ACADEMIA ROMÂNĂ Rev. Roum. Chim., Revue Roumaine de Chimie 2020, 65(1), 5-22 DOI:10.33224/rrch.2020.65.1.01 http://web.icf.ro/rrch/

Motto: “ Cyclobutadiene, (CH)4, is the Mona Lisa of organic chemistry…” D. Cram (1991, Nobel Price 1987).

MARGARETA AVRAM (1920–1984): A LIFE DEDICATED TO ORGANIC CHEMISTRY

Mircea D. GHEORGHIU*

Department of Chemistry, One Washington Square, San Jose State University, San Jose, CA 95192-0101, USA

Received June 1, 2019

The objective of the present paper is to outline the contribution of Prof. Avram to Organic Chemistry, to point out that her pioneering work in the field of cyclobutadiene, benzocyclobutadiene, Friedel-Crafts reactions, polycyclic hydrocarbons and derivatives and Pd(II) organochemistry are, together with contributions of a few international chemists, chemical seeds that proved over time (+50 years) to deliver an abundant intellectual crop that enlarged the area of research and provided a better definition of the scope. Starting a high stake professional life in the aftermath of the devastating second World War (WWII) was an improbable event. In 1940’ in all aspects of life, everything was in scarcity. In chemistry, shortages of chemical documentation (journals, books), unavailability of chemicals, poor equipped and limited lab space associated with instrumentation shortage was common condition. 1

* Corresponding author: [email protected]; Prof. Margareta Avram supervised both the author’s undergraduate Diploma Work and the PhD thesis, Polytechnic Institute, Bucharest, Romania. 6 Mircea D. Gheorghiu

Astoundingly, although these shortages, the Laboratory of Organic Chemistry of Polytechnic Institute of Bucharest, founded by Prof. Costin D. Nenitzescu, a German-educated chemist, was an island of delivering highly competitive chemistry. In this intellectual and material environment, the young talented chemist Margareta Avram defended on July 15, 1947 her Thesis “Syntheses in class of 10,11- Benzofluoranthrene” in front of a highly exigent commission: C.D. Nenitzescu, P. Spacu, and E. Georgeacopol. The topics studied in the Thesis are nicely endorsing the life-time interest of Prof. Nenitzescu in the chemistry of hydrocarbons and AlCl3 catalyzed reaction. The research topics were triggered by the confusing chemistry regarding the dimerization of dialin (1,2-dihydronaphthalene) produced by the Brönsted acid, H2SO4 and of tetralin (1,2,3,4- tetrahydronaphthalene) by the Lewis acid AlCl3. 1 In 1921, von Braun and Kirschbaum reported that dialin in presence of H2SO4 produces the hydrocarbon o C20H20 (m.p. 93 C) predicted to contain as structural subunit a four-membered ring. Avram in the Thesis and in the subsequent paper published2 provided an unambiguous support that the correct structure for compound having the m.p. 93 oC is 1 (Scheme 1), without any four-membered ring.

Fig. 1 – The cover and the second page of the PhD thesis.

3 o In 1941, Dansi and Ferri described the action of AlCl3 on tetralin at 30-80 C to produce the o hydrocarbon C20H20, m.p. 150.5 C, that afterwards subjected to dehydrogenation gave a hydrocarbon C20H12 with a m.p. 165 oC. M. Avram failed to reproduce the chemistry claimed by the Italian authors. Moreover, when M. Avram have treated tetralin with AlCl3 under various conditions, confirmed the results obtained by G. Schroeter4 who identified as reaction products octahydroanthracene and octahydrophenanthrene. In the PhD Thesis and the published paper is shown eloquently that the intermediates (C20H20) and the dehydrogenated aromatic final product (C20H12) does not contain a cyclobutane ring. Instead, the structures of the intermediates are 1 and 2 (Scheme 1), and the aromatic compound resulted by dehydrogenation is benzo[j]fluoranthene (BjF).

Scheme 1

Margareta Avram: a life dedicated to organic chemistry 7

While structure of hydrocarbon 2 was firmly established, for the structure of hydrocarbon with m.p. 93oC, Nenitzescu-Avram opted, with reservation, that probably is 5,6,7,8,9,12,13,14-octahydrobenzofluoranthrene 1 (Scheme 1). The hesitation, a testimony of a distinguished professional ethics, was confirmed after 30 years, when the correct structure including stereochemistry details established by X-ray analysis (see Scheme 1)5 concluded that hydrocarbon 1 and hydrocarbon 2 are diastereoisomers. The structure of the low melting point (93 oC) hydrocarbon resulted in kinetic control is (±)1a (Scheme 1) while the high melting point hydrocarbon (150.5 oC) resulted in thermodynamic control, has the structure of (±)2a. Additionally, six independent syntheses strongly support its aromatic structure shown in Scheme 1 as BjF. The paper resulted from the PhD Thesis was submitted and accepted in 1948 to be published in the Journal of the American Chemical Society (JACS):

Fig. 2 – An excerpt from JACS.

