' 1 R2 H1 6 H2-s H7 8 Hg Har Hothers • '

19c p-tolSe CH 3 2.82(m) 6.03(m) 5.07(d) 7.47-6.77(AB) 2.28(s); 1.3(s) -19d p-tolSe prenyl 2.92(m) 6. 17 (m) 5.23(d) 7.63-6.93(AB) 5.73-5.23(m); 2.3 (s); 2.1(d); 1. 73 ( s) ; 1.4S(s), -18e PhC(OH)H p-tolSe 3.2(m) 6.09(m) 5.09(m) 7.67-6.67(m) 2.52(s); 2.3(s); 2.SS(m) 4.38(s). -19e p-tolSe PhC(OH)H 2.97(m) 6.08(m) 4,52(d) 7.60-6.73(m) 3.53(s); 2.3(s); 3.53(m) 4.33(s). -18f RC(OH) p-tolSe 2.88(m) 6.10- 4.8(m) 7.67-6.83(m) 3.6-3.1(m); 2.3 2.47(m) 5.43(m) ( s) ; 1.36(d) -19f p-tolSe RC(OH) 3. 1 (m) 6,03(m) 4.92(m) 7.33-6.8(m) 3.67(d); 2.9-2.7 3.0(m) (m) i 2,27(s); 1 • 2 (d) .!!& RC(OH) p-tolSe 2.8- 6.0(m) 5.33- 7 .67-6.93(A:6) 3.3-2.8(m); 2.28( 2.S(m) 4.83(m) s}; 2.28-0.57(m). ~ p-tolSe RC(OH) 2.83- 6.0(m) 4.93(m) 7.4-6.7(AB) 3.47-2.97(m); 2.27 2.47(m) (s); 1,6-0.43(m). -23a H o-tolSe 3.33(t) 6.33(m) 5.4(d) 3.8(t) 7.7-6.9(m) 2.33(s) -24a o-tolSe H 3.17(d) 5.83(m) 5.17(d) 3.37(s) 7.4-6.73(m) 2.33(s) -24c o-tolSe CH 3 2.87(m) 6.00(m) S.02(d) 7.5-6.7(m) 2.42(s); 1.22(s). t ~able VI: 1 H NMR Speatral data aompounds formed via eleatrophilia aromatia eubstitution

R x Hg Others H1 • 6 Hz-s H7 • 8 Har -15b H D 3.30(t) 6.10(m) 5.33(d) 3.77(t) 7.53-6.87(m) 15c H CH 3 3.23(t) 6.00(m) 5.23(d) 3.66(t) 7.53-6.73(m) 2.37(s) -15d H PhC(OH)H 3.13(t) 5.90(m) 5.13(d) 3.SO(t) 7.70-6.70(m) 6.1(s); 2.8(s) 15e H Phz(OH) 3.07(t) 5.90(m) S.ZO(d) 3.52(t) 7.60-6.70(m) 5.67(s) 15f H C(O)H 3.30(t) 6.03(m) 5.30(d) 3.77(t) 7.60-6.70(m) 10.20(s) .!.§.& H C(O)OH 3.40(m) 6.00(m) 5.37(d) 3.83(t) 8.67-7.00(m) -ZOb p-CH3 D 3.20(m) 5.90(m) 5.13(d) 3.57(t) 7.37-6.70(m) 2.27(s) 20c p-CH 3 CH 3 3.17(t) 5.97(m) 5.20(d) 3.53(t) 7.40-6.73(m) 2.33(s); 2.22(s) -20d p-CH3 PhC(OH)H 3.50(t) 5.98(m) 5.18(d) 3.70(t) 7.67-6.73(m) 2.28(s); 2.9(s); 6.18(s) 25b o-CH 3 D 3.33(t) 6.33(m) 5.40(d) 3.80(t) 7.70-6.90(m) 2.43(s) -25c o-CH 3 CH 3 3.20(t) 6.00(m) 5.18(d) 3.60(t) 7.50-6.70(m) 2.33(s)

,, Table VII: 13C NMR Speatral data for -substituted c9 produats~

c c c c2,5 c3 4 c7,8 Cg ei 0 m p cothers c 1 '6 ' 13a 49. 10 135.32 127.22 125.10 42. 13 132.41 130.0 134.41 129.87 14a 51.33 136.31 125.37 122.54 41.95 1 31 • 90 130. 1 7 134.10 1 28. 1 0 -14b 51.33 136.31 125.37 122.54 41.95 1 31 • 90 130. 17 1 34. 1 0 128.10 14c 55.63 135.69 127.35 121.93 46.76 129.03 129.56 137.85 129.56 29.30 -14d 47.11 134. 19 128.63 119.63 76.09 128.37 130.04 136.92 129.64 63.70 51.08 135.51 127.44 1 20. 16 14e 51 • 12 135.34 127.22 117.56 68.99 128.94 126.75 129.25 129.95 84.73 18a 48.79 134.89 127.22 124.62 42.26 128.76 130.39 134.89 137. 1 22.14 19a 51.39 136.00 125.23 122.19 46.80 128.19 130.66 134.63 137,32 22.19 19b 51.39 136.00 123.23 122. 19 46.80 128.19 130.66 134.63 137.32 22.19 137.98 137.98 22.28; 29.73 -19c 55.49 135.03 127.48 121.57 46.10 126.38 130.09 -18e 53.95 135.69 127.31 123.34 73.76 126.25 130.22 139.09 139.61 22.28; 66.17 52.05 126.56 122,06 -19e 50.99 134.23 127.57 120.07 76.01 124.62 130.92 137.06 139. 19 22.36; 63.52 46.89 135.64 128.10 119. 59 8f 54.26 136.58 127.48 123.94 68.02 7 8. 1 2; 21 • 68; 58.84 134.73 125.32 121.65 46.88; 22.81 -19f 51.34 135.68 128.67 120.83 65.56 77.51; 43.55; 48.58 135.41 127.89 120.29 22.58; 20.90 Table VII (aontinued)

Cg c. co c c1,6 Cz , s c3 , 4 c7,8 '1- m CP cothers I b .1.§..&T- 48.84 133.80 1 26. 51 117.83 61 • 1 0 73.00; 35.25; 45.65 132.89 125.34 117.23 29.43; 20.24; 12.99; 11 • 1 3 b 1..2..g_T- 51.69 133.50 124.87 121.07 65.84 72.96; 38.27; 132.81 1 24.39 120.47 26.92; 20.24; 14.11; 1 0. 61 23a 48.92 135.12 127. 26 124.70 40.94 133.57 140,63 127.44 127.70 23.86 134.37 130.62 -24a 51 • 26 136.04 125.41 122.32 45.39 133.30 140.14 127.31 127.44 23.42 132.42 130.79 24c 58.58 135.04 127.27 121.76 58.32 131.20 138.65 126.79 129.13 23 134.82 130.54 27.09

~See Table V for structures and numbering scheme. ~T designates the threo diastereoisomer; the speetral data for the erythro diastereoisomer could not be ànalyzed. Table VIII: 13 C NMR Speetral data for compounds foPmed via eleat~ophilic aromatic substitution~

R x c1 ,6 c2 5 c3,4 c7 8 Cg car Others ' ' -15b H D 49.10 135,32 127.22 125.10 42.13 132,41 130.00 134.41 129.87 -15c H CH 3 48.92 135.12 127.26 124.70 40.94 133.57 140.63 127.44 23.86 127.70 134.37 130.62 1Sd H PhC(OH)H 48.79 135.47 127.22 124.88 43.10 146.85 144.47 136.62 67.23 131 • 63 129.25 128.45 -15e H Ph 2C(OH) 48.53 135.42 127.46 124.92 44.05 150,38 1 48. 1 3 1 38. 64 84.00 131 • 23 129.73 128.90 127.62 .!i& H C(O)OH 48.41 136.0 8 127.28 125.04 37.55 139,66 133.30 132.50 169.20 130,80 130.56 125.71 20b p-CH3 D 48.79 134.89 127.22 124.62 42.26 137.10 134.89 130.39 22. 14 128.76 134.98 127.18 124.62 41.24 140.94 137.98 20c p-CH3 CH 3 48.96 131.45 23.87 127.88 135.16 125.71 21 • 96 D 140,63 -25b o-CH 3 48.92 135.12 127.26 124.70 40.94 134.33 133.57 23.86 130.62 127.70 127.44

~ ~ See Table VI for structure and numbering scheme. Tabt.e IX: 1 H NMR Speatroal data foro tetroaayalia aompounds

H Se R . H' x

R x Hl ,6 Hz H3 H3 4 H4 5 H5 H7,8 Others ' ' -16a H 5-H 2,85(m) 3.50(m) 5,07(d) 2.85(m) 5.88(t) 7.4-6.7(m) 2.30(m) -17c H 3-CH 3 2.80(m) 2.15(m) 2.47(q) 5.45(m) 6.10(t) 7.4-6.67(m) 2.15(m) 1.15(d) 21 a p-CH3 5-H 2. 7 5 (m) 3.SO(m) 5.13(d) 2.75(m) 5.93(t) 7,3-6.67(m) 2.06 2.06(s) -26a o-CH3 5-H 2,53(m) 3,50(m) S.OO(d) 2.53(m) 5.90(t) 7,2-6.9(m) 2.30(m) 2.30(s) -26b o-CH 3 5-D 2.88(m) 3.60(m) 5.20(d) 2.30(m) 6.10(t) 7.2-6.8(m) 2.30(s) 27c o-CH 3-CH 3.25(m) 3.25(m) 2.40(q) 5. 1 0 (m) 6.17(t) 7.06-6.7(m) - 3 3 3.03(m) 1.20(d) RefePenaes and Notes

1. H.M.J. Gillissen, P. Schipper, P.J.J.M. v. Ool, H.M. Buck, J. Org. Chem., 1980, 45, 319. 2. a. M.J. Goldstein, J. Am. Chem. Soc., 1967, 89, 6357. b. M.J. Goldstein, R. Hoffmann, J, Am. Chem. Soc., 1971, 93, 6193. 3. a. T.A. Antkowiak, D.C. Sanders, G.B. Trimitsis, J.B. Press, H. Shechter, J. Am. Chem. Soc., 1972, 94, 5366. b. D.C. Sanders, H. Shechter, ibid., 1973; 95, 6858. c. A.F. Diaz, J. Fulcher, M. Sakai, S. Winstein, ibid., 1974, 96, 1264. d. A.F. Diaz, J, Fulcher, ibid., 1974, 96, 7954. e. "w. Kirmse, G. Voigt, ibid., 1974, 96, 7598. f. A.F. Diaz, J. Fulcher, ibid., 1976, 98, 798. 4. a. P. Schipper, Thesis, Eindhoven, 1977. b. P. Schipper, H.M. Buck, J. Am. Chem. Soc., 1978, 100, 5507. 5. H. Schmidt, A. Schweig, A.G. Anastassiou, H. Yamamoto, Chem. Commun., 1974, 218. 6. a. A.G. Anastassiou, E. Reichmanis, J. Am. Chem. Soc., 1976, 98, 8267. b. A.G. Anastassiou, H.S. Kasmai, R. Badri, Angew. Chem., 1980, 92, 657. 7. T.J. Katz, C.R. Nicholson, C.A. Reilly, J. Am. Chem. Soc., 1966, 88, 3822. 8. T.V. Rajan Babu, D.C. Sanders, H. Shechter, J. Am. Chem. Soc., 1977, 99, 6449. 9. S. Winstein, M. Ogliaruso, M. Sakai, J.M. Nicholson, J. Am. Chem. Soc., 1967, 89, 3656. 10. Reference 8, note 8. 11. G. Boche, D. Martens, Chem. Ber., 1979, 112, 175. 12. The following monographs andreviews cover modern erga noselenium chemistry: a. Methoden der Organischen Chemie (Houben-Weyl), Volume IX, TUbingen, 1955. b. D.L. Klayman, W.H.H. GUnther, Organic Selenium Com pounds, New York, 1973.

