ISOMERIZATION AND DEHYDROGENATION OF SOME AUTOCONDENSATION PRODUCTS OF CYCLOHEXANONE
ISOMERIZATION AND DEHYDROGENATION
OF SOME AUTOCONDENSATION PRODUCTS
OF CYCLOHEXANONE
PROEFSCHRIFT
TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL DELFT. OP GEZAG VAN DE RECTOR MAGNIFICUS IR. H.J. DE WIJS,
HOOGLERAAR IN DE AFDELING DER MIJNBOUWKUNDE, VOOR EEN COMMISSIE UIT DE SENAAT TE VERDEDIGEN
OP DONDERDAG 6 JULI 1967 TE U UUR DOOR
BERNARDUS HENDRIKUS BIBO
GEBOREN TE BAARN
/
DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR DE PROMOTOREN: PROF. DR. D. W. VAN KREVELEN
Aan mijn ouders
DANKBETUIGING
Aan de Raad van Bestuur van de Algemene Kunstzijde Unie N.V. en aan de Direktie van het Centraal Researchinstituut van de Algemene Kunstzijde Unie N.V. en daar-mee verbonden ondernemingen betuig ik mijn dank voor de toestemming tot pu-blikatie van dit onderzoek.
Veel dank ben ik verschuldigd aan Dr. O. E. van Lohuizen en Dr. W. J. Mijs voor hun adviezen en hun daadwerkelijke steun.
Ook betuig ik gaarne mijn dank aan de heren Dr. W. G. B. Huysmans, Dr. H.J. Hageman, Dr. Ir. J. G. Westra, J. L. Mulder, J. H. van Dijk en H. L. Louwerse voor hun waardevolle bijdragen aan de spektroskopische en chromatografische onderzoekingen. De heer J. B. Reeslnk ben ik erkentelijk voor zijn enthousiaste medewerking aan het praktische deel van dit onderzoek.
De heer R. Timmer dank ik voor het korrigeren van het manuskript.
Mijn erkentelijkheid gaat voorts uit naar allen die er toe hebben bijgedragen, dat dit proefschrift in deze vorm en op dit tijdstip t o t stand is gekomen.
CONTENTS
INTRODUCTION
Chapter 1 THE BASE-CATALYZED AUTOCONDENSATION OF
CYCLOHEXANONE
1.1 INTRODUCTION 11 1.2 RESULTS 12
1.2.1 Azeotropic condensation of cyclohexanone 12 1.2.2 Low-temperature condensation of cyclohexanone 18
1.3 DISCUSSION 18 1.3.1 Azeotropic condensation 18
1.3.1.1 2-(1-hydroxycyclohexyl)cyclohexanone 18 1.3.1.2 Bicyclic condensation products 20 1.3.1.3 Tricyclic condensation products 21
1.3.1.4 By-products 26 1.3.2 Low-temperature condensation 27
1.4 EXPERIMENTAL DETAILS 30
Chapter 2 ISOMERIZATION OF SOME OF THE CYCLOHEXANONE
CONDENSATION PRODUCTS
2.1 INTRODUCTION 38 2.2 RESULTS i 7 2.3 REACTION PRODUCTS OF THE PALLADIUM-CATALYZED REACTION . 49
2.4 DISCUSSION 52 2.4.1 Thermal, acid-catalyzed and base-catalyzed isomerlzatlon 52
2.4.2 Metal-catalyzed reactions 55 2.5 EXPERIMENTAL DETAILS 59
Chapter 3 DEHYDROGENATION OF SOME OF THE CYCLOHEXANONE
CONDENSATION PRODUCTS
3.1 INTRODUCTION 63 3.2 RESULTS 63 3.3 DISCUSSION 66 3.4 EXPERIMENTAL DETAILS 68
Chapter 4 BY-PRODUCTS OF THE DEHYDROGENATION REACTION 4.1 INTRODUCTION 71 4.2 RESULTS 71 4.3 DISCUSSION 71 4.3.1 Hydrogenolysis 74 4.3.2 Dehydro-cyclization 75 4.3.3 Isomerlzatlon 76 4.3.4 Dehydro-coupling 76 4.4 EXPERIMENTAL DETAILS 77 Chapter 5 STEREOCHEMICAL ANALYSIS OF SOME REACTION PRODUCTS
5.1 INTRODUCTION 80 5.2 RESULTS 80 5.3 DISCUSSION 83 5.3.1 NMR spectroscopy 83 5.3.2 Ultraviolet spectroscopy 85 5.3.3 Infrared spectroscopy , 86 5.4 EXPERIMENTAL DETAILS 87
Appendix QUANTITATIVE MEASUREMENT OF THE TRICYCLIC KETONES
SUMMARY 89
SAMENVATTING 91
INTRODUCTION
The industrial importance of cyclohexanone virtually lies in its use as an intermediate in the synthesis of starting materials for the manufacture of nylons. The present study was performed within the scope of an Investigation into new applications of cyclo-hexanone and its derivatives.