Fig. 3 – The chemical genealogy of Prof. Avram.

Unique for JACS, the paper was printed two years later, namely in August 1950, “because of difficulty of communication.” Next, I would like to add a few comments concerning the professional trajectory at the Polytechnic Institute, Bucharest, Roumania and the Institute of Organic Chemistry, Bucharest, Roumania.

8 Mircea D. Gheorghiu

Prof. Avram was a dedicated academic having been a Professor at Bucharest Polytechnic and research scientist at “Costin D. Nenitzescu” Institute of Organic Chemistry from Bucharest. She was brilliant, far-sighted, and scientifically inquisitive. Prof. Avram academic carrier, according to the official “Polytechnic Institute-pages from history (1948– 1992),” presently published on web2 as well, started in 1950 as Instructor, (“asistent,” first level for Professorship in Roumania), then in 1955 she was promoted to Assistant Professor, and in 1968 to Full Professor. In order to facilitate the teaching of Organic Chemistry, she authored a textbook of Organic Chemistry (1983) in two volumes (vol.1 560 p; vol 2. 631 p). Additionally, Prof. Avram authored with Prof. Gh. Mateescu the first and only book in Roumania concerning “Infrared Spectroscopy. Application in Organic Chemistry” (in Roumanian, English, French). Since its inception in 1949, Prof. Avram was also working with what is presently known as Roumanian Academy’s “Costin D. Nenitzescu” Institute of Organic Chemistry, where she was until her death the director of a research group in hydrocarbon chemistry. The professional genealogy of all of us, who had been part of Prof. Nenitzescu’s Organic Chemistry Chair of Polytechnic Institute of Bucharest, is remarkable. It comprises giants of Organic Chemistry: Kekulé, von Bayer, Emil Fischer, Hans Fischer and Costin D. Nenitzescu. Prof. Avram is one of those whose teaching and research achievements has honored her privileged forebears.

Prof. Avram’s contributions to Organic Chemistry Now, it is appropriate to resume the chemistry contribution of Prof. Avram. After the JACS publication, Prof. Avram was occasionally involved for a short time in errand topics. The most prominent is the discovery of the mechanism of activation of AlCl3 by water for catalytic isomerization of saturated hydrocarbons. Traces of alkyl halide is also an active cocatalyst.6 In 1957, Prof. M. Avram started an extensive life-time investigation in the (i) Chemistry of Cyclobutane derivatives (61 papers), covering the cyclobutadiene (CBD), Benzo-CBD and related hydrocarbons with four membered ring. The scientific interest in the following years has been diversified to (ii) Reaction of acetylenes with transition metals (11 papers), (iii) Friedel-Crafts acylation of acetylenes (5 papers), (iv) Chemistry of transition-metal organic compounds (2 papers) (v) ketenes (3 papers) and, (vi) miscellaneous topics (40 papers).

A. Cyclobutanes and related derivatives The favorite area of research of M. Avram was the chemistry of cyclobutane derivatives. The most read papers are those dedicated to CBD and Benzo-CBD. For example, the paper dealing with CBD dimer has 83 citations:

Benzocyclobutadiene paper has 57 citations:

and the linear dimer of benzocylobutadiene has 59 citations:

A1. Cyclobutadiene (CBD) Cyclobutadiene (C4H4), is a very simple organic molecule that captured the interest of generation of organic chemist for more than a century. One of the longest running sagas of organic chemistry was the attempted preparation of CBD, a molecule with a deceptively simple structure, nevertheless, for many years proved more

Margareta Avram: a life dedicated to organic chemistry 9 difficult to access it than to conquer the Mount Everest itself. Cyclobutadiene is not a resonance stabilized molecule, on contrary has highly localized double bonds, and consists of a valence tautomeric equilibrium between two rectangular singlet ground state structures.7–92 Starting in 1957, defying intrinsic difficulties, Nenitzescu and M. Avram have set mapping strategies of CBD synthesis. Their pioneering papers provided convincing proofs that indeed, the elusive CBD10–17 and benzo-CBD18,19 were “freely” involved in the trapping experiments. About the same time, in Germany, R. Criegee was specifically interested in tetramethyl-CBD,20–15 and G. Maier in the parent CBD26-30, and in USA and Canada, S. Masamune31 was appealed in the parent CBD and M. P. Cava32–34 in Benzo-CBD. Unfortunately, none of the above efforts has been finalized successfully, neither the parent CBD nor substituted CBD and neither the parent or substituted Benzo-CBD have been isolated. The relevance of these failures was captured in a superb intellectual analogy by Donald Cram (Nobel Prize in Chemistry 1987) in 1991:35