49 c. D. Clive, Tetrahedron, 1978, 34, 1049. d. H.J. Reich, Acc. Chem. Research, 1979, 12, 23. e.A. Krief, Tetrahedron, 1980, 38, 2531. f. A. Krief, Bull. Soc. Chim. de France, 1980, 519. 13. a. D. Seebach, N. Pelleties, Chem. Ber., 1972, 10E, 511. b. D. Seebach, A.K. Beek, Angew. Chem., 1974, 13, 806. c. W. Dumont, P. Bayet, A. Krief, ibid., 1974, 13, 804. 14. D.J. Cram, F.A. Abn El Hafez, J. Am. Chem. Soc., 1952, 74, 5828, 5851. 1 5. H.J. Reich, M.L. Cohen, J. Am. Chem. Soc., 1979, 101, 1307. 16. w. Todd Wipke, P. Gund, J. Am. Chem. Soc., 1976, 98, 8107, 17. M. Sevrin, G.N. Denis, A. Krief, Angew. Chem., 1978, 90, 550. 18. Y. Pocken, S.H. Exner, J. Am. Chem. Soc., 1968, 90, 6764. 19. W.D. Kollmeyer, D.J. Cram, J. Am. Chem. Soc., 1968, 90, 1784, 20. a. J,M, Brown, J.L. Occolowi_tz, Chem. Commun., 1965, 376. b. J .M. Brown, ibid., 1967, 638. c. J.M. Brown, J.L. Occolowitz, J. Chem. Soc. B, 1968, 411. d. J.M. Brown, E.L. Caine, J. Am. Chem. Soc., 1970, 92, 3821. e. See reference 9. 21. a. J.B. Grutzner, W.L. Jorgensen, J. Am. Chem. Soc., 1981, 103, 1372. b. E. Kaufmann, H. Mayr, J. Chandrasekhar, P.v.R. Schle yer, ibid., 1981, 103, 1375. 22. a. D.G. Foster, Organic Syntheses, Col!. Vol. III, New York, 1955. b.D. Seebach, A.K. Beek, Chem. Ber., 1975, 108, 314. c. S.H. Shu, W.H.H. GUnther, H.G. Mautner, Biochem. Prep., 1963, 10, 153. 23. C.A. Brown, Chem. Commun., 1969, 600. 24. w. Dumont, A. Krief, Angew. Chem., 1977, 89, 559. 25. The reaction did not occur in pure furan.

50 CHAPTER_ 111

REDUCTIVE ELIMINATION AND SKELETAL REARRANGEMENT OF S-HYDROXY SELENIDE DERIVATIVES OF BICYCL0[4.2.1]NONA-2,4,7- TRIENE IN A SUPER ACID MEDIUM 1

III.l IntPoduction

With the introduetion of synthetic methods, based on 2 organoselenium chemistry , heterosubstituted derivatives of bicyclo [4.2.1]nona-2,4,7-triene become readily available. Aldehydes and ketones react with 9-(arylseleno)bicyclo~.Z.l] nona-2,4,7-trien-9-yl carbanions to produce S-hydroxy sele nides 1 and 2.

OH OH ~ R1=H Rz= CH(CH 3) 2 I R R1-..110 .J?. R R 1=H 2= Ph R d5c9seAr .5:. R =R = CH A•Sx~; 2 1 2 3 ~ R =H Rz= (Ph)CHCH f 1 ~ 1 3 Ar= p-CHçC H ~ 6 --- 6 4 2

Protonation of the hydroxy function in the syn-alcohols l• and subsequent dehydration would yield a carbocation in which through-space interactions can occur between the emp ty atomie orbital at c10 and the proximate diene ribbon. The nature of these interactions will strongly be influen ced by the rotation around the c9-c 10 bond. A simplified topological analysis prediets three distinct modes of in teraction between the empty AO at c10 and the HOMO of the

51 butadiene segment (Scheme I).

? c via A

Saheme I

In situation A, the orientation of the empty p-orbital at c10 is parallel with respect to the mirror plane which bisects the c1-c 9-c 6 angle. This yields a 4 ~-electron system, whièh is destabilized by Hückel-antiaromaticity (two sign inversions). A Conrotatory motion of the diene segment removes one double bond out of conjugation. This leads to the asymmetrie carbocations B, which are energetically more favourable than

52 4 the antiaromatic carbocations A • In the third case the empty p-orbital at c10 is posi tioned perpendicularly to the mirror plane of the cations. In this configuration, the homocyclic interaction between c10 and the butadiene moiety will result in an aromatic 4 rr-elec tron system (one sign inversion). The carbocations Care stabilized by ground-state Möbius aromaticity. The carbocations A bear a close relationship to the cyclopentadienyl cation 3. The antiaromatic character of this cation follows from the silver-assisted salvolysis of 5-iodo cyclopentadiene i which is at least 105 ~lower than the sal 3 volysis of the fully saturated derivative i • Further evi- Q Q I 3 4 5 dence comes from the electrochemical determination of pKR+ for various cyclopentadienyl cations 3 • ESR experiments 3 show that cation 3 has a triplet ground-state, which per- fectly fits with -Hund ' s rule for degenerate half-filled molecular orbitals. Asymmetrie interactions of a diene segment with an empty p-orbital have been found to occur in the 9-methoxy bicyclo~.2.1 )nona-2,4-dien-9-yl cation ~ and in the 4 11-methoxy-bicyclo ~.4.1]undeca-2,4,8-trien-11-yl cation z •

6 7

53 The through-space interaction in cations C closely resembles the transition state of a [1 ,4] C sigmatropie shift 5 under inversion of the migrating carbon ! • The observation of cations, which display this mode of interaction, would provide the first example of ground-state Möbius. aromatici ty.

In our opinion, the chemistry of the carbocations A-C forms at present the only entry in the field of ground-state 6 Möbius aromaticity • The role of Hückel aromaticity in a flexible model system has already been reported: 8(7-norbor nenyl)ethyl brosylate ~ solvolyses with extensive w-electron delocalization in both the rate- and product-determining 7 steps • The results of these studies indicate that the same modus opePandi can be used in the study of Möbius aromatici ty. Therefore, the chemistry of the S-hydroxy selenides 1 in super acid media was investigated.

OBs

9 111.2 ReaPPangement of 8-hydromy selenides

Treatment of solutions of compounds .! in liquid sulfur dioxide or sulfuryl chloride fluoride with an excess of fluo rosulfonic acid at -78°C immediately produced red coloured

54 solutions. Direct low temperature 1 H NMR spectroscopie in vestigations were unsuccessful in the characterization of intermediates in these solutions. After quenching with wa ter and/or methanol, the product mixture yielded the re arranged products 11 and 11, together with di-p-tolyldisele nide (Scheme II). Compound 1 afforded not only rearranged

Ar Se H

~ + + :b--- H 10 11

la 10a (-) 11 a (31.4%) 12a (-) lb lOb (22.9'6) 11 b (14.7%) 1 ( -) lc lOc {- ) 11 c (49.0%) 12c (-)

Saheme II product 11b but also exocyclic olefin lOb. Exocyclic olefins, like lOb, are also obtained upon reductive eliminatien of B-hydroxy selenides 8 under basic reaction conditions. Thus, methanesulfonyl chloride/triethyl amine8 at 0°C reacts with ~ and Za to produce the exocyclic olefins ll and !i' respectively. Reductive eliminatien of 8 B-hydroxy selenides can be effected in an acidic medium • Therefore, the isolation of 10b indicates that exocyclic olefins are intermediates in the skeletal rearrangement to 1 1 and 12.

13 14

55 III.3 Diecuesion

Reductive eliminatien of 8-hydroxy selenides constitu 8 tes an important route to substituted olefins • Stereoche mical and other mechanistic evidence suggest a reaction pathway invalving an episelenonium ion in the reversible 8 olefin-forming step ' 9 • The reagents employed for reductive eliminatien have in common the ability to convert the hydro xy functionality into a better leaving group. In the case of methanesulfonyl chloride/triethylamine, an excess of the reagent is used for the disposal of the active selenenyl electrophile, which is produced in the olefin-forming step. Presumably, the selenenyl electrophila is sèavenged by the 8 sulfene CH 2=so 2 • Since reductive eliminatien can be brought about by the use of acidic reagents, the isolation of lOb makes it obvious that the first steps of the observed skeletal re arrangement consist of an eliminatien sequence. This leads to the formulation of the following reaction mechanism (Scheme III).

R1 .R2

R2 + H+ 1 "'\: -H20 };"' -- r:h. - 15 16 H

Ar Se H 12 ~ I 1,2 I c R1 ~cl. 11 R2

Saheme III

56 The protonation of the hydroxy group and the subse quent loss of water lead via the episelenonium ion 15 to the exocyclic olefin 16 and the areneselenenyl cation (ArSe+) in a solvent cage. Ex~attack of ArSe+ on the etheno-bridge of~~ foliowed by preferential 0,2]migration of the butadiene segment, affords the allylic cation ~ via the epi selenonium ion 11· Internal electrophilic aromatic substi tution produces the tetracyclic compounds !l; deprotonation of ~ leads to the formation of the rearranged selenide ~· Relief of strain in the intermediate 12 and charge delocali zation into an allylic cation (~) appear to be the driving forces for the bond reorganization. If ArSe+ diffuses out of the cage, the exocyclic ole ~ • fin is protonated at c10 Subsequent rearrangements lead 11 to the formation of indenes 10 ' • The liberated selenenyl electrophile is hydrolized during work-up to di-p-tolyldi selenide12. The proposed reaction mechanism closely resembles the reaction of 9-methylenebicyclo[4.2.1]nona-2,4,7-triene ~ 13 with chlorosulfonyl isocyanate • Themainproduct in this reaction is the lactam 1Q, which is formed via a pathway, similar to that proposed for the rearrangement of the a hydroxy selenides 1.

19 20 The importance of the generation of ArSe+ in the vici nity of the etheno-bridge of olefins ~ is illustrated by an independent cross experiment. When 9-methylenebicyclo [4.2.1]nona-2,4,7-triene 19 is added toa mixture of p-tolu eneselenenyl bromide and fluorosulfonic acid in so 2 at -78°C, no rearranged products l! are formed, Instead, indenes are isolated from the reaction mixture. In our experiments, the areneselenenyl electrophile competes successfully with H+ because it is generated in a solvent cage together with the

57 target olefine. This observation underlines the importance of the disposal of selenenyl electrophiles in the reductive eliminatien of 8-hydroxy selenides. Every time the hydroxy group is transformed into a powerful leaving group, reductive eliminatien is observed; it is related to the strong neighbouring group participation of the seleno substituent 1 ~. The formation of an episeleno nium ion is a very fast reaction because of the high effec tive concentratien of the Se-nucleophile at the reaction site and the small degree of bond reorganization required to reach the transition state. This neighbouring group par ticipation preelucles the formation of free c,o-carboéations. Thus, 8-hydroxy selenides l are nat suitable as model sys tems for the study of ground-state M~bius aromaticity.

III.4 Experimental

Starting compounds l 2 ,l2 and ~ 13 were prepared acear ding to the literature. All new products gave satisfactory analytica! data and/or the expected molecular ion. 1 H and 13C NMR speetral data are collected in Table I and II, res pectively.

- Isobutyraldehyde quenah produate (~~2a)

A salution of 9,9-bis(p-tolylseleno)bicyclo ~.2.1]no na-2,4,7-triene2 (2g, 4.4 mmol) in 10 mL of dry THF was treated with 3.5 mL n-BuLi (15% in n-hexane) at -78°C under a nitrogen atmosphere. After 5 min at -78°C the carbanionic salution was quenched with isobutyraldehyd. The reaction mixture was poured onto water and extracted into Et2o. The combined organic layers were washed with water, dried (MgS04) and concentrated. High performance LC (CHC1 3) yielded 0.68 g (43%) of~ (mp 73-74°C from n-hexane) and 0.28 g (18%) of lb. 1 la: H NMR (CDC1 3) ö 7.67-7.00 (AB,4); 6,20 (m,4); 5.10 (m,4); 3.40 (m,1); 3,13 (m,l); 2.83 (m,1); 2.73 (m,1); 2.32 (s,3); 1.60 (m,l); 0.83 (d,6). Anal. calcd. for c20 H24 ose: C, 66.84; H, 6.73. Found:

58 C,66.66; H, 6.67. 1 1b: H NMR (CDC1 3) o 7.80-7,03 (AB,4); 6.07 (m,4); 5.12 (m,2); 3.17 (m,1); 2.90 (m,1); 2.77 (m,1); 2.37 (s,3); 1.97 (m, 1); 1.83 (m, 1); 1.00 (d,3); 0.80 (d,3).