Chapter 1 of this thesis discusses the azeotropic condensation of cyclohexanone cata-lyzed by potassium hydroxide. The reaction products are anacata-lyzed and the course of the reaction is described. In Chapter 2 some thermal, acid-, base- and metal-catalyzed Isomerlzatlon experiments with a number of tricyclic cyclohexanone condensation products are discussed. The products of the metal-catalyzed reaction are studied in some detail. Chapter 3 deals with the platinum- and the palladium-catalyzed de-hydrogenation of the tricyclic cyclohexanone condensation products; the by-products of these reactions are discussed in Chapter 4. A stereochemical analysis of a number of compounds is given In Chapter 5. In an Appendix the method used for analyzing the condensation products is described.
Chapter 1
THE BASE-CATALYZED AUTOCONDENSATION
OF CYCLOHEXANONE •)
1.1 INTRODUCTION
Cyclohexanone has long been known to condense with itself under various conditions. Catalyzed by acids and bases - and even without a catalyst {Sapiro, 1938) - its autocon-densation yields a multitude of interesting and useful products, a number of which are presented on the inside of the front-cover foldout.
The number of papers dealing with the autocondensation of cyclohexanone being rather formidable, no attempt has been made to offer a complete bibliography here; only the most characteristic papers will be mentioned. More comprehensive literature surveys can be found in the papers of Plesek (1956), Roginskaya et al. (1958) and
Wenken et al. (1964).
The base-catalyzed autocondensation of cyclohexanone, which will be discussed in this chapter, was performed by Wallach as long ago as 1896. The reaction of
cyclo-hexanone with sodium ethoxide at room temperature was found t o give two products: a colourless oil having the composition C,jH,gO, formed by condensation of two molecules of cyclohexanone, and a yellow crystalline mass, which was proposed to be the condensation product of three molecules of cyclohexanone. These products were not further examined at the time.
Sodium methoxide in methanol was used as a catalyst for the autocondensation by Svetozarskli et al. (1963). From the reaction product they isolated compound 16, which was converted into 18 by treatment with hydrogen chloride. The probable intermediate 17 was obtained by the reaction of cyclohexanone with sodium me-thoxide in dimethylformamide {Pettit and Thomas, 1963).
COO
c& o^
16 17 18
When the autocondensation was carried out at 200° and with an excess of KOH, sym. dodecahydrotriphenylene (12) was obtained (Wa//ach, 1909). This compound is also formed by condensation of cyclohexanone catalyzed by sulfuric acid {Mannich, 1907).
*) The formulas of the compounds to be discussed in this chapter can be found on the front-cover foldout.
This coupling of three molecules of cyclohexanone to 12 is analogous t o the well-known condensation of three molecules of acetone t o mesitylene.
The KOH-catalyzed autocondensation of cyclohexanone in toluene with continuous azeotropic removal of reaction water was described in a patent by Beucker (1943). This procedure was reported to yield the bicyclic ketone 4 (Plesek, 1956) and a mixture of tricyclic ketones {Munk and Plesek, 1957). From this mixture compound 8 was isolated (Mleziva, 1953; Plesek 1956).
^
The present work was done to investigate the KOH-catalyzed autocondensation of cyclohexanone under these azeotropic conditions. In this chapter the structure of the reaction products will be elucidated and the course of the reaction will be discussed. The analyses were partly effected by the usual chromatographic techniques, such as gas-liquid chromatography and thin-layer chromatography, and partly by a new chromatographic technique t o be described in the Appendix t o this thesis.
As the reaction of cyclohexanone, performed at low temperature (7-10°), was re-ported t o yield a compound (10) (Razuvaev et al., 1961) which greatly differs from the compounds obtained under azeotropic conditions, this compound was also included
11
in the investigations. It was found that dehydration of 10 by sulfuric acid under the conditions mentioned in the literature (Svetozarskli et al., 1959) does not yield 11, as described by these authors, but gives a mixture of compounds which are shown t o have the structure of 13 and/or its isomers.
1.2 RESULTS
1.2.1 Azeotropic condensation of cyclohexanone
The azeotropic condensation of 1963 g cyclohexanone in 800 ml toluene, using 30 g KOH as catalyst, was effected in a reaction vessel equipped with a Dean-Stark apparatus to drain the reaction water. During the condensation samples were taken without
interrupting the reaction. The samples were analyzed by thin-layer chromatography (TLC) and gas-liquid chromatography (GLC).
In Fig. 1.2 a thin-layer chromatogram is presented which shows the change in composition of the condensation mixture with reaction time. It has been possible t o identify most of the products on this chromatogram, as can be seen from Fig. 1.3, which shows the analysis of a condensation mixture together with the individual components on a thin-layer chromatogram (for a summary see Table 1.1). Fig. 1.1 gives an over-all picture of the concentration of cyclohexanone, the combined bicyclic and the combined tricyclic ketones during the reaction, as measured by GLC. The graph also includes the amount of water formed during the reaction (the axis on the right hand side).
cyclohexanone bicyclic ketones
tricyclic ketones H j O
^ r e a c t i o n time (h)
Fig. 1.1 Formation of products during the azeotropic condensation of cyclohexanone, as shown by GLC of the volatile products (full lines) and by measurement of the reaaion water (broken line)
Further analysis of the reaction mixture was accomplished by vacuum distillation, which yielded a fraction (22%) containing bicyclic, and a fraction (68%) containing tricyclic ketones.