“Cyclobutadiene, (CH)4, is the Mona Lisa of organic chemistry in its ability to elicit wonder, stimulate the imagination, and challenge interpretive instincts.” What was the intellectual knowledge concerning the thermodynamic and kinetic stability of CBD when Nenitzescu-Avram started their work in this field? The answer is that it was still fragile, prone to errors; nevertheless, started to emerge with relatively slow steps. In 1931 Erich Hückel36 using quantum mechanics and the principle of π–σ separation, recommended that aromaticity is recognized when continuous conjugated, monocyclic coplanar organic compounds (Hückel topology) with a number of 2, 6, 10, 14…. electrons that populates the π molecular orbitals, possess relative electronic stability and, therefore, aromatic character. Aromaticity is a virtual quantity, not an observable (measurable directly experimentally) quantity, and, therefore, since it is not directly measurable, it must be defined by convention. Early 1950’s organic chemists started to appreciate the novelty and the importance of Hückel discovery. Thus, in 1951, William von Eggers Doering, was first to invent the succinctly holy grail for organic chemistry, the “4n+2” rule (which was not invented by Hückel himself).37,38 Note also that the 4n rule was not invented yet. Next is J. D. Roberts landmark paper39 “Molecular Orbital Calculations of Properties of Some Small-Ring Hydrocarbons and Free Radicals.” It is interestingly to remark that for Roberts, CBD is a pseudoaromatic molecule. Later, in 1965, Breslow’s description of antiaromaticity (destabilizing cyclic conjugation)40–42 based on Hückel’s and others’ publications, reformulate the rule as Hückel 4n + 2/4n electron rule.43,44 All these works have stimulated an explosive growth in an extensive and exciting new CBD chemistry. A definite peak (a coup in chemistry) in providing to the synthetic chemist tip-offs to handle the CBD, was a theoretical paper in 1956 entitled “The Possible Existence of Transition Metal Complexes of Cyclobutadiene” by H. C. Longuet- Higgins and L. E. Orgel.45 Theory has preceded experiment! Three years after the publication of the Longuet- Higgins and Orgel paper, two groups reported the synthesis of CBD-metal complexes. Thus, Walter Hübel46 made 21,47 48 in good yield tetraphenyl-CBD*Fe(CO)3 and, Criegee isolated tetramethyl-CBD*NiCl2 which later by X-ray was shown to be a dimer. A breakthrough in CBD chemistry represented the synthesis of (η4-cyclobutadiene)iron tricarbonyl complex (compound 1, Scheme 2) by Pettit49–52 in 1965, by the reaction of cis-3,4-dichlorocyclobutene (first synthesis accomplished by M. Avram, therefore let us name it as Avram’s dichloride) with Fe2(CO)9. Subsequently, a large variety of (substituted CBD)*Fe(CO)3 became a pool for free CBDs. The ready release of CBD from its iron complex by oxidative decomposition led to important insights into its electronic and structural nature. Presently, there are two additional approaches to stabilize CBD: low temperature matrix and substitution with sterically bulky groups. CBD was isolated at temperature 8 K in the matrix of argon atoms53–59, however, is stable at room temperature in the cavity of a spherical crown ether (hemicarceplex).29,30,35,60,61 Bulky groups like t-Bu- and (CH3)3Si- kinetically stabilize (prevent dimerization) of both CBD (see Scheme 2) and Benzo-CBD.

2 Institutul Politehnic Bucuresti, Pagini de istorie din perioada 1948-1992, https://energetica.ga/universulenergiei/ istorie/ politehnica/1948-1992/ (accessed June 10, 2018).

10 Mircea D. Gheorghiu

The first post-Willstätter period paper concerning CBD was published in 1957 by Criegee20 who prepared the dimer of tetramethyl-BCD from 3,4-dichloro-1,2,3,4-tetramethylcyclobutene (1, Scheme 3), by vicinal chlorine elimination with Li(Hg) in absolute ether in an attempt to obtain tetramethyl-CBD. However, the first paper concerning the synthesis attempt to prepare the parent CBD was published by Nenitzescu and Avram in 1957. Time tested reactions leading to double bond formation, such as Hofmann elimination of quaternary salts of 1,3-diamino-cyclobutane and retro-Diels-Alder reaction of cyclooctatetraene adducts with di-Me acetylenedicarboxylate and quinones, failed to provide CBD.18

Scheme 2

Scheme 3

Scheme 4

11 In 1959, C. D. Nenitzescu and M. Avram have assumed that they have isolated C4H4*AgNO3 from the reaction of all-trans-1,2,3,4-tetrabromocyclobutane and the Wittig dehalogenation reagent Li(Hg).62, 63