~ Acetone quench pPoduct (~)

15 1 is prepared and isolatedas for != yield 101 , H NMR (CDC1 3) o 7.63-6.83 (AB,4); 6,07 (m,4); 5,00 (d,2); 3.30 (s,2); 2,58 (s, 1); 2.27 (s,3); 1.23 (s,6).

- Reductive etimination of !4 and 2a

To a stirred salution of (0,5 g; 1.4 mmol) in 2 mL of CH 2c1 2 was added 1 mL of dry triethylamine. At 0°C, a so lution of 0.32 mL of methanesulfonyl chloride in 1.5 mL of CH 2c12 was added in 5 min via a syringe. After stirring for 30 min at 0°C and 30 min at room temperature, the reaction mixture was poured onto water and extracted into CHC1 3 • After washing with water, drying (MgS0 4) and concentrating, high performance LC yielded 0.12 g (SOl) of!± (eluens: benzene n-hexane 10/90), Compound 1 was prepared and isolated in the same way; yield 61%.

- GenePat pPoceduPe foP the PeaPPangement Peaation

To a stirred salution of B-hydroxy selenide ! (250- 500 mg) in liquid so 2, fluorosulfonic acid (1-2 mL) was added at -78°C under a nitrogen blanket. After 15 min, the reaction was stopped by the addition of cold methanol. The reaction mixture was poured onto water and extracted into CH 2c1 2• After washing with water, 10% aqueous NaOH, and wa ter, drying and concentrating, products were isolated with the aid of high-performance LC (benzene-n-hexane 10/90 as eluens).

59 H(1,6} H{2-5) H(7,8) H(8) H(9) Others

-10b 3.87(d) 6.58-5,90(m) 5.48(d} 7.5-6,9(m,S,aryl); 6.30(s, 1 ,H 10 ) 3.60(d) -11 a 3.07(d) 6.37-5.43(m) 3.83(s) 3,70(s) 7.6-6.76(m,3,aryl); 2.27(s,3,ArC!:!,3); 4.07(d) 0.95(s,3,CH3); 0.83(s,3,C!:!,3); 2.27 (m, 1 ,methin); S.ZO(d,1,olefin,J 9Hz); -11 b 3.05(d) 6.32-5,47(m) 4.00(s) 3,77(s) 7.33-6.83(m,3,aryl); 2,27(s,3,ArC!:!,3); 4.07(d) 1.88(s,3,C!:!,3); 1 • 6 3 ( s , 3 , C!:!,3) • 11 c 3.13(d) 6.30-5.70(m) 3.93(s) 3.72(s) 6.4-6.77(m,8,aryl); 6.37(s,1,olefin); 4.47(d) 2.23(s,3,C!:!,3). -12a 3.2(dd) 6.40-5.70(m) 5.30(d) 3,30(s) 7.7-7.0(AB,4,aryl); S.SO(d.l,olefin); 3.40(d) 2.30(s,3,ArC!:!,3); 1.SO(s,6,C!:!,3). -13 3.63(d) 5.60-S.SO(m) 5.22(d) 7.03(m,S,aryl); 5.10(d,1,olefin,J 9 3.27(d) Hz); 2.47(m,1,methin); 1.30(d,3,C!:!,3). -14 3.70(d) 6.37-5,67(m) 5.33(d) 4.93(d,1,olefin,J 9 Hz); 2.43(m,1, 3.32(d) methin); 0.97(d,3,C!:!,3); O.SS(d,3,C!:!,3).

Table I: 1 H NMR speetral data for exocyaZic olefine and rearrangement produats een C(2,5) C(3,4) . C(6) C(7) C(8) C(9) c ( 1 0) C arom. Others -11 a 50.02 135.6 125.99 56.28 149.90 63.88 41 • 88 143.38 122.67 129,03 32.49(methin) 133.99 124.72 129.68 129.25 23,70(methyl) 133.24 135.6 23,49(methyl) 21.98(Arf.H3) -11b 50.89 135.38 125.28 58.06 141.63 60,73 41 • 88 146.43 123.55 127.82 25.01(methyl) 1 34. 81 124.41 129.03 129.29 22.50(methyl) 130.67 134.81 21.90(Arf.H3) -11 c 49.00 133.95 125,80 56.68 142.54 66.56 42.70 153.37 138.37 135.98 21.98(methyl) 133.65 125.50 122.78 126.88 129.98 128.68 129.29 129,12 127.65 125.45 -13 45.85 136.63 126.36 51 • 0 7 124.50 123.85 137.57 127.74 127.95 128.43 39.50(methin) 135.07 .1 25. 54 129,51 147.33 22.94(methyl) -14 45.46 136.97 126.36 50.64 124.20 123.55 136.11 128.38 28.88(methin) 135.63 124.98 24.53(methyl) 24.36(methyl)

Table II: 13 C NMR speatral data for exoayalic olefine and rearranged products Referenaea and Notea

1. H.M.J. Gillissen, P. Schipper, H.M. Buck, Reel. Trav.

Chim. Pays-Bas, 1980 1 99, 346. 2. See Chapter II. 3. a. R. Breslow, J.M. Hoffmann Jr., J. Am. Chem. Soc., 1972, 94, 2110. b. R.Breslow, S. Mazur, J. Am. Chem. Soc., 1973, 95,584. c. M. Saunders, R. Berger, A. Jaffe, J. M. Mc.Bride, J. 0 ' Neill, R. Breslow,' J.M. Hoffmann Jr., C. Perchonock, E. Wassermann, R.S. Hutton, V.J. Kuck, J. Am. Chem. Soc., 1973, 95, 3017. 4. P. Schipper, H.M. Buck, J. Am. Chem. Soc.,1978, 100, 5507. 5. P. Vogel, M. Saunders, N.M. Hasty, J.A. Berson, J. Am. Chem. Soc, 1971, 93, 1551. 6. Recently, a theoretica! investigation postulated combi ned HUckel-Mtlbius aromaticity in doubly lithium-bridged R4c4Li2-systems: A.J. Kos, P.v.R. Schleyer, J. Am. Chem. Soc., 1980, 102, 7928. 7. R.S. Bly, T.L. Maier, J. Org. Chem., 1980, 45, 980 and references cited herein. 8. a. H.J. Reich, F. Chow, S. Shah, J. Am. Chem. Soc.,1979, 101, 6638. b. H.J. Reich, F. Chow, Chem. Commun., 1975, 790. c. J. Rémion, W. Dumont, A.Krief, Tetrahedron Lett., 1976, 1385. d. A.M. Leonard-Coppens, A. Krief, ibid, 1976, 3227, e. J. Rémion, A. Krief, ibid, 1976, 3743. f. J. Luchetti, A. Krief, ibid, 1978, 2693. g. S. Halazy, A. Krief, Chem. Commun., 1979, 1136. 9. G.H. Schid, D.G. Garrat, Tetrahedron Lett., 1975, 3991. 10. D.C. Sanders, H. Shechter, J, Am. Chem. Soc., 1973, 95, 6858. 11. At -78°C, addition of HFS0 3 toa salution of 1 in so2 produced indenes (independent experiment). 12. a. 0. Behaghel, H. Seibert, Chem. Ber., 1932,'65, 812. b. 0. Behaghel, W. MUller, ibid, 1935, 68, 1540.

62 13. a. L.A. Paquette, M.J. Broadhurst, J. Org. Chem., 1973, 38, 1886. b. L.A .• Paquette, M.J • Broadhurst, J. Org. Chem., 1973, 38, 1893. 14. A. Krief, Tetrahedron, 1980, 38,2531. 15. The main reaction products are syn- and anti-9-p-tolyl selenobicyclo [4.2.1] nona-2,4,7-triene (yield: 75%). The tolueneselenoketal yields protic quench products as sole products upon reaction with esters, acid chlorides and acid anhydrides.

63 CHAPTER IV

CATIONIC DERIVATIVES OF BICYCLO (4. 2 ,1) NONA-Z ,4, 7-TRIENE AS MODELSYSTEMS FOR GROUND-STATE MöBIUS AROMATICITY

IV.1 Synthetia Conside~ations

A modelsystem 1 for the investigation of ground-state Möbius aromaticity should lack S-substituents, which can interact with the (developing) charge at c10 via neighbouring group participation. This can be concluded from the chemis try of S-hydroxy selenides in super acid media (modelsystem 1 1!) • Substitution of hydrogen for selenium would afford

.Q. R1 =SeAr .Q. R1 :: H

modelsystem ~ in which neighbouring group participation is absent. However, the reduction of selenium containing com pounds2 failed. Therefore, new pathways for the synthesis of precursors to modelsystem ~ were explored. Hydraboration of 9-methylenebicyclo~.2.1]nona-2,4,7- triene ~ with 9-borabicyclo[3.3.1]nonane (9-BBN) occurs at the anti-side. Oxidation yields alcohol ~; further oxida tion with pyridinium chlorochromate (PCC) affords aldehyde ±· The overall yield of this reaction sequence is about 9%

64 ,!. 9BBN PCC 13" because of the reluctancy of 2 in the hydraboration reaction and the occurrence of oxidative cleavage in the oxidation of 3, This indicates that the direct introduetion of a functionalized carbon chain 3 is to be preferred over a di vergent reaction route. The logica! starting compound for such an approach is bicyclo[4.2.1)nona-2,4,7-trien-9-one 5. Various 13-hetero substituted derivatives ~ are obtainable upon the reaction of~ with suitably functionalized carbanions. Acidic hydro-

2. lysis of~ would afford aldehydes, ketones and carboxylic acid derivatives. However, in order to obtain modelsystems for the investigation of Möbius aromaticity, the protona tion step of the hydralysis reaction has to proceed from the anti-direction. It is known that the hydralysis of ketene 7.. proceeds with 100~ stereospecificity to produce carboxylic acid 8~. The carbanion 9 reacts with HCl at 0°C to produce the two epi- a 11 ~ 2

65 N0

HCI ~ dj + 9 10 11 meric nitriles 10 and 11. At -80°C, only anti-protonated 5 nitrile 10 is formed • These results make it clear that anti-protonation of sp 2 -hybridized hetero-substituted deri vatives of bicyclo ~.2.1]nona-2,4,7-triene (6) is definitely favoured over syn-protonation. Thus, the synthetic approach to modelsystem ~ via hydralysis of compounds ~ is fully supported by the available experimental evidence. The synthesis of various potentially useful derivatives H OCH3 I

1§. Soheme I

66 of type~ is depicted in Scheme I. Hydrolysis of vinyl ether 12 affords under special reaction conditions low yields of aldehyde 4. Under normal 6 conditions, dimericproduct 1! is formed • H 9CH3

12 18

Compounds 13-15 are precursors for the synthesis of ketene 19. This ketone is produced in good overall yield by the hydrolysis of enamine l±· Epimeric ketone 20 is also isolated. Under identical experimental conditions, vinyl

ether ~ affords exclusively ketene 19. Transition metal induced hydrolysis 7 of vinyl sulfide 15 is unsuccessful. Ketene S,S-thioacetal ~ is also resistent to metal induced hydrolysis. However, oxazoline 11 is easily con verted in carbonitriles .!Q and .!..!.,.thus making carboxylic acid derivatives of bicyclo ~.z.Dnona-2,4,7-triene available. The a-hetero-substituted olefins ll-~ can be used directly as precursors to modelsystems for the investigation of ground-state Möbius aromaticity. Upon protonation these compounds produce a-hetero-substituted cations. a-Hetero substituted cations are also available via protonation of the carbonyl functionality of the carbonyl compounds ± and ~· Finally, the carbonyl compounds ± and ~ can be reduced to the alcohols ~ and ll· These alcohols may serve as pre cursors for the generation of carbocations.

