P a R T I Recent Advances in the Field of Macrccyclic

P A R T I RECENT ADVANCES IN THE FIELD OF MACRCCYCLIC COMPOUNDS - 2 - ABSTRACT The stereochemistry of alicyclic compounds along v/ith the modern concept of conformational analysis have been discussed. Various methods for the preparation of macrocyclic compounds involving the high-dilution principle, the acyloin condensation and the recently developed method for the oxidative couplinj^ of terminal diacetylenes have been described. The practical methods developed in this Laboratory for the preparation of civetone, dihydro- civetone, exaltone and exaltollde from indigenous raw materials are mentioned as well. The odour and constitution of macrocycllc compounds have been correlated. In addition, the possible biogenetlc pathways of these compounds along with their occurrence in nature have been presented. - 3 - The chemistry of alicyclic compounds is of interest primarily because of stereochemical properties inherent in the ring form as opposed to open chain structures, prior to about 1880, no compound containing a ring structure of other than six members had been isolated from a natural source or synthesised in the laboratory, and it was generally agreed that ring structures of other sizes were incapable of existence. > It is evident from the personal reminiscences of Perkin" that such eminent organic chemists of the period as A.von Baeyer, Victor Meyer, and Emil Fischer considered it highly improbable that three-, four-, and five- membered carbon rings should be capable of existence. The Early Syntheses of Small Rings During the period 1881-1885, the incorrectness of this view was clearly demonstrated by the synthesis of compounds containing three-, four-, and five-membered carbonrings. The first such synthesis was that of 1,3-cyclobutane-dicarboxylic acid by Markovnikov and Krestovnikov,^ which surprisingly excited no comment in chemical circles. It was only after the elegant synthetic work on small ring compounds by Perkin, this 4 ,5 conception of the finite existence of small ring compounds received a firmer support and subsequently aroused enough interest in this field. - 4 - Baeyer* s Strain Theory In order to explain the prevalence of six- raembered carbon rings in nature, the difficulty in formation of the small rings, and the great reactivity of such unsaturated linkages as the carbon-carbon double and triple bonds, Bieyer brought forth his famous Strain Theory,^ Baeyer based his theory upon the Van’ t Hoff^ and Le Bel^ conception of the tetrahydral distribution of carbon valences in space. Bayer concluded from this concept that?” the four valences of the c'^rbon atom act in directions which connect the centre of the sphere with the corners of an inscribed tetrahydron, and form an angle of 109° 2B' with each other. The direction of attraction (valence) can undergo a bending or distortion, which results in a tension (spannung) proportional to the amount of this bending.”® Any deviation from the normal valence angle was supposed to set up a condition of strain which exhibited itself by a corresponding decrease in the stability of the molecule. Baeyer's conception of this strain theory was based on the assumption that the rings under consideration were planar. However, this conception later on underwent considerable modifications (vide infra). Seeming confirmation of the general concept of the strain theory was immediately obtained by Perkin," - 5 - who succeeded in preparing cyclopentane-l,!^-dicarboxylic acid, which was found to be extremely stable, and the yield in the cyclisation step was very high,in distinct contrast to the low yields obtained during the formation of three- and four- mernbered rings. Limitations of the Strain Theory Many other early observations give general support to Bayer’ s strain theory as applied tc smaller ring systems, although the physical nature of this strain is not yet fully understood. The theory,however, breaks down completely when employed for interpreting the properties of macrocyclic rings. Thus cyclopenta- decane (muscane) with a negative valency deflection of “^3® 16’ might be expected to possess the same order of stability as cyclopropane with a positive valence deflection of 24® 44’ . Infact muscane approximates in stability to cyclohexane and tne same is true for all the macrocyclic ring systems. Strainless Rings Sachse^® furnished an explanation for this anomaly but his conceptions remained neglected until revived and elaborated by Mohr^^ thirty years later. They showed that the erroneous conclusions stemmed from the assumption that all rings must necessarily be uniplanar. This is indeed true for rings upto - 6 and including five-merabered systems, but from cyclohexane upwards, puckered, raultiplanar configurations can be envisaged which involve little or no