Margareta Avram: a life dedicated to organic chemistry 11

Among the two product candidates that Profs. Nenitzescu and Avram have been considered were (i) the silver complex C4H4*AgNO3, that was preferred, and (ii) the dimer C8H8*2AgNO3 that unfortunately was rejected. It is interesting to learn the reason why C8H8*2AgNO3 structure was rejected in preference for the wrong structure of silver complex of BCD. WHY it failed? First, the failure is due to a shortage and the infant status of analytical instruments such as a NMR and X-crystallographic instruments. The only analytical instrument available in Bucharest was an IR spectrometer. However, at that time the only structural assignment of the reaction product64 was provided by a rather complicated IR signature. Experimental facts have been invoked for the structure of the silver complex as C4H4*AgNO3 or C8H8*2AgNO3. First, by decomposition with water was not yielding the expected C8H8 isomers either tricylooctadiene or cyclooctatetraene. Second, the double complexation with Ag+ is less stable than the mono + complexation with Ag , like in C4H4*AgNO3 complex, fact that was in consensus with some analogy published in the literature of the time. Additionally, the remarkable stability of the monomer structure of CBD complex with AgNO3 was also supported by quantum chemical calculation of Longuet-Higgins and Orgel.45 In 1961, Prof. Avram published a paper13 that brings more support concerning the dimer structure of C8H8 based on mass spectroscopy. C8H8 was the sole product resulted from the aqueous NaCl or thermal decomposition of what was believe to be the C4H4*AgNO3 complex. The IR was interpreted erroneously that symmetry would suggest an anti-dimer, instead of correct syn-dimer. Interestingly to note, that the idea of the monomeric C4H4*AgNO3 complex was not yet abandoned for some years. Thus, by reaction the dimer with AgNO3 gave a silver complex that was assumed to be C4H4*AgNO3 for the reason that during complexation C8H8 is split back to C4H4, an assumption that a few years later was demonstrated to be incorrect. In the years that followed more facts have started to be accumulated in order to clarify if indeed 65, 66 C4H4*AgNO3 does not exist. The dehalogenation of cis-3,4-dichlorocyclobutenes in the presence of Li(Hg) gave the CBD dimer. This procedure was proven over the next years to be arguably the most straightforward route for the synthesis of many derivatives of BCD including the stable complex 67 C4H4*Fe(CO)3. Cis-3,4-dichlorocyclobutene preparation based on Reppe methodology was improved in Nenitzescu’s Lab. In 1964 M. Avram17 provided details on the isolated dimers of CBD. Interestingly an “unpredictable” the syn- dimer resulted by treating cis-3,4-dichlorocyclobutene with 0.5% Na(Hg) in diethyl ether, while 0.5% Li(Hg) in the same solvent gives anti-dimer:

Scheme 5

Fig. 4 – Excerpt from Organic Syntheses. The stereochemistry as syn-dimer was assumed to result from the free CBD via a Diels-Alder cycloaddition to itself, while the anti-dimer, most probable resulted via a double Wurtz reaction. It is worth of mentioning that even after +50 years, the most convenient method for the preparation of cis-3,4- dichlorocyclobutene is still the Nenitzescu-Avram procedure that involves three steps shown below.

12 Mircea D. Gheorghiu

“Sadly,” the Nenitzescu-Avram preparation was published by Pettit group in Organic Synthesis. Presently, cyclobutene, cis-3,4-dichloro(3R,4S) is commercially available. Among the chemical contributions to chemistry of cis-3,4-dichlorocyclobutene perhaps the Diels- Alder reactions are more interesting. Thus, cis-3,4-dichlorocyclobutene reacts with dienes to produce [π4s + 68 π2s] cycloaddition products. In 1968 Nenitzescu and Avram reported the cycloaddition of cis-3,4- dichlorocyclobutene to cyclopentadiene producing the endo-syn adduct (3, Scheme 6) in high yield. Ten years later, Warrener and coworkers69 have reported a revised structure for the major adduct as endo-anti adduct (4, Scheme 6).

Scheme 6

A2. Benzocyclobutadiene (Benzo-CBD) Benzocyclobutadiene (Benzo-CBD) is kinetically unstable. One aromatic ring is not enough to diffuse, at least in part, the antiaromaticity of CBD. Nevertheless, benzo-CBD in Ar matrix is stable up to 75 K.70 Three dimerization products have been so far isolated: Cava angular (1), Nenitzescu anti-linear (2)71 and Pettit dibenzosemibulvalene (3).72 Cava, in 1956, have prepared the angular dimer of Benzo-CBD from 1,2- dibromo- (or 1,2-diiodo)-benzocyclobutene (1, Scheme 8) and Zn in ethanol.31, 32

Scheme 7

Scheme 8

At present, there are two standpoints concerning the mechanism of Cava angular dimer formation. Cava32, 34 suggested that the mechanism involves the [4+2] cycloaddition of two molecules of Benzo-CBD resulted by