67 21

IV.2 Stereoahemistry of protonation

The transition metal induced hydrolysis of vinyl sul fide ~ is unsuccessful. However, vinyl sulfides can ·be converted to thioketals when reacted with thiols in the 8 presence of dry HC1 • Reaction of 15 with ethanethiol results in the formation of thioketal 22. Under identical conditions,

EtSH HCI

vinyl ether 11 reacts with a thiol to produce the hemithio ketal 23, The syn-protonation of vinyl sulfide ~ is a very sur prising result in view of the predominant or even exclusive anti-protonation of other .B-hetero-substituted derivatives ~(vide infra). TableI displays data on the stereochemistry of protonation9 of various trienyl derivatives ~· Data with respect to the side of protonation of the dienyl derivatives 24-26 are included in Table I. These data indicate that the aberrant protonation of ~ cannot be attributed to the pre senee of the etheno-bridge in ~· Vinyl sulfide 26 yields upon protonation in the presence of ethanethiol the syn protonated product ~· The other compounds display the ex pected behaviour (vide infra). Thus, the preserree of the etheno-bridge in the compounds 11- has no influence on

68 the stereochemisty of protonation.

H OCH3 I I EtS CH3 ~c::b

24 26 27

Table I: StePeoahemistPy of pPotonation

~ a Substrate . (°C) % anti a % syn- Reaction cond. 74 !L 100 0 dioxane/water gs - 0 65 35 HCl/THF -80 100 Q HCl/THF -1 2 0 100 0 HC1/PhSH/CHC1 3 20 100 0 HC10 4/water.4 -80 100 0 CF 3COOH/S0 2 -13 20 100 0 Si02/CHCll- -14 20 85 15 Si0z/CHC13.Ë 20 85 15 (COOH) 2/Me0H/H 20 1 5 0 0 100 EtSH/HCl/CHC1 - d 3 -24 20 100 0 HC10 4/H2o=- -25 20 85 15 Si02/CHC1 3.Ë -26 0 0 100 EtSH/HCl/CHC13

~ Refers to side of protonation. ~ Not specified • .Ë Hydro lysis upon chromatography. 4 Yields a dimeric Prins-product.

The acid catalyzed hydralysis of numerous vinylic sub 10 12 strates has been thoroughly investigated in recent years - • It has been established that the reaction proceeds via rate determining and irreversible protonation of the olefinic linkage. The quench result of the carbanion ~ 5 make it clear that anti-approach of the proton is favoured over syn approach. Other evidence confirms this conclusion (Table I). Anti-protonation yields a-hetero-substituted cations, which may be stabilized by Möbius aromaticity, The intermediate

69 cations are investigated with the aid of NMR spectroscopy. The protonation of vinyl sulfide 15 is included in this study in order to obtain an answer for the aberrant syn protonation.

IV.3 NMR speatPosaopia investigations of aations undeP long life aonditions

Möbius aromaticity should be reflected in the NMR spec tral parameters of the carbocationic modelsystem ~· There fore, precursors to modelsystem ~ were investigated in su per acid media with the aid of 1 H and 13C NMR spectróscopy. Alcohols ~. l! and ~ are precursors for the genera tion of carbocations. Addition of HFS03 to a solution of

21 29

~ in so 2c1F at -78°C leads to protonation of the hydroxyl group. This follows directly from the downfield shift of the a-protons. Dehydration of protonated ~ in excess acid initiates extensive rearrangement reactions via a prior 13 ~,2]H shift from c9 to c 10 • Protonation of the hydroxyl group is also observed upon the addition of HFS0 3 to a so lution of alcohol l! in so 2;so 2ClF. Excess acid leads to the formation of an allylic cation ~ (Figure Ia: the sig nals for the allylic protons H3-H 5 appear in between 8.0-10.3 ppm). 13C NMR spectroscopy supports this assignment ( reso nances for the allylic carbons c 3_5 at 207.6, 184.9 and 182.4 ppm). Inverse addition of toa salution of excess HFS0 3 in so 2;so2ClF yields the same allylic cation ~· Quenching confirms that l! affords an allylic cation. After the addition of a cooled salution of sodium methoxide in methanol, the tetracyclic ethers 2Q and 31 are isolated. Tricyclic ethers 32 and 33 are produced upon pou-

70 ring the carbocationic salution onto saturated aqueous so dium bicarbonate. These results are in agreement with the reported generation of an allylic cation 2i upon protona 1 tion of bicyclo[4.2.1]nona-2,4,7-triene 34 ".

34 35

Alcohol ~ produces upon protonation with excess HFS0 3 a mixture of the oxonium ions ---36-38a. This follows directly from the 1 H and 13C NMR spectra (Figure Ib). Quenching affords the tricyclic ethers 36-38b. Thus, the protonation ":lc, ;_x

jja X= H b X= lone pair of electrans of the diene-bridge yields an allylic cation, which reacts intramolecularly with the hydroxyl group to produce oxonium

71 ppm 10 8 6 4 2 0

)

ppm 12 10 8 6 4 2 0

-~ 1 l J l I

ppm 140 80 20 FiguPe I: a: 60 MHz 1 H NMR speatrum of aation 29 at -?8°C; b: 60 MHz 1 H and 22.63 MHz 13C NMR speatra of the mixture of oxonium ions 36-38a at -78°C.

72 ions. The preferenee for the formation of allylic cations over dehydration products with the substrates ~ and 28 precludes the investigation of a possible Möbius interac tion in c 10-carbocations. However, a-hetero substituted cations are readily produced upon protonation of vinylic substrates .,!1-.:!.2, or upon protonation of the carbonyl func tionality of carbonyl compounds i and ~· Therefore, these compounds are studiedunder long life conditions. The satu rated substrates ~-il are included in this study as refe rence compounds.

Addition of HFS0 3 to a salution of vinyl ether g in so 2ClF leads to extensive polymerization. Aldehyde i also polymerizes under these conditions. Vinyl ether g reacts with the more nucleophilic CF 3COOH to produce the ester il' which is stable in a so 2c1F-solution. Quenching with aqueous

42 43 44 sodium bicarb.onate af fords aldehyde 4. Vinyl ether ~ reacts with so 2c1F. After quenching and 15 work-up the a-chloro ketene 44 is isolated • The reaction of ~ with CF 3GOOH in liquid so 2 leads to the formation of 16 theester 43. Vinyl sulfide ..:!.2, also reacts with so 2C1F • Protonation with excess CF 3COOH in so 2 leads to the forma-

73 tien of ester ii' which is in equilibrium with the starting compound li· This follows directly from the temperature

SCHc?cocF3

CH 3 --~ 15 45

dependence, displayed by the 1 H NMR spectrum. Thus, the pro 32 tcnation of vinyl sulfide li is reversible • Upon reaction with HFS0 3/SbF5 (5:1), the substrates 13, li, }2 and 39-±l all generate cationic solutions. The 13C and 1 H NMR chemical shifts for the resulting cations ~,±I are collected in Tables II and III, respectively. The chemical shifts of the ketones 19 and 39 are included. XR a X=O R=H ;scH3 b X=O R=CH 3 !:, X=S R=CH 3

The 1 H and 13 C NMR spectra of cations 46 and 47 remain unchanged over a temperature range of -100° to -30°C. This indicates that cations 46 and ±I exist in frozen configura tions or that rotatien around the c9-c 10 bond is very fast on the NMR time scale. Rotatien around the C-X (X=O, S) bond is not observed. The stereochemical assignment at c9 in cations 46c and 47c follows directly from the multipii 23 1 city of the H9-resonance in the 250 MHz H NMR spectra (Figure II). Decoupling experiments show that H9 couples with H1 and H6 (J= 5.85 and 4.75 Hz in 46c and 47c, respecti vely). Furthermore, H9 displays in both cations a long range coupling with the methyl group (~J= 2.0 Hz). This long range coupling was observed over the whole temperature range of -80° to -30°C. lts magnitude does not change upon tempera ture variation. No Nuclear Overhauser Effects are observed

74 H on 9 upon the saturation of the methyl and thiomethyl sub stituent, respectively. Unfortunately, during these experi ments is was omitted to abserve the butadiene protons. Quenching of the oxygen substituted cations affords the ketones 19 and 21, respectivelyi the sulfur substituted cations yield upon quenching unreacted starting material.

6 5 4 3

3 2

Figure II: 250 MHz 1 H NMR spectra of cation 46c (~) and !lË (b).

It can be concluded that tt-hetero substituted cations are readily accessible for direct NMR spectroscopie inves tigations. In cations 46 a Möbius-type of interaction may be operative. This possibility is discussed in the next section.

75 TabZe II: 13 C NMR ChemiaaZ shifts for aations 46 and 47~~k~~

c1 , 6 c2 , 5 c3 , 4 c7 , 8 Cg c10 CH 3 R

19 43.57 136.11 124.86 122.24 54.31 209.52 26.27 46a 43. 21 135.11 125.25 1 21 • 94 54.69 232.63 26.88 46b 43.52 134.65 125.33 121.71 56.08 241.02 25.42 69.10 46c 44.68 134.18 127.25 122.32 58.23 256.12 24.10 30.50 -39 37.44 32.58 24.88 31.74 60.54 213.91 28.73 47a 38.13 31 • 27 24.42 29.50 63.09 246.41 29.50 -47b 38.58 31.86 24.72 31.45 63.96 245.89 26.30 68.69 -47c 39.49 31 • 61 24.39 31.28 68.86 263.06 22.23 31.5

13 ~All chemical shifts are reported relative to external Me 4si. k C NMR spectra are recorded at 22.63 MHz. ~Solvent liquid so2. Table III: 1 H NMR chemical shifts for cations 46 and 47~,k,~

Hl 6 H2-5 H7,8 H9 CH R ' 3 -19 3.37 6.33-5.60 5.19 2.95 2.05 46a 3.77 6.58-5.83 5.40 3. 77 2.73 --46b 3.87 6.50-5.87 5.33 3.87 2.96 4.72 --46c 3.82 6.50-5.87 5.43 3.82 3.17 3.17 -39 2.7 2.2-1.2 2.7 2.20 47a 2.97 2.3-1.1 3.57 3.10 --47b 3.0 2.3-1.1 3.63 3.10 4.87 --47c 3. 1 2.5-1.2 3.37 3.25 3.25

~All chemica! shifts are reported relative to external Me 4Si. 1 k H NMR spectra are recorded at 60 MHz. ~Solvent liquid so 2 • ...... IV.4 Disaussion

Aromaticity and homoaromaticity are of importance in determining the stability of (homo)cyclic n-electron systems. Energy lowering of transition states and stabilization of reactive intermediates lead to enhanced reaction rates and enhanced stereospecificity, respectively. The stereochemi cal consequences of Möbius aromaticity in Û,3] C and [1,4] 17 C shifts are well known • Ground-state Möbius aromaticity has never been observed. This type of stabilization may be operative in modelsystem ~. i.e. in the cations 46. Upon protonation, the alcohols .[!_ and 28 do not -farm c10 -carbocations, but generate allylic cations. The intro duetion of a-hetero-substituents leads to stabilization of the c10 -cations. The cations 46a-f could be observed un der long life conditions. These cations exhibit NMR spectra which suggest a mirror symmetrical structure for the cations. The 13C and 1 H NMR spectra of the cations 46 do notchange over the temperature range of -100° to -30°C. The 250 MHz 1 H NMR spectrum of cation 46c reveals a long range coupling between H9 and the methyl group; the magnitude of this long range coupling is temperature independent. From these results it is obvious that an asymmetrie interaction between H10 and one of the double honds of the diene moiety, as in 1!• can be excluded. This type of interaction would result in more complex NMR spectra due to the absence of a mirror plane of symmetry. An asymmetrie through-space interaction has been

48 49

18 reported to occur in the structural related cation 49 • The observed "symmetrical" NMR spectra may arise from frezen configurations A and A', or via fast equilibria re-

78 sulting from rotatien around the c9-c 10 bond (Scheme II).