It was shown by TLC and by UV- and NMR-spectroscopy that the bicyclic ketone fraction contained about 87% of 2-(cyclohexen-1-yl)cyclohexanone (4) and 13% of 2-cyclohexylidenecyclohexanone(3). It will be seen from the thin-layer chromatogram presented in Fig. 1.4 that these t w o compounds were also present in the initial con-densation mixture.
Fig. 1.6 shows that the tricyclic ketone distillation fraction contained four main components. These proved t o be cis- and trans-2,6-di(cyclohexen-1-yl)cyclohexanone (8 and 7), 2-(cyclohexen-1-yl)-6-cyclohexylidenecyclohexanone (6) and
2,6-dicyclo-Table 1.1 IDENTIFICATION OF PRODUCTS OF THE AUTOCONDENSATION OF CYCLOHEXANONE
Spot in Compound Compound
Fig. 1.2 No. 0
Ö
2-(1-hydroxycyclohexyl)cyclohexanone 2 cyclohexanone C*) C j T J 2-cyclohexylidenecyclohexanone 3 0 C*) C J X J 2-(cyclohexen-1-yl)cyclohexanone 4 0 ^ C J T T J I J 2,6-dicyclohexylidenecyclohexanone 5 0 E ^ - v . ^ ^ ^ 2-(cyclohexen-1-yl)-6-cyclo-K^ ' - ^ k ^ hexylidenecyclohexanone 6 0 F C J ~ C J ' C J trans-2,6-di(cyclohexen-1-yl)cyclohexanone 7 0 G C T L X T J cis-2,6-di(cyclohexen-1-yl)cyclohexanone 8Spot Reaction t i m e
E E E E ^ ^
E E E 'E 'i 'Ë jz ^ J: XL jz jz
o o o m o o c o i n r ^ o ^ ^ c o
Fig. 1.2 Thin-layer chromatogram showing the base-catalyzed autocondensation of cyclohexanone
Spot H G F E D C Compound N o . 4 5 6 7 8
• I
^ I F ^ ^ A SFig. 1.3 Thin-layer chromatogram showing the separate compounds formed by the base-catalyzed autocondensation of cyclohexanone
10
Reaction time
12
# 9 ^
11
Fig. 1.4 Thin-layer chromatogram
bicyclic ketones (CH2CI2 eluant)
of the
Reaction product of the azeotropic cyclo-hexanone autocondensation
Distillation fraction containing the bicyclic ketones
§
* J w w *
• f ;
Fig. 1.5 Conversion of compound 10 under the conditions of the azeotropic condensation of cyclohexanone (benzene eluant)
I. Reaction mixture of the azeotropic cyclo-hexanone autocondensation
#
•
•
!
"
"
"
IV
f
I
II. bicyclic ketones (86-97°/0.6 mm) III. tricyclic ketones ( 1 3 7 - U 2 ° / 0 . 2 m m ) IV. distillation residue
f
o
ó
OH , ^ - ^ 10 0* azeotr.6p
4 H,SC'.
azeotr. azeotr. ? azeotr. 13Cró-O
5+
+
aó)-o
7+
8hexylidenecyclohexanone (5). As a quantitative analysis of these four compounds is very difficult t o realize by conventional means, a new chromatographic technique*) was used. It was demonstrated that the tricyclic ketones were present in the ratio 8 :7 : (6 -f- 5) = 36 :33 : 29 (Table 1.2). The infrared spectrum of the tricyclic ketone distillation fraction further shows that the mixture contained only a small percentage of 5.
In addition t o the above-mentioned compounds minor amounts of some other products were formed, as is seen from Fig. 1.2 (Spots S, H and I). Attempts to identify these products were unsuccessful.
1.2.2 Low-temperature condensation of cyclohexanone
In an attempt t o obtain 2-(2'-(cyclohexen-1"-yl)cyclohexylidene)-cyclohexanone (11) by condensation of cyclohexanone with KOH at 0° and subsequent dehydration with sulfuric acid, a product was obtained which, judged by its physical and spectral data, was identical t o that described in the literature. It appeared, however, that this pro-duct does not have the proposed structure, but probably is a mixture of some isomers of octahydrodibenzo[bd]pyran-6-spirocyclohexane (13, 14 and 15).
Neither these asymmetric condensation products, nor sym. dodecahydrotriphenylene (12), which can also be formed by asymmetric coupling of three molecules of cyclo-hexanone, were present in the reaction mixture of the azeotropic condensation described above, as shown by GLC.
It was demonstrated by TLC that the primary asymmetric product of the low-temperature reaction (10) is converted into the symmetrically coupled products 5, 6, 7 and 8 under the conditions of the azeotropic condensation (Fig. 1.5).
A summary of the above-mentioned reactions is found in Scheme 1.1.