Margareta Avram: a life dedicated to organic chemistry 13 dibromide elimination with Zn from 1,2-dibromobenzocyclobutene, followed by rearrangement to Cava angular dimer (6a,10b-dihydrobenzo[a]biphenylene, (5, Scheme 8). Trahanovsky73,74 studied by flow NMR spectroscopy the dimerization of benzocyclobutadiene labelled with deuterium at C1. Benzo-CBD, generated from 2-(trimethylsily)benzocyclobutenyl-1-mesylate by fluoride ion-induced elimination of trimethylsilyl mesilate, dimerize to produce six deuterated isotopomers. The deuterium distribution is rationalized by the mechanism presented below that assumes dibenzo[a,d]cyclooctatetraene (4, Scheme 8) to be the actual precursor of Cava’s dimer. In 1957, Nenitzescu, Avram and Dinu designed a milder reaction condition (room temperature) to produce Benzo-CBD. The elimination of dibromide with Li(Hg) in ether from 1,2-dibromobenzocyclobutene, produced the Cava angular dimer. If the bromine elimination was done in presence of cyclopentadiene, the Diels-Alder adduct 2 (Scheme 9) was isolated.18 Also, some other trapping dienes such as dimethylfulvene, spiro[2:4]hepta- 3,5-diene and 3,5-diphenyl-3:4-benzofuran were tested successfully.75 An unexpected reaction course, however rewarding, was noticed in 1959 by Nenitzescu, Avram and 19 Dinu. The debromination with Li(Hg) in presence of Ni(CO)4, gave the “linear” dimer 3 (Scheme 9) as a new Benzo-CBD dimer. Unfortunately, there are no detailed information available even today (in year 2019) to rationalize the role of Ni(CO)4 in this reaction. The anti- configuration of the two aromatic rings was confirmed in 1961 by ozonolysis of the linear dimer, followed by reaction with diazomethane to yield cis-trans-cis tetracarbomethoxycyclobutane.76 The dimer is thermally converted (half-life 20 minutes at 140 oC) into dibenzocyclooctatetraene after refluxing in o- dichlorobenzene (180 oC) for 4-5 hr. In metal catalyzed isomerization a dramatic reversal of the reaction temperature and reaction time has been observed. For example, Pettit has noticed that in presence of Ag+ the rearrangement occurs almost instantaneously at room temperature (see Scheme 9). Nenitzescu-Avram71 have envisaged that the thermal rearrangement of the linear dimer occurs in one step, involving two sigma bond concerted cleavage of the central cyclobutane rings. Three years later evidences have been published by Avram and Nenitzescu that the reaction takes place in two steps.77 Cava provided evidence that the process proceeds in two stages.78 In the first step an o-quinonoid intermediate is formed by opening the adjacent cyclobutane ring to the benzene, and in the second step the remaining cyclobutane ring opens yielding the dibenzocycloocatetraene. The ortho-quinonoid intermediate was trapped by Cava with maleic anhydride.

Scheme 9

Scheme 10

14 Mircea D. Gheorghiu

Fe(CO)3 Scheme 11

The Benzo-CBD iron tricarbonyl complex72 became also known very soon after the brilliant synthesis of CBD*Fe(CO)3 by Pettit and coworkers. Since the Benzo-CBD is so unstable, it is very tempting to assume that by 79, 80 adding bulky groups at C1 and C2 would prevent dimerization. In 1969, M. Avram was first to embrace the idea of kinetically stabilized Benzo-CBD with bulky groups. She started to investigate the 1-t-Bu-Benzo-CBD and 1,2-di-t-Bu-Benzo-CBD chemistry. Unfortunately, no stable t-butyl-benzo-CBD was isolated. Thus, dehydrobromination with KO-t-Bu of 1-bromo-1-t-Bu-benzocyclobutene yielded the Cava type dimer 3 (Scheme 11), strongly suggesting that one t-Bu group in not enough to stabilize Benzo-CBD to preclude dimerization. Attempt to make the 1,2 di t-Bu substituted Benzo-CBD failed: by thermal (140 -150 oC) dehydrobromination, 1-bromo-1,2-di-t-bu-benzocyclobutene evades di-t-Bu-BenzoBCD formation, however, is channeled to indene derivatives as result of neopentylic rearrangement (Scheme 12). Elimination of HBr with KO-t-Bu furnishes oxygen containing derivatives of benzene. In conclusion, in 2019 we are still looking forward for the synthesis of the parent 1,2-di-t-Bu-Benzo-CBD. Nevertheless, presently are known Benzo-exo that are kinetically stabilized. Examples are 1,2-di-t-Bu-3,4,5,6-tetramethylbenzocyclobutadiene,81–84 1,2-diphenylnapthocyclobutadi- ene85 and 1,2-di-TMS-Benzo-CBD.86 Prof. Avram explored the chemistry of compounds mostly resulted from trapping of Benzo-BCD with cyclopentadiene or angular dimerization of the parent or substituted Benzo-CBD. Many papers published as “ Investigations in the cyclobutane series” are describing compounds specifically containing a “spectator” cyclobutane ring attached to the norbornane skeleton ring such as in endo- (1, Scheme 13) and exo- benzocyclobutanonorbornene (2, exo-BCBN) Scheme 13), and derivatives of basic and substituted Cava angular Benzo-BCD hydrocarbons. The chemistry examined by Prof. Avram is localized on the norbornane skeleton rather than on cyclobutane moiety, which in some studied cases proved not to be “dormant.” Both endo- and exo-BCBN are annelated with a cyclobutene (3, Scheme 13) ring if are reacted with HC CCOOMe 87 88–90 and AlCl3. Electrophilic addition of Cl2, Br2, HBr, to endo-BCBN yielded rearranged halide derivatives of exo-BCBN, as consequence of carbocation localized on norbornane skeleton that is well-known to be prone for Wagner-Meerwein rearrangement.91 As result the endo-BCBN ring flips into exo-BCBN configuration. For example, by hydrobromination of endo-BCBN isomer, under kinetic control, a mixture of endo-BCBN (compound 2, Scheme 13) and exo-BCBN bromide (compound 3, Scheme 13) are formed. In a separate experiment, it was shown that the endo bromide 4 (Scheme 13) is converted into the most stable thermodynamically exo-BCBN bromide 5 (Scheme 13).