B' Saheme II

The configurations A and A' have the correct geometry for the occurrence of a Möbius interaction. In saturated systems, the 4J couplings in freely ro tating fragments, e.g. CH 3-C-CH3 , are very small (aa. zero). In acyclic systems with a preferred configuration, methyl group couplings to trans- and gauahe-oriented protons have coupling constantsof 0.4 to 1.0 and 0 to -0.3 Hz, res pectively. Methyl group couplings to ais-oriented protons have not been reported. However, on the basis of theoretica! calculations in unstrained systems, this coupling should be approximately equal to the coupling constant between methyl 19 30 groups·and trans-oriented protons ' • The long range coupling between H9 and the methyl group in cation 46c points to configuration A and A' for this cation, because the methyl group is oriented trans and ais, respectively, with respect to the proton at c9• Pree rotatien around the

79 c9-c 10 bond should result in a very smal! coupling constant (vide sup.r>a). The saturated cations 47a-f also display NMR spectra, which suggest a symmetrical structure for the cations. Si milarly, the 250 MHz 1 H NMR spectrum of 47c shows a tempe rature independent long range coupling constant between H9 and the methyl group. Thus, one could conclude that cation 47c also exists in a mirror symmetrical configuration si milar to configurations A and A'. However, the C-X (X= O, SJ bond in cations 46 and 47 has partial double bond character. Freely rotating species like acetone, in which the bonding situation is camparabie to that in cations 46 and ±1, also display long range cou 31 pling constants (0.54 Hz in the case of acetone ), So, it must be concluded that it is impossible to deduce from the observed speetral characteristics of cations ±2 and 47 whether these cations are freely rotating or that they exist in frozen configurations like A and A' (see Scheme 11). Therefore, the observed NMR spectra cannot give unambiguous prove for ground-state Möbius aromaticity. Generally, protonation of aliphatic ketones induces a downfield shift of the carbonyl carbon of approximately 20 30-40 ppm , For aryl ketones, smaller downfield shifts (10-20 ppm) are observed due to charge delocalization into 20 21 the aryl ring(s) ' • The resonance of c10 in 46a appears 23.1 ppm downfield with respect to the carbonyl carbon in ketone ~· Reference compound 47a displays a downfield shift of 32.5 ppm relative to c10 in ketone 39 (Table II). The difference in chemica! shift of c10 between 46a and 47a comes to 13.8 ppm (Table II). The shift differences between 46b and 46c with respect to their saturated analogues are smaller (4.87 and 6.94 ppm, respectively. See Table 11) • . Möbius aromaticity in cations 46 should give rise to charge delocalization between c10 and the diene moiety and to rehybridization at c10 • Both charge transfer and rehybri dization should result in a relative upfield shift of the cationic center with respect to the saturated analogues. So, the shift differences for 46a may suggest a certain degree

80 of charge delocalization via a Möbius interaction.

IV.S EwpePimentaZ

Starting compounds 9-methylenebicyclo~.2.1]nona-2,4,7- 22 23 triene 1 , bicyclo[4.2.1]nona-2,4,7-trien-9-one ~ , bicy clo [4. 2 .1] nona-2 ,4-dien-9-one 2.Q.H, methoxymethyl diphenyl phosphine oxide ~ 25 , 1-methoxyethyl diphenylphosphine oxide ~ 26 , diethyl (1-methylthio)ethyl phosphonate 53 27 , diethyl 28 (1-N-benzylideneamino)ethyl phosphonate l! , S,S-acetal of diethyl formyl phosphonate ~ 29 are synthesized according to literature procedures. All new compounds gave satisfac tory elemental analyses and/or the expected molecular ion. 1 H and 13C NMR speetral data are collected in Tables IV and V, respectively.

Toa salution of 1 (lg; 7.7 mmol) in 10 mL of dry THF, 9-borabicyclo[3.3.1]nonane (1 eq.) was added under a nitro gen atmosphere. After refluxing for 2 h, the salution was caoled to 0°C and 0.5 mL of H2o, 2.6 mL of 3N aqueous NaOH and 2.6 mL of H2o2 (30%) were added. After stirring for 1 h, the reaction mixture was poured onto water, extracted into CH 2C1 2 and dried (MgS0 4). Chromatography (CHC1 3-s% me thanol) yielded 0.53 g (47%) of~; mp 58-60°C.

- Syn-9-aaPbowybicyaZo [4,2.1]nona-2.4,7-triene (4)

A salution of~ (0.37 g; 2.5 mmol) in 1 mL of CH 2c12 was added rapidly to a stirred suspension of pyridinium chlorochromate (1.09 g) in 5 mL of CH 2c1 2• After 3 h the dark coloured reaction mixture was diluted with 20 mL of Et2o. The solvent was decanted, and the black residue was washed twice with Et2o. The product was isolated by filtra tien over florisil, concentratien and chromatography (CHC1 3). 1 Yield: 0,095 g (26%); IR (neat) vC=O 1730 cm- •

81 Toa salution of 0.76 g of dry diisopropylamine in 15 mL of dry THF, 5 mL of n-BuLi (15\ in hexane) was added at. 0°C under a nitrogen blanket, After 5 min, solid 11 (1.86 g; 7.6 mmol) was added in small portions. The resulting red coloured solution was stirred for 10 min after the addition was completed. Then, a solution of i (1 g; 7.6 mmol) in 5 mL of dry THF was added via a dropping funnel. After stirring for 3 h at room temperature, the reaction mixture was poured onto water and extracted into E;2o. The organic layers were washed with water, 1N aqueous HCl, saturated aqueous NaHC0 3, and water, dried (MgS0 4) and concentrated. Chromatography yielded 0.46 g (38%) of 12.

Hydrolysis of with trifluoroaaetia aaid

Toa solution of 11 (0,5 g; 3.1 mmol) in 2 mL of CHC1 3, trifluoroacetic acid (1.5 eq.) was added. After stirring for 30 s, the reaction mixture was poured onto water and stirred for 1 min. The mixture was rendered alkaline by the addition of saturated aqueous NaHC0 3 • Extraction (Et 20), drying (MgS0 4) and chromatography (CHC1 3) yielded 0.13 g (30%) of ±·

Hydrolysis of with perahloria aaid

A suspension of 0.5 g of 11. 2 mL of Et2o and 2 mL of aqueous perchloric acid (65% in acid) was stirred for 15 min. After the addition of 20 mL of Et 2o, the organic phase was washed with water, saturated aqueous NaHC0 3, and water, dried (MgS04) and concentrated. Chromatography (CHC1 3) 1 yields pure l!i mass spectroscopy m/e 292; H NMR (CDC1 3) ê 6.33-5.57 (m,9); 5.25 (t,2); 4.25 (t,1); 3.6-3.0 (m,8). 13 C NMR (CDC1 3) ó 136.1; 134.9; 133,6; 132.6; 130.8; 129.9; 126.2; 125.7; 123.8; 122.5; 100.0; 77.0; 76.2; 55.7; 49.1; 44.4; 44.1; 43.5; 40.8; 40.3.

82 ._ B-(1-methoroyethyZidene)bicyaZo ~.2.1]nona-2,4,?-t~iene (ll) ._ syn-B-aaetyZbiaycZo ~.2.1]nona-2,4,?-t~iene (1!)

A stirred salution of diisopropylamine (0.76 g; 7.6 mmol) in 15 mL of dry THF was treated at 0°C.~ith n-BuLi (5 mL; 7.6 mmol) under a nitrogen blanket. After 10 min, 52 (1.97 g; 7.6 mmol), dissolved in 10 mL of dry THF, was added via a dropping funnel. The yl~d salution was stirred for 10 min. Subsequently, a salution of i (1 g; 7.6 mmol) in THF (5 mL) was added. After stirring for 30 min at 0°C and 1.5 h at room temperature, the reaction was stoppad by pouring the reaction mixture onto water. The reaction pro ducts were extracted in Et2o. The combined organic layers were washad with water, dried (MgS0 4), filtered and concen trated. Chromatography (Si02/CHC1 3) of the crude reaction mix ture yielded pure ketone ~; overall yield 64%. Enol ether ~ could be obtained by destillation of the crude reaction mixture. The purest fraction (bp 62-63°C/0.6 mm Hg) con tained approximately 5-10% of starting material ~ (GLC ana lysis). Alternatively, ~ can be isolated by means of chro matography (basic A1 2o3, hexane-ethyl acetate 85:15) •

.- 9-(1-N-benzyZideneaminoethyZidene)biayalo ~.2.1]nona- 2~4,?-t~iene (l!) ._ syn-B-acetyZbicycZo ~.2.1]nona-2~4,?-t~iene (2!)

To a stirred salution of 2.53 mL of n-BuLi (3.8 mmol) in 15 mL of dry THF, a salution of~ (1.02 g; 3.8 mmol) in 5 mL of dry THF was added with a dropping funnel, at -78 °C under a nitrogen atmosphere. After 1 h, a salution of ketone 5 (0.5 g; 3.8 mmol) in dry THF (5 mL) was added. Stirring at -78°C was continued for 10 min. Then, the reac tion mixture was allowed to warm to room temperature and refluxed for 3 h. The reaction mixture was poured onto wa ter and extracted into Et2o. Drying (MgS04) and concentra ting yielded 1.1 g of crude azadiene l±• which could be

83 purified by trituration with MeOH. Hydrolysis of the aza diene was effected by passing it through a column of Si02 with CHC1 3 as eluens. Chromatography (CHC1 3) afforded a mixture of~ and ~ (55\ overall yield; ratio~:~ 85:15). Pure 19 was obtained with the aid of high-performance LC 1 ( hexane- 10% ethyl acetate). IR (neat) vC=O 1715 cm- ; mass spectroscopy m/e 160; UV (MeOH) 220 nm, 257.5 nm, 265 nm and 276 nm (shoulder).

- 9- ( 1-methy l thioethy Zidene) biayaZo [4. 2. 1] nona-2. 4. 7- triene ( l.§)

A stirred solution of diisopropylamine (0.8 g; 8.8 mmol) in 15 mL of dry THF was treated with n-BuLi (5,5 mL; 8.25 mmol) at 0°C under nitrogen. After 10 min,~ (1.68 g; 8.0 mmol), dissolved in 5 mL of dry THF, was added with a drop ping funnel. Stirring at 0°C was continued for 4 h. Then, a solution of~ (1 g; 7.6 mmol) in 5 mL of dry THF was added. The mixture was stirred for 20 h, quenched with ice-cold saturated aqueous NH 4Cl, extracted into Et2o, wasbed with water, dried (MgS0 4) and concentrated. High-performance LC afforded 0.64 g (59%) of li (eluens hexane-10% ethyl aceta te) •

- Ketene S • S-thioaae tal ( ]:..§)

Toa salution of SS (3.03 g; 11.8 mmol) in 40 mL of dry THF, 7.9 mL of n-BuLi was added at -20°C under nitrogen. After stirring for 30 min, the mixture was allowed to warm toroom temperature, and a solution of~ (1.55 g; 11.8 mmol) in 10 mL of dry THF was added. The mixture was stirred for one night and then poured onto water. Extraction (Et2o), washing with water, drying (Mgso 4), concentratien and tri turation (iPr20) yielded 1.6 g (58%) of pure !2; mp 136- 1370C. Anal. Calcld. for c13H14 s2: C, 66.61; H, 6.02. Found: C, 66.43; H, 5.98,

84 ~ O~azotine (dL)

To a stirred suspension of sodium cyanide (0.076 g) in 15 mL of absolute EtOH, a solution of 1.48 g of tosylmethyl isocyanide and 1 g (7.6 mmol) of~ in 7 mL of dry THF was added under nitrogen. After 2.5 h, the solvent was stripped off and 15 mL of CC1 4 were added. After 1 h at 0°C, the mixture was filtrated. The remaining solid was recrystal lized from acetone, yielding 1.87 g (76%) of 11; mp 167°C with decomposition. Anal. Calcld. for c18H17 No 3s: C, 66.03; H, 5.23; N, 4.28. Found: C, 66.15; H, 5.40; N, 4.48.