1.3 DISCUSSION 1.3.1 Azeotropic condensation
1.3.1.1 2-(f-/iydroxycyc/o/7exy/)cyc/ohexanone (2; Spot A)
The ability of cyclohexanone t o condense with itself under the influence of a base is due t o t w o factors:
a. The presence of two a-methylene groups that are activated by the neighbouring carbonyl group which makes the hydrogen atoms of these methylene groups more acidic. This activation is caused by the inductive electron-withdrawing action of the carbonyl group and, in addition, by the ability of this group t o delocalize the negative charge when a proton is split off.
o r o o®
-Ö —' — [
ö ' —
ó J ^
-b. The possibility that nucleophilic compounds are added to the carbonyl group,
due to the polarization of the C = 0 bond. When the nucleophilic agent is the
enolate ion of cyclohexanone itself, a bicyclic anion is formed, which after protonation
gives hydroxy ketone 2.
0 CK 0 e
at
—=
cxb
0 QS '^ OH
2
Thustheformationof hydroxy ketone 2 is governed b)'the above-mentioned equilibria.
In the case of the autocondensation of ketones these equilibria are usually unfavourable
for the formation of the hydroxy ketone, and a reasonable amount of this is only
formed when it is removed from the reaction mixture, so that the equilibria are
dis-placed to the right. This is the case, for example, in the synthesis of diacetone alcohol
from acetone in a SoxhIet apparatus (Conant and Tuttle, 1941). The equilibria are also
displaced to the right, of course, when the ketol is dehydrated and the water is
withdrawn from the reaction mixture.
Although hydroxy ketone 2 is generally accepted to be the intermediate in the
autocondensation of cyclohexanone, it has not yet been synthesized by the
base-catalyzed coupling of cyclohexanone (the isolation claimed by Stanek (1952) was wrong,
as was demonstrated by Plesek and Munk (1957)). Hydroxy ketone 2 has so far only
been prepared with the aid of Grignard compounds (Cologne, 1934; Dubois, 1955).
In the Experimental Details of this chapter the synthesis of hydroxy ketone 2 by
coupling of cyclohexanone, catalyzed by KOH, is described. Hydroxy ketone 2 is a
crystalline compound with a m.p. of 32-33° that can be distilled under vacuum without
dehydration. The product described by Cologne was reported to melt at 56°. V\^hen
his preparation was repeated, however, a compound was isolated which melted at 33°.
This compound was identical with the one described above (IR, mixed melting point,
oxime).
By TLC it was shown that hydroxy ketone 2 was indeed present in the reaction
mixture in the initial stage of the condensation reaction (Figs. 1.2 and 1.3). The
com-pound could not be analyzed quantitatively by GLC, because it decomposes into cyclohexanone under the conditions of the GLC-analysis.
1.3.1.2 Bicyclic condensation products (3 and 4 ; Spot C)
As the a-protons of hydroxy ketone 2 are activated by the carbonyl group, water will be split off under the influence of a base and compound 3 will result:
ÖX) =^= 6 b
=^^ Ó-0
2 3 Once the a,;3-double bond is formed, the y-protons become activated, whereupon
3 may be isomerized to 4:
&Ö - ^ CTÖ
3 I 0 j_^ H O HC:rt)
H H Öt)
4When the bicyclic ketone distillation fraction was examined by TLC (Fig. 1.4) it was indeed found to contain both bicyclic ketones 3 and 4. UV- and NMR-analysis showed the proportion to be 87% of 4 and 13% of 3, the same as found by Wenkert et al. (1964) in a fraction of bicyclic ketones prepared by dehydrochlorination of 1.
This preference for the (unconjugated) endo-isomer is not unusual; several examples of a similar behaviour in other unsaturated six-membered compounds have been collected by Brown et al. (1954).
Compound 3 was prepared by the method of Reese (1942). The pure compound 4 had not been described earlier; its isolation from the bicyclic ketone distillation fraction by repeated crystallization is described in the Experimental Details of this chapter.
1.3.1.3 Tricyclic condensation products (5, 6, 7 and 8; Spots D, E, F and G)
It was mentioned above that compounds 2, 3 and 4 are present during the azeotropic condensation. In principle any of these compounds may condense with cyclohexanone t o a tricyclic ketone. For two reasons, however, the picture is even more complicated.
Firstly, more than one (polydent) anion may be formed from the bicyclic ketones, so that the coupling with cyclohexanone may take place in more than one position.
Secondly, the bicyclic ketones are not only nucleophilic as mentioned above -but also electrophilic in character. This means that they may act as receptors for the enolate anion of cyclohexanone.
The condensation of the bicyclic ketones with cyclohexanone will thus take place by one or more of the reactions summarized in Scheme 1.2.
fa' of^fp'''
5(+6, 7. 8) 3(+4)
Scheme 1.2 Possible reactions between bicyclic ketones and cyclohexanone
(and/or isomers)
Which of the tricyclic ketones is formed will depend o n :
a. the relative rates of formation of the different enolate anions of 2, 3, 4 and cyclo-hexanone,
b. the relative rates of addition of these anions to the carbonyl groups of 2, 3, 4 and cyclohexanone,
c. the relative rates of dehydration of the intermediate hydroxy ketones t o unsatu-rated tricyclic ketones.