Scheme 12

Margareta Avram: a life dedicated to organic chemistry 15

Scheme 13

A3. Nenitzescu’s hydrocarbon (perhaps, more fair Nenitzescu-Avram hydrocarbon). 92 Nenitzescu and Avram become engaged in the synthesis of a C10H10 hydrocarbon which was finalized in the paper published in 1960; six years later the compound will be name by Doering93 as Nenitzescu’s hydrocarbon. The starting material was cyclooctatetraene that was reacted with maleic anhydride, then the Diels- Alder adduct was then converted into the dicarboxylic acid. The latter was subjected to Grob reaction94 (lead acetate and pyridine) to yield the hydrocarbon 2 (10–15%) that was also separated as C10H10*PdCl2 and 95 C10H10*2AgNO3 complexes. More experimental details and thermal comportment surfaced three years later. o A pure sample (bp 165 C) of hydrocarbon has resulted from PdCl2 complex by decomposition with KCN. Soon, it was realized that the hydrocarbon has no shortage of surprising properties to study. For example, the 96,97 relationship among C10H10 isomers on the thermal energy surface, on which it seems that the thermodynamic sink of all interconversions of (CH)10 hydrocarbons is apparently cis-9,10- 98 dihydronaphthalene. Additionally, the PdCl2 complex obtained originally by Nenitzescu and Avram exibit antitumor activities.99 The three isomers of mono-Benzo-Nenitzescu’s hydrocarbons 3, 4, 5 (see Scheme 14), all are document that are prepared.

Scheme 14

In 1970 the synthesis of anti-7,8-BenzotricycIo[4.2.2.02,5]deca-3,7,9-triene (compound 3, Scheme 14) was published in by Vedejs100 and independently, by Paquette.101, 102 In 1995, it was found103 a new synthesis of the anti-mono-Benzo Nenitzescu’s hydrocarbon 3 (Scheme 14). In 1973, the syn-7,8-BenzotricycIo[4.2.2.02,5] deca-3,7,9-triene (4, Scheme 14)104, 105 became available by the work of Vedejs et al. and independently by Murata et al. In 1979, the synthesis of benzo[c]tricycle [4.2.2.02.5]deca-3,7,9-triene (2, Scheme 15).106 was published by Prof. Avram. Thus the ketone 1 (Scheme 15) was enlarged with diazomethane, subsequently converted to tosylhydrazone followed by a Shapiro reaction91 with MeLi to yield the benzo-Nenitzescu’s hydrocarbon 2 (Scheme 15). Interestingly, as result of thermal conversion, compound 2 (Scheme 15) turned out to be on the same thermal hypersurface as Cava angular dimer 3 (Scheme 15) of Benzo-BCD. Among the three isomers of di-Benzo-Nenitzescu’s hydrocarbons 1, 2, 3 (see Scheme 16), compounds 1 and 2 are document that are prepared. Di-benzo-Nenitzescu’s hydrocarbons 3 (anti-dibenzo[c,j] tricyclo[4.2.2.02.5]deca-3,7,9-triene) has not, to our knowledge, been reported in the literature!