- Biayato~.l.l]nona-2~4~7-trien- syn- and anti-9-aarbo nitrite (lQJ~(ll)

A solution of 0.69 g potassium t-butoxide in a mixture of 5 mL of dry dimethoxyethane and 5 mL of dry t-butanol was added toa stirred suspension of 11 (1 g; 3.1 mmol) in ZO mL of dry dimethoxyethane at 0°C under a nitrogen atmos phere. The mixture was stirred for 0,5 h at 0°C and 3 h at room temperature. Then, the mixture was poured onto water and extracted into Et2o. After drying (Mgso 4) and concentra ting, chromatography (CHC1 3) yielded 0.35 g (80%) of car bonitriles .!.Q. and .U (ratio 65:35) •

._ 9-metho~ymethytidenebiayato~.2.l]nona-2 1 4-diene (24}

is prepared and isolated as described for yield 40-70% •

._ 9-(l-N-benzyLideneaminoethyLidene}biayato[4.2.l]nona- 214-diene (.2_!) ._ syn-9-aaetytbiayato~.2.l]nona-2 1 4-diene (~)

are prepared and isolated as described for compounds 14 and ~· Chromatography (CHC1 3) afforded pure ~; yield 1 42%; mp 35-40°C; IR (neat) vC=O 1720 cm- •

85 Anal. Calcld. for c11 H14o: C, 81,44; H, 8.70. Found: C, 80,g2; H, 8,77.

.... 9- ( 1-methy lthioethy tidene) bicycl.o [4. 2. 1] nona-2~ 4-diene (_!!)

is prepared and isolated as described for compound .:!2,; yield 46%.

.... Thioketal.s !! and !L

To a salution of vinyl sulfides 1.2. or ~ in cnci3 , ethanethiol (1.5 eq.) was added. Subsequently, dry HCl-gas was passed through the salution for 1 min at 0°C. The reac tion was monitored with 1 H NMR until completed. Then the mixture was poured onto saturated aqueous NaHco 3 and ex tracted into Et2o. After washing with .brine, drying (Mgso4) and concentrating, pure products were isolated with the aid of chromatography (CHC1 3); yields 80~gs%. 1 22: H NMR (CDC1 3) ó 6.37-5.58 (m,4); 5.07 (d,~); 3.45 (d,2); 2.52 (q,2); 2.22 (s,l); 1.g7 (d,3); 1.22 (s,3); 1.14 13 (t,3), C NMR (CDC1 3) ó 136,g4 (C 2, 5); 124,g3 (C 3 , 4); 121.20 (C 7 , 8); 64.54 (C 10 ); 51.56 (Cg); 46.51 (C 1 , 6); 24.25 (CH3); 24.23 (CH 2); 15.24 (CH 3); 13.18 (CH 3). 1 27: H NMR (CDC1 3) ó 6,23-5.32 (m,4); 3.05 (m,2); 2,75 (s,1); 2.62 (q,2); 2.05 (s,3); 2.05 (m,4); 1.50 (s,3); 1.18 13 (t,3). C NMR (CDC1 3) ó 13g,5Q (C 2, 5); 124.12 (C 3 , 4); 57.14 (Cg); 65.88 (C 10 ); 43.33 (C 1 6); 24.46 (CH3); . ' 15.13 (CH 3); 13.40 (CH 2).

.... Hemithioketal. ~

. is prepared and isolated as described for compounds 1 22 and !r; yield gs%; H NMR (CDC1 3) ó 7.67-7.17 (m,5); 6.30-5,70 (m,4); 5.30 (d,Z); 4.78 (d,l,J= 11Hz); 3.30 (m,2); 3.37 (s,1); 2.65 (dt,1, J= 11Hz and 6 Hz).

86 - Syn-9-( 1-hydr>o:eyethyZ) biayaZo [4, 2. 1J nona-2~ 4 ~ 7-tr>iene fll)

A salution of~ (0.34 g; 2.1 mmol) in 3 mL of dry Et 2o was dropped into a stirred suspension of lithium alu minium hydride (40 mg; 2 eq.) at 0°C. After stirring for 2 h at room temperature, the reaction was stopped by the addition of water, 10% aqueous NaOH, and water. Piltration yielded 0,32 g crude product (mp 76-80°C), which was puri fied by recrystallization from iPr2o (mp 80-82°C), Anal. Calcld. for c11 H14o: C, 81.44; H, 8.70. Found: C, 81.33; H, 8.84. .

- Syn-9-( 1-hydr>o:eyethyZJbiayalo [4, 2,1] nona-2~ 4-diene ( 28)

is synthesized from ketone ~ as described for com pound 11· Chromatography (CHC1 3) foliowed by recrystalliza tion from iPr2o at -78°C yielded 90% of pure product; mp 44-47°C. Anal. Calcld. for c11 H16o: C, 80.44; H, 9.82. Found: C, 80.82; H, 9.68.

- Unsaturated ayalia ethers ~-~

A salution of ll in dry CH 2c1 2 was added to a stirred salution of HFso3 (3 eq.) in so2;so2ClF (1:1) at -78°C. The reaction was stopped by pouring the reaction mixture onto saturated aqueous NaHC0 3 at 0°C. The mixture was extracted into Et2o, washed and dried (MgS04). High-performance LC (hexane- ethyl acetate 9:1) afforded 32 and 33 in a ratio of 2:3. 1 32: H NMR (CDC1 3) ö 6.26-5.40 (m,4); 4.53 (dd,1); 3.77 (dq, 1); 3.0-2.3 (m,3); 1.78 (m,2); 1.28 (d,3). 13C NMR ö 137.39 (d); 133.56 (d); 130.00 (d); 128.92 (d); 82.92 (d); 77.42 (d); 36.59 (d); 30.77 (t); 30.50 (d); 22.52 (q). Mass spectroscopy mie 162; UV (a-hexane) 223 nm. 1 33: H NMR (CDC1 3) ö 6,43-5.47 (m,4); 4.63-4.10 (m,Z); 3.10- 13 .2.48 (m,3); 1,78 (m,2); 1.26 (d,3). C NMR (CDC1 3) ö

87 138.63.(d); 135.61 (d); ll9.19 (d); 126.93 (d); 82.00 (d); 75,80 (d); 44.74 (d); 37.94 (d); 31.15 (t); 30.77 (d); 17.83 (q). Mass spectroscopy m/e 162; UV (o-hexa ne) Àmax 223 nm. Quenching by adding a cooled (-78°C) salution of NaOCH 3 in CH 30H to the reaction mixture afforded after the usual work up ~ and ll' together with a small amount of 32. 30: 1 H NMR (CDC1 ) 6,17-5.47 (dAB,Z); 4.18 (dd,1); 3.80 3 o (dq,1); 3.10-2.33 (m,5); 1.25 (d,3). 13C NMR (CDC1 ) ó 3 130.02 (d); 125.27 (d); 78.37 (d); 77.43 (d); 53.96 (d); 47.54 (d); 29.70 (d); 27.78 (d); 25.87 (d); 22.78 (q); 21.85 (t). Mass spectroscopy m/e 162. 31: 1 H NMR (CDC1 ) 6.12-5.57 (m,2); 4.50-3.90 (m,2); 3.33- 3 o 13 2.57 (m,2); 2.30-1.33 (m,5); 1.22 (d,3); C NMR (C9C1 3) 0 130.02(d); 129.00 (d); 76.65 (d); 76.50 (d); 51.16 (d); 47.73 (d); 28.96 (d); 26.70 (d); 26.51 (d); 22.54 (t); 20.19 (q). Mass spectroscopy m/e 162.

_. Unsaturated oyolio ethers 36-38

are prepared and isolated as described for 30-33. High-performance LC (hexane-ethyl acetate 9:1) yielded the tricyclic ethers in a ratio of 2:1:1; mass spectroscopy for all products m/e 164. 36: 1 H NMR (CDC1 ) 6,07-5.57 (AB,2); 4.17 (q,l); 4.07 (m,1); 3 o 2.9-1.4 (m,9); 1.28 (d,3), 13 C NMR(CDC1 ) 135.70 (d); 3 o 127.21 (d); 66.80 (d) j 66,28 (d) j 46.01 (d) j 45.14 (d) j 38.84 (t) j 33.23 (t); 30.08 (t) j 28.19 (d) j 22.36 (q). 1 H NMR (CDC1 ) 6.13-5.35 (dAB,2); 4.22 (dq,1); 4.07 3 o (m,1); 3.1-1.2 (m,9); 1.27 (d,3); 19C NMR (CDC1 ) ö 3 133.55 (d); 131.39 (d); 67.66 (d); 66.41 (d); 45.79 (d); 42.47 (d) j 38.97 (t) j 32.76 (t) j 31.77 (t); 31.29 (d); 21 • 71 ( q) • 38: 1 H NMR (CDC1 ) 5.73 (m,2); 4,37 (m,1); 4.17 (q,l); 3 ö 3.07-1.33 (m,9); 1.23 (d,3). 13C NMR (CDC1 ) 132.86 3 o (d); 130.31 (d); 77.42 (d); 73.88 (d); 55.41 (d); 46.22 (d); 37.72 (d); 34.96 (t); 32.33 (t); 23.61 (t); 22.49 ( q) •

88 ~ 9-(1-metho~yethylidene)biayaZo ~.2.1]nonane (iQ) - ayn-9-aaetylbicyaZo [4.2.1]nonane (39)

Compound 40 was prepared from bicyclo~.2.1]nonan-9-one 23 and 52 as described for 13. Destillation (bp 60-61°C/0.6 mm Hg) afforded pure![; yield 78%. Compound 40 was hydrolyzed quantitatively to ketone ~via chromatography (Si02/CHC1 3). 1 39: H NMR (CDC1 3) ó 2.7 (m,3); 2.20 (s,3); 2.2-1.2 (m,12). 1 40: H NMR (CDC1 3) ó 3.48 (s,3); 1.80 (s,3); 2.1-1.1 (m,14).

- 9-(1-methylthioethylidene)biayclo[4.2.1]nonane (41) is prepared and isolated as described for ~; yield 68%. Extremely pure product was obtained with the aid of high-performance LC (hexane). Mass spectroscopy mie 196; 1 H NMR (CDC1 3) ó 3.30 (m,1); 3.03 (m,1); 2.20 (s,3); 1.97 (s,3); 2.0-1.2 (m,12).

- Syn-9-aaetyl-9-chZorobicyalo [4. 2 .1] nona-2 .. 4 • 7-triene (!!)