As little or no quantitative information about these reaction rates is available, the formation of the tricyclic ketones will be discussed here on a qualitative basis only.
Bicyclic ketones as nucleophilic agents
The action of a base on asymmetric ketones in most cases leads to the formation of a mixture of enolate anions (House, 1965). Thus, from 3 and 4 the anions A-1, A-2 and A-3 may be obtained:
0 0
&0
0=0
''• 3
Electrophilic reagents may in principle react with the oxygen atom of these three polydent anions; in addition they may react with the a'-carbon atom of A-1 and A-3 and with the a- and y-carbon atoms of A-2.
Although alkylations at the oxygen atom of ketones have been found (Wash et al., 1941; Rinderknecht, 1951; He/szwo/f and Kloosterziel, 1966), autocondensat/on at the oxygen atom is not expected t o take place, for it is thermodynamically unfavourable (Roberts and Caserio, 1965). The fraction of tricyclic ketones, therefore, will only consist of products obtained by C-C coupling of the anions A-1, A-2 and A-3.
Under the influence of the double bonds the polydent anions will be formed at different rates. Moreover the relative reactivity of each of them will be different (House and Kramar, 1963; Van der Zeeuw and Gersmann, 1965). Hence it is not easy to predict which anion will react further.
It was found earlier that alkylations take place via anion A-2, for the bicyclic ketones are, e.g., methylated (Kon and Nutland, 1926), ethylated (Con/a, 1954), carbo-methoxylated (Schneider et al., 1950) and allylated (Con/a and Le Perchec, 1964) in the a-position. These reactions are in accordance with the normal behaviour of this type of polydent anions, which are reported to be alkylated at the a-c-atom (Con/a and Sandré-Le Craz, 1962) unless the a-position is sterically hindered; in that case the anion reacts at the y-carbon atom (Engel and Lessard, 1963).
Although alkylation of the bicyclic ketones has thus been shown to occur via the anion A-2, condensation with cyclohexanone via this anion has not been reported. As will be demonstrated in the next section, the condensation products (5, 6, 7 and 8)
are those derived from A-1 and A-3. This can be made plausible by the following con-siderations:
a. Stereoelectronic control requires addition of the anion t o the carbonyl group of cyclohexanone in such a way that the newly formed carbon-carbon bond is perpen-dicular t o the node of the ji-orbitals of the anion as well as t o that of the carbonyl group of cyclohexanone in order to attain a transition state showing maximum overlap. In the case of the rather bulky cyclohexanone molecule such an approach to the a- and y-carbon atoms of anion A-2 will be sterically hindered to a greater extent (a bulky substituent being present next to the y-position) than the approach to the a'-carbon atom in the anions A-1 and A-3. It must be expected that alkylating agents will also be hindered, but the hindrance will be less strong because the entering groups are smaller.
b. It was mentioned earlier that in the autocondensation of ketones the intermediate hydroxy ketone (compound 2 in the case of cyclohexanone) must be dehydrated in order t o force the reaction to completion. If the a-carbon atom of anion A-2 is added t o cyclohexanone the following hydroxy ketone will be formed:
In this hydroxy ketone there is no activated proton next t o the hydroxyl group, so that dehydration is not easily accomplished and the product will be decomposed again by the reverse reaction.
It is shown in Figs. 1.2 and 1.3 that, in addition to the products already discussed, hydroxy ketone 2 is found in the condensation mixture. A possible further con-densation of this compound may be effected via the following anions:
\
® ° OH ° ®
"&0 OX)
A-4 A-5
The preference for the formation of one of the ions will be less pronounced than in the foregoing case, since no activating vinyl group is present.
When A-5 is formed, it may be dehydrated to 3, the further reaction of which has been discussed above. As regards a possible addition of A-5 to cyclohexanone, the above-mentioned arguments against addition t o the a-carbon atom are equally valid. Nucleo-philic reaction of hydroxy ketone 2 is therefore expected to take place via anion A-4, which gives the tricyclic condensation products 5, 6, 7 and 8.
Bicyclic ketones as electrophilic reagents
As mentioned earlier, the bicyclic ketones may also be electrophilic in character; they will then react in the ^-position or at the carbon atom of the carbonyl group. a. Coupling in the /9-position may take place by substitution of the carbanion of cyclohexanone for the hydroxyl group of 2 but also by Michael addition of the cyclo-hexanone carbanion t o 3. In either case the same products will be formed. Several examples of the coupling reactions of ^-hydroxy ketones can be found in a paper by Co/ogne e t a l . (1956).
The first product formed by /3-coupling in cyclohexanone autocondensation is the ó-diketone 16, obtained by Svetozarskli et al. (1963) when they caused cyclohexanone to react with sodium methoxide for 75 days. The ó-diketone 16 can be converted fur-ther into the hydroxy ketone 17 by intramolecular aldol condensation. This compound was obtained by Pettit and Thomas (1963) by condensation of cyclohexanone with sodium methoxide in dimethylformamide at room temperature. By intramolecular condensation and dehydration of 16, ketone 18 is obtained almost quantitatively (Svetozarskli et al., 1963).