16 Mircea D. Gheorghiu

Scheme 15

1 2 3 ? 1966 1974 Scheme 16

The symmetrical dibenzo-Nenitzescu’s hydrocarbon compound 4, (Scheme 17) was prepared in 1966 by Nenitzescu-Avram team in two steps.107, 108 In the first step it was carried out the Diels-Alder adduct synthesis from 9,10-dibromoanthracene and cis-3,4-dichlorocyclobutene. A cautionary note: anthracene failed to react with cis-3,4-dichlorocyclobutene. In the second step, the elimination with Wittig reagent (LiHg) of the chlorine atoms is accompanied by reduction of the bridgehead bromines to yield dibenzo-Nenitzescu’s hydrocarbon 4 (Scheme 17).

Scheme 17

In 1963, Cava78 published the synthesis of the tri-Benzo substituted of Nenitzescu’s hydrocarbon (tribenzo[c,g,j]tricyclo[4.2.2.02.5]deca-3,7,9-triene, 3) from anthracene and benzo-CBD (generated in situ from trans-1,2-dibromobenzocyclobutene and Zn):

Scheme 18

Margareta Avram: a life dedicated to organic chemistry 17

A4. Alkyne chemistry 1. Friedel-Crafts acylation of alkynes Addition of acid chloride derivatives to alkynes is a useful reaction. For example, is affording - chloroalkenyl ketones, which allow numerous synthetic applications, in particular, the synthesis of heterocyclic compounds. The acylation of alkynes is a well-known reaction in the preparation of α,β-enones. However, the scope of this reaction is generally limited by the presence of numerous by-products such as β-chloro-α,β- enones, β,γ-enones, or β-acyloxy ketones. Prof. Avram have shown that terminal alkynes are acylated with AlCl3 or AgClO4 to yield in a non- selective way a mixture of reaction products.109–113 For example, in presence of non- nucleophilic solvents, propyne, acetyl chloride and, AlCl3 gave the normal addition product, namely, the β-chloro-α,β-unsaturated ketone (3, Scheme 19) and variable amount of isomeric the β-chloro-β,γ-unsaturated ketone (4, Scheme 19). If o AgClO4 is the catalyst, in CH2Cl2 at -50 C, besides the β-chloro-αβ-unsaturated ketone, chlorodienic compounds (4, Scheme 20) are also formed.

Scheme 19

Scheme 20

2. Reaction of alkyne with Pd compounds114–123 Assembling the CBD*metal complex by a dimerization reaction from acetylenes by using a transition metal complex is, on paper at least, a simple and attractive approach to obtain a CBD*metal complex. Soon, it turned out to be very frustrating, it requires a lot of long and patient work. Most of the time research goes in different directions. For the case of Pd(II) reagents the reaction mechanism of acetylene oligomerization will be presented below. As it will be seen there is no cyclobutadiene intermediate in any steps! In the years that followed, it turned out that acetylene reacts, for example, with palladium(II) compounds to yield metal-containing red-brown product. Monosubstituted acetylenes form a complex mixture, while disubstituted acetylenes could form a single substance. The extent of reaction is very much governed by the size of the acetylenic substituents rather than electronic factors. In both cases, what is still an issue is to define clearly all the steps in a complicated overall process. Peter Maitlis, a prominent contributor to this chemistry have realistically and eloquently wrote:124 “The number of different strange, unusual, and apparently unrelated types of molecules isolated from these reactions reminds one of the early days of organic natural product chemistry; the tale of the unravelling of their structures and of the elucidation of apparently tortuous mechanisms by which they are formed is reminiscent of a detective story. Clues abound, there are many red herrings, and the answer to the puzzle is seldom obvious even halfway through the problem.” In 1969, by Nenitzescu and Avram125 embarked to study whether dimerization of acetylenes triggered by transition metals, in particular compounds of Pd(II), could be a simple and direct access to CBD metal complexes. Thus, t-butyl-phenyl acetylene in presence of benzonitrile palladium dichloride (Kharasch reagent126) generate the complex 3 (Scheme 21) which subsequently treated with HCl in dimethylformamide yielded the 1,2-di-t-butyl- 3,4-diphenylcyclobutadiene palladium chloride complex 4 (Scheme 21). A ligand exchange reaction of cyclobutadiene complex 4 with iron pentacarbonyl produces the iron tricarbonyl complex 5 (Scheme 21). Furthermore, in 1969, Avram and Nenitzescu published a paper127 describing the case of a monosubstituted acetylene, namely t-butyl acetylene reaction promoted by Karasch complex (solubilized PdCl2: 126 123 (C6H5CN)2*PdCl2). In 1971 a reinvestigation corrected the structures of some derived compounds, but

18 Mircea D. Gheorghiu

has not provide the structure of the primary palladium derivative C18H30PdCl2, which in the first paper was o wrongly assign to be a Dewar Benzene*PdCl2. In acetone at 20 C, t-butylacetylene gave only trimer product: 1,3,5-tri-tert-butylbenzene (4, Scheme 22). All attempts to generate 4 from 3 were unsuccessful therefore, the trimer complexes do not appear to be intermediates in the formation of the benzene derivative 4 (Scheme 22).