To a solution of vinyl ether 11 in so 2 at -78°C, an excess (3 eq.) of so 2ClF was added. The reaction was instan taneous. The reaction mixture was poured onto saturated aqueous NaHC0 3 and extracted into Et 2o. After drying (MgS0 4) and concentrating1 hydrolysis of the intermediate ester was effected by passing the reaction mixture through a column of Si02 (CHC1 3 as eluens). 1 H NMR (CDC1 3) ö 6.0-5.7 (m,4); 5.30 (d,2); 3.53 (d,2); 2.27 (s,3); mass spectroscopy m/e 194 and 196,

- Carboaation generation

NMR samples were prepared by condensing so 2 from a gas cylinder into a NMR tube containing the substrate and caoled in a dry ice/acetone bath. The concentratien of the samples was about 100-200 mg/0.3 mL of solvent. To the cooled so lution, freshly prepared HFS0 3/SbF5 (5:1) was added care fully via the wall of the tube. In the case of the unsatu-

89 rated substrates ~, li and ~ one equivalent of acid was used; the cations 47a-~ were generated with a twofold excess of acid. Mixing was effected by shaking the samples vigo rously with the aid of a vibromixer. Samples were checked with 60 MHz 1 H NMR spectroscopy. Spectroscopie investiga tions were performed in the temperature range of -100° to -30°C. Quenching was effected by pouring the samples onto saturated aqueous NaHco 3•

90 1 TabZ.e IV: CoZ.Z.eated H NMR speatraZ. data reZ.ative to internat Me 4Si

H1 and H6 Hz-5 H7,8 Hothers

3 3.15 lmJ b.:.::~-!:>.4~ lmJ !:J,jj ld.J j,jU là,I,HlOJ; :.::.:.::!:> lffi, I ,HgJ j l,b lS 1 1,UHJ. 4 3.50 (t) 6.60-5.92 (m) 5.31 (d) 9.85 (s,1,H10 ); 2.91 (t, 1,H9). -12 3.87 (d) 3.35 (d) 6.33-5.74 (m) 5.25 (d) 5.67 ( s , 1 , H1 O) ; 3 • 4 5 ( s , 3 , OCH 3) • 13 3.87 (d) 3.47 (d) 6.37-5,60 (m) 5.23 (d) 3.40 (s,3,0CH3); 1. 73 (s ,3 ,CH3) 14 4.37 (d) 3.72 (d) 6.40-5.50 (m) 5.30 (d) 8.00 ( s , 1 , N=CH) ; 7. 8-7. 1 (m, 5 ,Ar); 1. 85 (s ,CH 3). -15 3.93 (d) 3.65 (d) 6.27-5.53 (m) 5.28 (d) 2 , 0 8 ( s , 3 , SCH 3) ; 1 • 8 7 ( s , 3 , CH 3) • -16 4.00 (d) 6.40-5.63 (m) 5.40 (d) 3.2-2.5 (m, 4); 2.5-1.87 (m, 2) • -17 4,27 (m) 2.90 (m) 6.33-5.80 (m) 5.40 (m) 7.93-7.2 AB,4,Ar); 7.07 (d,1,NCHO); 4.73 (s, 1,NCHC); 2.43 (s,3,CH3). -19 ~.40 (t) 6.30-5.67 (m) 5.15 (d) 2.45 (t,1,H9); 2.05 (s,3,CH3). -20 3.40 (d) 6.40-5.65 (m) 5.13 (d) 2.50 (s, 1 ,H9); 2.13 (s,3,CH3). -21 3.27 (m) 2.97 (m) 6.30-5.83 (m) 5.04 (d) 2.03 (dt,1,H9); 3,37 (dq,1 ,H 1 0); 2.17 ( s, 1 , OH); 1.13 (d,3,CH3). -24 2.83 (m) 2.30 (m) 6.20-5.40 (m) 1.93 (m) 5.60 (s,1,H10 ); 3.53 (s, 3 ,OCH 3). -25 4.03 (m) 3.33 (m) 6.20-5.33 (m) 2.03 (m) 8.06 (s,1,NCH); 7.93-7.13 (m,5,Ar); 1.95 (s, 3 ,CH 3) •. -26 3.63 (m) 3.28 (m) 6.33-5.32 (m) 1.97 (m) 2.33 (s,3,SCH3); 2.17 (s ,3 ,CH3). -28 ?.50 (m) 6.13-5.50 (m) 1. 78 (m) 2.5 (m,1,H9);.3.90 (dq;1,H10 ); 2.5 (s,l,OH); 1. 21 (d,3,CH3). -co -56 3.23-2.2Z (m) 6.20-5.40 (m) 1. 90 (m) 2.7 (m, 1 ,H9); 2. 13 (s, 3 ,CH3). Table V: ColZected 13 C NMR speetral data~

Others c1 ,6 c 2,5 c3,4 c7J8 Cg c, 0 3 44.90 135.42 126.75 124.16 40. 19 61.68 4 44.41 135.45 126.39 123.10 51.64 200.11 0 46.04 133,08 127.04 121.81 29.00 -11 48.52 134.49 125.53 121 • 54 33.96 1 2 46.41 137.36 124.98 123.64 116.09 137.74 60.52 (OCH 3) 43.73 137.19 124.24 123.02 (OCH ) -13 46.35 137.50 124.66 123.28 126.39 141 • 60 57.46 3 44.74 136.04 125.04 123.74 14. 1 0 (CH3) 15 48.08 135.72 124.77 123.58 129.30 139.60 18.09 (SCH 3) - 15.45 ) 4 7.16 134.05 124.28 122.83 (CH 3 (CH ); 48,42 (SCH ) -16 30.97 134.39 125.07 123.60 144.63 26.21 2 2 19 44.35 135.96 125.44 122.61 54.93 206.06 27.09 (CH 3) 20 45.90 135.96 125.37 121 • 40 55.07 208.29 28.37 (CH 3) -21 45.33 136.45 127.31 124.46 46.80 67.33 22.89 (CH 3) 45.24 135.25 127,09 124.37 -24 43.86 137,49 124.46 38.73 121.05 137.88 60.39 (OCH 3) 40.80 124.11 38.56 (SCH ); -26 44.52 137.07 125.13 39.51 129.0 144.56 19 .• 28 3 44.09 135.29 124.45 38.80 16. 21 (CH 3) Tabte V (Continued)

c1, 6 Cg Others c2,5 c3,4 G7 I 8 c10 28 41 . 88 137.65 126.82 41.39 51.09 68.00 - 23.89 (CH 3) 41.73 136.62 126.47 41.09 39 38.91 33.83 26.05 32.90 61.71 210.30 26.97 - (CH 3) 40 40.38 35.67 26.44 33. 14 130.35 142.90 57 .17 - (OCH 3) 38.61 14.42 (CH 3) 41 44.03 36.39 28.33 34.53 117.68 - 147.28 21 • 62 (S.CH 3) 43.36 18.57 (CH 3) 43 54.55 133.12 125.57 121.64 54.55 198.90 24.12 - (CH 3) 56 36.55 143.90 130.36 35.57 56.20 221.35 - 27.00 (CH 3)

Chemical shifts are reported relative to internal Me Si. Solvent: CDC1 • ~ 4 3 Referenaes and Notes

1. See Chapter III. 2. a.M. Sevrin, D.v. Ende, A. Krief, Tetrahedron Lett., 1976, 2643. b.D. Clive, G. Chittatu, C.K. Wong, Chem. Commun., 1978, 41. c. D. Clive, G. Chittatu, V. Farina, W.A. Kiel, S.M. Menchen, e.G. Russel, A. Singh, e.K. Wong, N.J. Cur tis, J. Am. eheni. Soc., 1980, 102,'4438. 3. Fora recent review see S.F. Martin, Synthesis, 1977, 633. 4. J.B. Press, H. Shechter, J. Org. ehem., 1976, 40, 2446. 5. G. Boche, D. Martens, Chem. Ber., 1979, 112, 175. 6. Dimeric product l! is also formed by the reaction of aldehyde i with 60~ aqueous HC10 4• 7. For a recent review see B-T. Gr5bel, D. Seebach, Synthe sis, 1978, 357. 8. a. K.H. Geiss, B. Seuring, R. Pieter, D, Seebach, Angew. Chem., 1974, 86,484. b. A.J. Mura, G. Matejich, P.A. Grieco, T. eohen, Tetra hedron Lett., 1975, 4437. c. K.H. Geiss, B. Seuring, D. Seebach, ehem. Ber., 1977, 110, 1833. 9. The assignment is based on the multiplicity of the H9- resonance in the 1 H NMR spectrum. Further evidence comes from 1 H NMR homodecoupling experiments. 10. a. D.M. Woods, N.F. Jones, J. ehem. Soc. B, 1964, 5400. b. A.J. Kresje and coworkers, J. Am. Chem. Soc., 1971, 9J, 413; ibid., 1972, 94, 2814, 2818; ibid., 1973, 95, 803; ibid., 1977, 99, 802' 805, 7228; ibid.' 1978, 100, 1249. 11. a. T. Okuyama, M. Nakada, T. Fueno, Tetrahedron, 1976, J2, 2249. b. R.A. Mc.Clelland, Can. J. ehem., 1977, 55, 548. c. T. Okuyama, M. Massago, M. Nakkada, T. Fueno, Tetra- hedron, 1977' JJ, 2249. 12. a. E.J. Stamhuis, w. Maas, J. Org., 1965, 30, 2156.

94 b. E.J. Stamhuis, W. Maas, H. Wijnberg, J. Org. Chem., 1965, 30, 2160. c. w. Maas, M.J. Janssen, H. Wijnberg, J. Org. Chem., 1967, 32, 1111. 13. See also D.C. Sanders, H. Shechter, J. Am. Chem. Soc., 1973, 95, 6858. 14. M. Roberts, H. Hamberger, S. Winstein, J. Am. Chem. Soc., 1970, 92, 6346 •. 15. a, Sulfuryl chloride fluoride has found only limited applications in synthetic organic chemistry. The reaction of so 2c1F with vinyl ethers to produce an ~-chloro ketone might very well constitute a new syn thetic reaction, which is characterized by mild reaction conditions and ease of work-up. b. Synthetic applications of so 2ClF have been reported by G.A. Olah and co-workers: Synthesis, 1980, 659 and 661; ibid., 1981, 146. 16. Vinyl sulfide.~ reacts with so 2ClF. The resulting fluorosulfinate ester is unstable. No product could be isolated after attempted chromatography on silicagel. 17. a. J.A. Berson, Accts. Chem. Res., 1972, 5, 406. b. P.Vogel, M. Saunders, N.M. Hasty, Jr., J.A. Berson, J. Am. Chem. Soc., 1971, 93, 1551. 18. P.Schipper, H.M. Buck, J. Am. Chem. Soc., 1978,100, 5507. 19. a.M. Barfield, B. Chakrabartà·, Chem. Revs;, 1!)69, 69, 757. b. M. Barfield, J. Am. Chem. Soc., 1971, 93, 1066. · c. M. Barfield, A.M. Dean, C.J. Fallick, R.J. Spear, S. Sternhell, P.W. Westerman, J. Am. Chem. Soc., 1975, 97, 1482. 20. a. G.A. Olah, A.M. White, J. Am. Chem •. Soc., 1969, 91, 5801 • b. G.A. Olah, T. Nakajima, G.K.S. Prakash, Angew. Chem., 1980, 92, 837. 21. G.E. Maciel, D.D. Traficante, J. Phys. Chem., 1965, 69" 1030. 22. L.A. Paquette, M,J, Broadhurst, J. Org. Chem., 1973, 38, 1886 and 1893. 23. T.A. Antkowiak, D.C •. Sanders, G.B. Trimitsis, J.B. Press,

95 H. Shechter, J. Am. Chem. Soc., 1972, 94, 5366. 24. H.M.J. Gillissen, P. Schipper, P.J.J.M. van Ool, H.M. Buck, J. Org. Chem., 1980, 45, 319. 25. S. Trippet, J. Chem. Soc., 1961, 2813. 26. C. Earnshaw, C.J. Wallis, s. Warren, Chem. Commun., 1977, 314. 27. E.J. Corey, J.I. Shulman, J. Org. Chem., 1970, 36, 377. 28. a. R.W. Ratcliffe, B.G. Cristensen, Tetrahedron Lett., 1973, 4645. b. A. Dehnel, J.P. Finet, Synthesis, 1977, 474. c. S.F. Martin, G.W. Phillips, J. Org. Chem., 1978, 43, 3792. 29. e.G. Cruse, N.L.J.M. Broekhof, A. Wijsman, A. v.d. Gen, Tetrahedron Lett., 1977, 885. 30. R.J. Abraham, P. Loftus, Proton and Carbon-13 NMR Spec troscopy, Londen, 1978. 31. J.R. Holmes, D. Kivelson, J. Am. Chem. Soc., 1961, 83, 2954. 32. Recently, L. Hevesi reported reversible protonation in the hydrolysis of vinyl selenides: L. Hevesi, J-1. Piquard, H. Wautier, J. Am. Chem. Soc., 1981, 103, 870.