For the rest there are no indications that more than traces of these compounds are formed during the azeotropic condensation of cyclohexanone.
b. Formation of tricyclic compounds may in principle take place by addition of the enolate anion of cyclohexanone t o the carbonyl group of all three compounds 2,3 and 4. Actually only compound 10, formed by addition of cyclohexanone to hydroxy ketone 2 and subsequent cyclization of the intermediate 9, has been reported (Svetozarskli, 1959; Razuvaev, 1961). An explanation of the absence of substitution at the carbonyl groups of 3 and 4 may be found in steric hindrance by the bulky a-substituents in these compounds. An influence of a-substituents on the rates of addition reactions at the carbonyl group was found earlier. The formation of cyanohydrins of cyclohexanones, for example, proceeds more slowly when bulky substituents are present in the
«-position (Wheeler, 1964). More closely related to the present work is the study of Con/a (1953), who showed that cyclohexanone is oximated much faster than 4, so that this reaction can be used for the determination of cyclohexanone in the presence of compound 4. The addition to the carbonyl group of hydroxy ketone 2, which also has
a voluminous a-substituent, may be facilitated by the intramolecular hydrogen bond between the carbonyl and the ^-hydroxy group. By this hydrogen bond the carbonyl group may become more polarized, so that in this case addition reactions occur more easily.
The structures of the tricyclic compounds
The molecular composition of the distillation fraction of the azeotropic condensation boiling at 137-142°/0.2 is C,eHjjO. It is thus composed of compounds obtained by con-densation of three molecules of cyclohexanone. TLC (Fig. 1.6) shows the spots D, E, F and G, representing the main components of the mixture. It will now be shown that these spots are caused by, respectively, compounds 5, 6, 7 and 8.
Cr6o OtrO OÓ-Q Ot^K)
5 (Spot D) 6 (Spot E) 7 (Spot F) 8 (Spot G)
2,6-dicyclohexylidenecyclohexanone (Compound 5, Spot D)
The compound represented by spot D was isolated from the tricyclic ketone distil-lation fraction by crystallization. By its IR and NMR spectra it proved to be identical with a compound prepared in a different way by Munk and Plesek (1957) to which these authors assigned the structure of 5. The presence of an a,^-a',/9'-unsaturated ketone is shown by absorption maxima in the infrared spectrum at 1662 and 1612 cm-' and by the presence of an absorption band in the ultraviolet spectrum at 285 m[i (13,500). In accordance with the suggested structure no vinyl protons are found in the NMR spectrum. The suggested skeletal arrangement was confirmed by the isomerlzatlon of 5 t o 2,6-dicyclohexylphenol (to be discussed in Chapter 2).
2-(cyclohexen-1-yl)-6-cyclohexylidenecyclohexanone (Compound 6, Spot E) This compound isolated from the distillation fraction by column chromatography -has a carbonyl group conjugated with a C = C bond, as is indicated by the infrared (maxima at 1680 and 1615 cm-') and ultraviolet ( A „ ^ 256 mjA (9200)) spectra. The NMR spectrum shows one vinyl proton (d 5.4 ppm) and one methine proton between a carbonyl and a C = C bond ( C = C — C H — C = 0 ; ö 2.8 ppm, compare the NMR spectrum of 2-(cyclohexen-1-yl)-cyclohexanone (4)). Chemical evidence of the struc-ture above is provided by the isomerlzatlon experiments described in Chapter 2.
Trans-2,6-di(cyclohexen-1-yl)cyclohexanone (Compound 7, Spot F)
shows the presence of non-conjugated carbonyl and C = C bonds (1712 and 1660 cm-'). The NMR spectrum shows two vinyl protons (5 5.4 ppm) and two methine protons between C = C and C = 0 («5 2.8 ppm).
Cis-2,6-di(cyclohexen-1-yl)cyclohexanone (Compound 8, Spot G)
This compound - isolated from the distillation fraction by crystallization - was iden-tified earlier by P/esek (1956). In the spectra of this compound the same characteristic absorptions are observed as in those of 7. Compound 8 thus also contains non-con-jugated carbonyl and carbon-carbon double bonds, two vinyl protons and two methine protons between C=C and C = 0 . This suggests that 7 and 8 are stereoisomers, as can also be deduced from the easily accomplished interconversion of these compounds (Chapter 2).
TABLE 1.2 QUANTITATIVE ANALYSIS OF THE TRICYCLIC KETONE FRACTION») Compound Compound %
No. unidentified products with high Rp
cis-2,6-di(cyclohexen-1-yl)cyclohexanone trans-2,6-di(cyclohexen-1-yl)cyclohexanone
2-(cyclohexen-1-yl)-6-cyclohexilidenecyclohexanone 2,6-dicyclohexylidenecyclohexanone
bicyclic ketones
unidentified products with low Rp
*) Experimental details can be found in the Appendix
It can be seen from Table 1.2 that about two-thirds of the tricyclic ketone fraction consists of compounds 7 and 8; the infrared spectrum of this fraction further shows that the concentration of compound 5 is rather low. So in this case also the compounds having the double bonds in the cyclohexyl side-rings (endo-position) prevail. This again is in accordance with the general rule for the exo-endo ratio of double bonds in six-membered ring compounds (Brown et al., 1954).