Scheme 21

Scheme 22

Scheme 23

A5. Cyclopropanation with π-allylpalladium chloride complexes Norbornenes (see Scheme 23), possessing a strained double bond, are cyclopropanated with diazomethane or ethyl diazoacetic ester in presence of π -allylpalladium chloride:128, 129 The benzonorbornadiene, exo-BCBN and endo-BCBN are the alkenes that have been cyclopropanated. The diazomethane yield exo-cyclopropane derivatives 3 (Scheme 24) in 85–100% yield. Diazoacetic acid ethyl ester add to produce both exo- (4a, Scheme 24) and endo- (4b, Scheme 24) derivatives. The cyclopropanation130 describe above was instrumental to synthesis exo-cyclobutene ring attached to benzo- (1, Scheme 25), exo-BCBN (2, Scheme 25) and exo-BCBN skeleton (3, Scheme 25). A6. Ketene as synthon for cyclobutane and cyclobutene derivative syntheses Prof. Avram was interested in the synthesis of four membered rings bearing bulky groups as potential precursors of sterically hindered cyclobutadiene as it was described above. The cycloaddition of a ketene with a t-Bu substituent to an acetylene with bulky substituent(s) would be a tempting project, because the

Margareta Avram: a life dedicated to organic chemistry 19 resulting cyclobutenone would be a closer step to this goal. I took these thoughts to Prof. Avram, who with her usual amiability had no objection to my trying this approach

. Scheme 24

Scheme 25

Scheme 26

Four membered rings, such as cyclobutanone and cyclobutenone derivatives, are easily available by Staudinger reaction131, 132 that involves ketene cycloaddition to alkenes or alkynes. The ketene studied is t- butylcyanoketene (TBCK) discovered by Moore133 in 1970. Shortage of hard currency obligated chemist from Romania to synthesize all the precursors from available starting material. Thus, we134, 135 have developed a convenient synthetic route for the TBCK starting from hydroquinone that was converted in 4 o steps in dichloro-quinone 2, followed by conversion into di-azide 3 with NaN3. Heated at 80 C in benzene compound 3 produces TBCK. The [2+2] cycloaddition reaction according to Woodward and Hoffmann136 when concerted, occurs via a π2s + π2a reaction mode, the suprafacial component is the alkene, and the reagents approach is orthogonal. Initially, the ketene moves towards the ketenophile with the smaller group (in this case CN) closer to the aromatic group of the vinyl moiety. The more advance is the reaction, as result of the anticlockwise rotation of ketene carbon end, the bulky t-Bu group ends in facing the larger substituent on alkene. Most of ketonophiles such as styrene137-139 and p-substituted styrenes140-143 with groups like methyl-, 144 phenyl, p-NO2, than with indene, α- and β-vinyl naphthalenes yield cyclobutanones with t-Bu group facing the aromatic ring. The stereochemistry outcome is exactly the one predicted by Woodward –Hoffman rule for a 2+2 concerted cycloaddition process. X-ray measurements endorse the stereochemistry. If the vinyl group is electron reach, as result of MeO-, p-halogen electron donation, or a vinyl group connected to a ferrocene,145 two cyclobutanone isomers are formed, the “normal” cyclobutanone 3 (Scheme 27) a second cyclobutanone 3 (Scheme 28), with aromatic ring and t-Bu group are in trans configuration was isolated. If the aromatic ring is large, as for example in 9-vinylanthracene, the two large groups, t-Bu of ketene and of ketenophile are in trans configuration in the cyclobutanone 3 (Scheme 28). TBCK reacts easily with acetylenes.146, 147 The cycloaddition is regiospecific. For example, TBCK (6, Scheme 29) adds to phenyl acetylene 1, 3, 4, 5 to yield the cyclobutenones 7 (Scheme 29) with the phenyl at C3.

20 Mircea D. Gheorghiu

Scheme 27

Scheme 28

Scheme 29

X-ray measurement confirm that the cyclobutenone resulted from TBCK and chlorophenylacetylene and has the structure 7 (R=Cl) (Scheme 29). The Prof. Avram legacy is very reach. Her remarkable chemistry achievements, mostly at the level of the hard period of groundbreaking, has open avenues in many fields of Organic Chemistry that presently covers a large surface of interest and sophistication. She has always been interested in exploring the development of ideas, the connections between those ideas and ways of inspiring others to study new concepts.

Acknowledgements. The author is grateful to Prof. A. T. Balaban, a witness to many chemical events described in the present paper, for critical reading the manuscript, Prof. Michaela D. Stanescu for suggesting to write the present paper and Profs. Luminita Parvulescu, Anca Marton and Dr. Filip Petru for providing many useful information. Conversation over the phone with Dr. Doina Dinu-Constantinescu have been very instrumental in the wiping the early history “dust” on CBD and benzo-CBD.

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