96 SuDJ.DJ.ary

This thesis describes investigations concerning the role of aromaticity in the stabilization of charged deri vatives of bicyclo[4.2.1]nona-2,4,7-triene. The bicyclo ~.2.~ nona-2,4,7-trien-9-yl carbanion has evoked interest because of fts possible homoaromatic and bicycloaromatic character. Arylseleno-substituted Cg-carb anions are generated by the n-BuLi mediated cleavage of the corresponding selenoketals. At -78°C, electrophiles tend to react with the syn-c9 carbanions. This result is interpreted in terms of stereoelectronic control in consequence of the involvement of a bishomoaromatic interaction in the syn-Cg carbanions ( 6 ~-electron Hückel aromaticity). However, the chemistry of the trien-9-yl carbanions is domi nated at -78°C by a complete stereospecific isomerization of the anti-Cg carbanions to aryllithium compounds as a re sult of transposition of negative charge from Cg to the aryl ring via proton transfer. At room temperature, the aryllithium compounds isomerize to allylic carbanions via the attack of the aryllithium moiety on the butadiene bridge. The allylic carbanions are identified with 1 H NMR spectro scopy. Syn-c10 carbocations of bicyclo~.2.1]nona-2,4,7-triene are possible model systems for th~ investigation of ground state Möbius aromaticity because the empty atomie orbital at c10 can orientate its.elf in such a way that a homocyclic

97 ring occurs which includes one phase inversion, thus gene rating a Möbius array (4 v-electron Möbius aromaticity). S-Hydroxy selenide derivatives of bicyclo [4.2.1]nona- 2,4,7-triene do not form free c,o-carbocations upon prote nation in super acid media. It is demonstrated that neigh bouring group participation by selenium induces an elimina tion reaction, which leads to the formation of exocyclic olefins and selenenyl cations in a solvent cage. A rearrange ment reaction occurs via an electrophilic attack of the se lenenyl cation on the etheno-bridge of the exocyclic ole fin. A mechanism for this reaction is given. c 10 -carbocations are not available by the dehydration of the syn-9-(1-hydroxyethyl)-substituted bicyclo ~.2.D nona-2,4,7-triene respectively -2,4-diene precursors. In super acid media, the protonation of an endocyclic double bond leads to the formation of allylic cations. This is demon strated with 1 H and 13 C NMR spectroscopy. The generation of a-hetero substituted syn-c10 cations is accomplished by the protonation of S-hetero-substituted olefinic derivatives of bicyclo [4.2.1]nona-2,4,7-triene at low temperature. Saturated analogues of these cations are generated in a similar way. 13 C and 1 H NMR spectroscopie investigations suggest that in both types of cations, the p-orbital at c 10 is orientated perpendicularly with respect to the mirror plane in the cations. This geometry precludes an asymmetrie interaction between c 10 and one of the double honds of the butadiene segment. The geometry and the che mical shift differences between the unsaturated and the saturated cations may be compatible with the notion of a certain degree of charge delocalization via a MBbius inter action.

98 Sainenvatting

In dit proefschrift wordt een onderzoek beschreven naar Hückel en Möbius aromaticiteit ter verklaring van de stabiliteit van negatief en positief geladen derivaten van bicyclo [4. 2 .1] nona-2 ,4, 7-triene. Het bicyclo ~.2.D nona-2,4,7-trien-9-yl carbanion is daarom interessant vanwege de mogelijkheid om homoaromati citeit en bicycloaromaticiteit te genereren. Arylseleno-ge substitueerde c9-carbanionen worden bereid uit de overeen komstige seleneketalen door het verbreken van een C-Se bin ding met behulp van n-butyllithium. Bij -78°C vertonen electrofielen de neiging om met de syn-C9 carbanionen te reageren •. Dit resultaat wordt verklaard in termen van ste reoelectronische controle als gevolg van het optreden van een· bishomoaromatische interactie (6 1r-electron Hückel aro maticiteit), De chemie van de bicyclo~.2.D nona-2,4,7- trien-9-yl carbanionen wordt echter beheerst door een ste reospecifieke isomerisatie van anti-C9 carbanionen tot aryl lithium verbindingen, welke ontstaan door een protonover dracht van de ortho-positie van de aryl ring naar c9 • Bij verhoogde temperatuur isomeriseren de aryllithium verbin dingen verder tot allyl anionen. Deze anionen ontstaan door een intramoleculaire aanval van het aryllithium fragment op de butadieen-brug. De allyl anionen worden geidentifi ceerd met 1 H NMR spectroscopie.

Syn-c 10 carbocationen van bicyclo ~.z.D nona-2,4,7-

99 trieen kunnen als modelsystemen dienen voor een onderzoek naar het optreden van Möbius aromaticiteit in de grondtoe stand. In deze kationen kan de lege p-orbital op c10 zich zodanig crienteren dat een homocyclische ring ontstaa_t waar in één fase-omkering optreedt. Op deze wijze ontstaat een bishomoaromatisch 4 TI-electron systeem (4 TI-electron Möbius aromaticiteit). Protenering van S-hydroxy selenide derivaten van bicy clo ~.2.Dnona-2,4,7-trieen leidt niet tot de vorming van vrije c 10 -kationen. Het optreden van neighbouring group partioipation door selenium induceert een eliminatie-reac tie. Hierdoor ontstaan exocyclische olefinen en selenenyl kationen in een solvent-kooi. De electrafiele aanval van een selenenyl kation op de etheno-brug van een exocyclisch olefine initieert een omleggingsreactie. c,o-carbokationen zijn niet te genereren door dehydra tie van syn-9-(1-hydroxyethyl)-derivaten van respectievelijk bicyclo [4. 2. 1] nona- 2, 4, 7 -trieen en -2, 4-dieen. In superzure media leidt de protenering van een endecyclische dubbele binding tot de vorming van allyl kationen. Dit wordt aange toond met 1 H en 13 C NMR spectroscopie. De a-hetero-gesubstitueerde syn-c10 kationen worden bereid door protenering van a-hetero-gesubstitueerde olefi nische derivaten van bicyclo ~.2.1]nona-2,4,7-trieen. De overeenkomstige verzadigde kationen worden op dezelfde manier gegenereerd. 1 H en 13C NMR spectroscopische onder zoekingen wijzen erop dat de lege orbital op c 10 zich in beide kationen loodrecht crienteert ten opzichte van het spiegelvlak in deze kationen. Een asymmetrische interactie tussen c10 en één van de dubbele bindingen van de butadieen brug kan dus uitgesloten worden. De geometrie en de ohemi oat shift verschillen suggeren het optreden van ladings delocalisatie via een Möbius interactie,

100 CurriculuDJ. vit:ae

De schrijver van dit proefschrift werd geboren op 17 januari 1953 te Kerkrade. Na het behalen van het diploma HBS-b aan het Antonius Doctor College te Kerkrade in 1970, werd begonnen met de studie aan de afdeling der Scheikundi ge Technologie van de Technische Hogeschool te Eindhoven. Het afstudeerwerk werd verricht bij de vakgroep Organische Chemie o.l.v. prof. dr. H.M. Buck en dr. P. Schipper. Het ingenieursexamen werd afgelegd in februari 1977. Vanaf 1 januari 1978 tot 1 januari 1982 was hij verbon den aan de Technische Hogeschool Eindhoven als wetenschap pelijk ambtenaar op het laboratorium voor Organische Che mie. In deze periode werd onder leiding van prof. dr. H.M. Buck het onderzoek uitgevoerd zoals beschreven in dit proef schrift.

101 Dank~oord

Gedurende het onderzoek dat geleid heeft tot dit proef schrift heb ik van velen steun ondervonden op synthetisch en spectroscopisch gebied, alsmede bij de interpretatie van re sultaten, zowel binnen als buiten de vakgroep Organische Chemie. Met velen heb ik bijzonder stimulerende discussies mogen voeren. Voor deze hulp ben ik hen zeer erkentelijk. Verder wil ik diegenen bedanken die een bijdrage heb ben geleverd aan de uiteindelijke vormgeving van dit proef schrift.

102 Stellingen

1. Het bicyclo[2.2.2)octa-2,5,7 trieen (barreleen) wordt niet gestabiliseerd door Möbiusaromaticiteit. H.E. Zimmermann, Acc. Chem. Res., 1971, 4, 272.

2. Met behulp van 77 Se of 13 C NMR spectroscopie kan in principe niet worden aangetoond dat selenaat-complexen als intermediair optreden bij de generering van a-me thylseleno- en a-phenylseleno-alkyllithiumverbindingen. A. Krief, Tetrahedron, 1980, 36, 2640

3. Een groot deel van de producten die ontstaan bij de directe bestraling van 1 ,5-hexadienen en toegeschreven worden aan het optreden van [1,3]C shifts, kan met evenveel recht verklaard worden met behulp van de Cope omlegging. T.D.R. Manning, P.J. Kropp, J. Am. Chem. Soc., 1981, 103, 889.

4. Het verdient aanbeveling om te onderzoeken of de de oxygenatieve thioacetal-vorming uitgaande van aldehy den, disulfiden en tri-n-butylfosfine ook toe te pas sen is bij de synthese van selenoacetalen. M. Tazaki, M. Takagi, Chem. Lett., 1979, 767.

5. Het is opmerkelijk dat Kimura et al. blijven vasthouden aan de gedachte dat bij de reactie van adenosine met triphenylfosfine en diethyl azodicarboxylaat het 3', 5' fosforaan ontstaat en niet het 2' ,3'-fosforaan. Uit hun artikel blijkt dat zij bekend zijn met het werk van Men gel en Bartke die met behulp van kernspinresonantie heb- ben aangetoond dat het 2' ,3'-fosforaan gevormd wordt. J. Kimura, K. Yagi, H. Suzuki, 0. Mitsunobu, Bull. Chem. Soc. Jpn., 1980, 53, 3670. R. Mengel, M. Bartke, Angew. Chem., 1978, 90, 725.

6. Bij de bestudering van de tabel die March geeft voor de oxidatiegetallen van organische verbindingen, zal de lezer zich ongetwijfeld afvragen wat nu precies be doeld wordt met "approximate oxidation numbers". Een groot gedeelte van de getabelleerde oxidatiegetallen is zelfs bij benadering niet juist. J. March, Advanced Organic Chemistry, Tokyo, 1977, p. 1074.

7. Olah's uitspraak dat de betekenis van sterische fac toren op de chemica! shift van het thion-koolstofatoom gedemonstreerd wordt door het ontbreken van een corre latie met de chemica! shift van het carboxy-koolstof atoom in de overeenkomstige ketonen, is zeer twijfel achtig omdat Olah's meetresultaten zeer redelijk voor speld kunnen worden met behulp van een door Pedersen ontwikkelde relatie. G.A. Olah, T. Nakajima, G.K.S. Prakash, Angew. Chem., 1980, 92, 837. B.S. Pedersen, S. Schèibye, N.H. Nilson, S.O. Lawreson, Bull. Soc. Chim. Belg., 1978, 87, 223.

8. Boche en Martens hadden beter H/D-uitwisselingsexperi menten kunnen uitvoeren aan bicyclo[4.2.1] nona-2,4,7- trieen-anti-9-nitril dan aan het -syn-9-nitril. In de eerste verbinding zou energieverlaging van de overgangs toestand als gevolg van een homoaromatische interactie aangetoond kunnen worden. G. Boche, D. Martens, Chem.Ber., 1979, 112, 175. 9. Het door elkaar gebruiken van de omschrijving carbonium ionen, carbenium ionen, alkoxy- en hydroxycarbenium ionen, oxonium ionen, oxycarbenium ionen en carbokationen voor dezelfde klasse van verbindingen vraagt een groot doorzettingsvermogen van allen die een literatuuronder zoek in dit gebied starten. Enige normalisatie van de nomenclatuur zou dan ook aan te bevelen zijn. Carbonium ions, G.A. Olah, P. von R. Schleyer Eds., New York, 1976. G.A. Olah, Angew. Chem., 1973, 85, 183.

10. Het toepassen van Dewar's eenvoudige regel dat de overgangstoestand van thermische electrocyclische re acties aromatisch moet zijn, kan leiden tot een ver keerde voorspelling van het stereochemisch verloop van de ringopening van onverzadigde bicyclo[m.n.O]verbin dingen. M.J.S. Dewar, Angew. Chem., 1971, 83, 859.

11. Bij de constructie van een theoretisch model voor de beschrijving van de moleculaire organisatie in micellen en vesicles kunnen de energieverschillen tussen de anti en gauche conformeren niet verwaarloosd worden. K.A. Dill, P.J. Flory, Proc. Natl. Acad. Sci. JJSA, 1981, 78, 676.

12. De invoering van de giropas als het enige identifica tiebewijs voor het innen van kascheques bij de Rijks postspaarbank zal de kans op fraude niet verminderen.

H. Gillissen Eindhoven, 15 januari 1982