1.3.1.4 By-products of the azeotropic condensation
It can be seen from Fig. 1.2 that, in addition t o the compounds mentioned, a number of other products are formed (Spots S, H and 1). In this section some data of these products will be given.
8 7 6
5
3 and 4 < 1 36 33 29 1Spots
When the neutralized condensation mixture or the (yellow) tricyclic ketone fraction is chromatographed with benzene as the eluant, some yellow zones are invariably retained at the very top ofthe column. These zones can be extracted with polar solvents, the extracts giving a small spot at the starting point (S) of thin-layer chromatograms (Fig. 1.2). The infrared spectrum ofthe mixture indicates the presence of one associated hydroxyl and three different carbonyl groups. The "Spot S products", which constitute a considerable part ofthe distillation residue, are possibly formed by further coupling o f t h e bicyclic and tricyclic ketones, without complete dehydration, however.
SpotH
From the distillation fraction of tricyclic ketones a small amount of the "Spot H " compound was isolated by column chromatography. The infrared spectrum of this compound shows the characteristic frequencies of C—H stretching and of a non-conjugated carbonyl group.
Spot I
From Fig. 1.2 it would seem that this spot is brought about by one or two compounds. However, when a TLC analysis, using silica gel with CCI^, is made it appears that Spot I represents a series of compounds. These cannot be analyzed by GLC as they are not eluted from the columns. Attempts to separate the mixture by column chro-matography were unsuccessful, no complete separation being attained. The infrared spectrum o f t h e mixture only shows saturated and vinylic C—H stretching and also very weak absorption of a conjugated carbonyl group.
These compounds are probably formed by further condensation of the bicyclic or tricyclic ketones. Accordingly, they are found in the distillation residue; large amounts of them are also formed on heating a mixture of tricyclic ketones at 300° (under nitrogen). As can be seen from Table 1.2 and Fig. 1.6, small amounts o f t h e "Spot I products" are also present in the distillation fraction o f t h e tricyclic ketones.
1.3.2 Low-tem/)erature condensation
As mentioned earlier, three molecules of cyclohexanone may condense not only to the symmetrically coupled *) tricyclic ketones 5, 6, 7 and 8, but also to asymmetrically coupled compounds like 11. Compound 11 was reported to be prepared by Sveto-zarskli et al. (1959) by condensation of cyclohexanone at room temperature in the presence of solid sodium hydroxide as the catalyst, and subsequent dehydration ofthe
intermediate, which was supposed to be the dihydroxy ketone 9, under relatively mild conditions.
NaOH H - 2 H2O -H2O
The structure of 11 was assumed by Svetozarskli on the basis o f t h e molecular compo-sition CigHjjO, its UV spectrum ( A „ „ 263 my., e „ „ 13,500 in diethyl ether) and the fact that 11 could be converted into 12 by further dehydration under more extreme conditions.
In a later publication by the same group of workers (Razuvaev et al., 1961) structure 10 was proposed for the initial condensation product C,gH3o03 instead of the open structure 9.
This conclusion was based on the infrared spectrum o f t h e compound, which showed no absorption in the carbonyl region, while at 3507 c m - ' (hydrogen-bonded hydroxyl) an absorption band was observed. When the measurements were repeated in the present work, this band was not found but instead of it two bands were visible in the O—H stretch region, viz. at 3590 cm-' and 3520 c m - ' , the ratio of which did not change on dilution, thus indicating the presence of a free and an intramolecularly bonded hydroxyl group (Be//amy, 1958). This different observation, however, only confirms the conclusions o f t h e Russian authors, because the 1,3-diol structure in 10 can be expected to contain a free as well as an intramolecularly bonded hydroxyl group (when the OH groups have the cis-configuration) (Rao, 1963).
Dehydration of 10 yielded a product whose melting point and ultraviolet spectrum were identical to those of the compound obtained by the above-mentioned authors and for which they had proposed the structure 11. When in the present work this product was analyzed by TLC, however, it was shown to be a mixture of two com-pounds that could not be separated by column chromatography. The infrared spectrum of this mixture shows peaks at 1660 cm-' (w) and 1640 cm-' (m). These frequencies are too low to be caused by a conjugated ketone. As there is no other absorption in the carbonyl region, it is unlikely that the product obtained by dehydration of 10 has
the open structure 11. It ts more probable that the pyran ring is retained, so that a mixture ofthe following products is formed:
•o
CX^
cxP
14 15
The conjugated enol ethers in these structures may cause the above-mentioned absorption in the infrared. In consequence ofthe unusual skeleton no simple rules for calculating absorption maxima in the ultraviolet spectrum of the above compounds can be found in order to make a comparison with the observed value. It appeared, however, that the solvent dependence o f t h e absorption maximum in the ultraviolet spectra of this product is very low, which suggests a diene structure (Scott, 1964). As the NMR spectrum only shows "0.6 vinylic protons", the dehydration product probably is a mixture of about 40% of 13 and 60% of H or 16. Hydrogenation of this mixture leads t o several compounds, as is shown by TLC. Three of them were isolated by column chromatography. Their molecular composition is CjgHjgO and they show almost the same infrared spectrum. In their NMR spectrum a signal of one proton is found, which is ascribed to the proton next to a C—O bond (—CH—O). These three compounds probably are stereoisomers having the following structure:
The above-mentioned facts cannot be accounted for if the dehydration product (CigH^jO) has the open structure 11.