distortion of the tetrahydral valence angles. Boat- and Chair- qoniormatlons Thus cyclohexane ma- exist in two ’’strainless” configurations in wnich four of the carbon atoras are coplanar and two other carbon atoms occupy a second plane; these are commonly referred to as the boat- forra(I), and the chair form(II), IlgC CH2 H2 C -CHg'"'/ ....... HgC------------ CHg Crf2--- CH2. \ N. CH2 (I) (II) Examination of the individual structures (I) and (II) suggests the eiistence of several stereoisomers of each of the monosubstitution derivatives of cyclo hexane. No such isomers, hOFever, have been isolated, probably due to the fact that the various steric forms of the cyclohexane ring are easily interconvertible, Mohr^^ pointed out that, whereas the simple cyclohexane - 7 - derivatives may fail to exhibit ” boat-chair’* conformation fused ring systems might afford better opportunity for the isolation of stereo-isomeric forms. This prediction has been amply verified experimentally. Thus decalin (decahydronaphthalene) has been shown to exist in two forms, which are cis- trans isomers. The separation of the indubitable els- trans isomers of decalin^^ afforded Incontrovertible evidence that the Sachse-Mohr conception of strainless nonplanar rings is essentially correct. Ruzicka’ s discovery that muscone and civetone, the odourous principles of natural musk and civet respectively were representatives of the group of large ring ketones, gave the final blow to Baeyer's strain theory and put the strainless ring theory on firmer fccting. These large rings show no strain in the Baeyer sense. However, there is certain evidence that "strain” exists in higher ring systems^^ due to steric rppulsions, as described in the sequel. Conformational Analysis A somewhat different approach to an understanding of the effects that steric factors exert on the properties of organic substances has led to the valuable new concept that is now described as conformational analysis ,which has been established in recent years as a valuable approach to the solution of a wide variety oi problems in structural organic chemistry.^'^ - 8 - By ’ conformation' is meant any arrangement in space of the atoms of a molecule that can arise by rotation about a single bond and that is capable of finite existence.^® Such arrangements would correspond to a potential minimum with respect to all types of small displacements in bond lengths, in bond angles, or in angles of rotation about single bonds (or double bonds). Defined in this way, confor mations are rotational isomers entirely analogous to isomers, related by rotation about a double bond. However, since the potential barriers associated with rotation about single bonds are relatively low,isolation of such isomers is not likely to be feasible. Neverthe less, each potential isomer or conformation has finite and distinct physical properties, and the seperate spectra of various conformations h^ve been identified in a number of cases. preferred Conformations of some Hydrocarbons In the last two decades many of the powerful methods of modern chemical physics including electron and x-ray diffraction, infrared, Raman and microwave spectroscopy and statistical mechanics, have been used to demonstrate the existence and nature of preferred conformations in simple molecules. - s - n-Batane The conformation of n-batane with lowest energy is the fully transoid, staggered conformation (III), whereas the energies for the fully eclipsed (IV), eclipsed (V ), and skew (VI) conformations are about 3.6, 2.9 and 0.8 kcal. per mole respectively graater than that of the staggered conformation. (H) H H(H) (Me)H H(H) Me Me (Ke) Staggered Fully eclipsed Eclipsed Skew (III) (IV) (V) (VI) In the aliphatic as well as alicyclic compounds, the most stable conformation is usually that in which the substituents on adjacent tetrahydral carbon atoms adopt the fully staggered confoi^nation as ( I I I ) , the two largest groups (or, in qualification, the two most strongly repelling dipoles) taking up the 180°arrangement. 16 Eclipsed conformations are always avoided whenever possible. - 10 - In cycloalkanes, the possibility of attaining the favourable staggered conformation will be severely conditioned by the size of the ring. Cyclohexanes The conclusion by Sachse and Mohr that cyclohexane can exist in only two conforraations free from anglo-strain has long been accepted by chemists. That the chciir confornation (VII), is more stable than the boat (VIII), is attested by considerable physical evidence including infrared and Raman spectroscopy, and electron diffraction^'^ and by thermodynamic considerations, 1 9 a e (VII) (VIII) Derivatives of cyclohexane always tend to take up the chair conformation, whenever this is stereo- po chemically possible.

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