Summarizing, it would seem that this product is a mixture of 13 and isomers. Further work will be necessary, however, to give a complete description of this mixture.
Asymmetrically coupled compounds from azeotropic condensation
The asymmetrically coupled compounds are not expected to be formed under the conditions ofthe azeotropic condensation as described above. Firstly, it was found by Razuvaev et al. (1961) that the yield ofthe coupling product 10 greatly diminishes when the condensation is performed at elevated temperatures. At 50°, for example, only 2 % of 10 is obtained, while at 7-10° the yield is 75%. It must therefore be expected
that little or no 10 will be formed at the temperature ofthe azeotropic condensation (130°). Secondly, it is shown in Fig. 1.5 that compound 10 is converted into symmetri-cally coupled products under the conditions ofthe azeotropic condensation.
In accordance with this neither the above-described asymmetrically coupled com-pounds nor sym. dodecahydrotriphenylene (12), formed by dehydraton of "11", have been found by GLC in the azeotropic condensation of cyclohexanone.
1.4 EXPERIMENTAL DETAILS
The thin-layer chromatograms discussed in this chapter were made on silica gel GFj54 (Merck, Darm-stadt). Unless otherwise mentioned, benzene was used as the eluant. The spots were made visible by irradiation with UV-light and coloured afterwards with phosphomolybdic acid.
Melting points were determined under a Leitz melting point microscope and are uncorrected. Infrared spectra were recorded using a Perkin-Elmer 221 spectrophotometer; unless otherwise stated, they were taken In carbon tetrachloride. NMR spectra were produced on a Varian A-60 spectro-meter using tetramethyl silane as internal standard. Ultraviolet spectra were recorded by a Beekman D K 24 spectrophotometer.
Microanalyses were carried out by Mr. W . J . Buis and Mr. H. Pieters, Organic-Chemical Laboratory o f t h e University of Amsterdam and by Mr. G. H. Holtslag, Analytical Department o f t h e Central Research Institute of A K U .
Azeotropic condensation of cyclohexanone
1963 g cyclohexanone, 800 ml toluene and 30 g K O H were refluxed in a 5 I reaction vessel equipped with a water-cooled Dean-Stark apparatus, a thermometer and a device for taking samples from the reaction mixture without interrupting the reaction. During the reaction the temperatures in the vessel rose from 130°to139°. The contents of the vessel were analyzed by TLC. A photo of the chromatogram showing the course ofthe reaction Is given in Fig. 1.2. Fig. 1.3 shows a chromatogram made to identify the components o f t h e condensation mixture.
After a reaction time of 13 hours the red-brown reaction mixture was neutralized by extracting the K O H with water. It appeared that several extractions were necessary to remove the K O H completely. The neutral mixture was distilled under reduced pressure, giving the following fractions:
1 . bicyclic ketones 393 g (22%), b.p. 8 6 - 9 7 ° / 0 . 5 - 0 . 6 mm 2. 18 g b.p. 109-138°/0.2 mm 3. tricyclic ketones 1172 g (68%), b.p. 137-142°/0.1-0.2 mm 4. 17 g b.p. 146-153°/0.3 mm 5. residue 54 g
In another experiment 892 g cyclohexanone was condensed under the same conditions. This time the reaction was followed by measurement of the water formed during the reaction and by gas-liquid chromatography (GLC) o f t h e volatile components o f t h e reaction mixture, viz. cyclohexanone, the combined bicyclic and the combined tricyclic compounds, and traces of three unidentified products. The results of these measurements are shown in Fig. 1.1.
The bicyclic ketone distillation fraction is a colourless liquid. TLC (with methylene chloride as sol-vent) shows that it is composed of compounds 3 and 4. The ultraviolet spectrum of the mixture has Amax (methanol) 254 mfx, with an "£max" of 900, indicating the presence of 1 3 % of 3 and 8 7 % of 4. In the NMR spectrum ofthe mixture "0.86 protons" are found at ö 5.4 ppm,corresponding w i t h 8 6 % o f 4 . The tricyclic ketone fraction is a very viscous yellow liquid which partly crystallizes on standing. Microanalysis of the fraction gave C 83.4%, H 10.2%. Calculated for C^H^.O : C 83.65%, H 10.16%. TLC shows that the fraction mainly consists of compounds 5, 6, 7 and 8 (Fig. 1.6). This qualitative ob-servation was completed by a quantitative measurement using the chromatographic technique
des-cribed in the Appendix. The results of these measurements are summarized in Table 1.2. An infrared spectrum o f t h e tricyclic ketone distillation fraction shows bands at 1710 c m - ' (non-conjugated carbonyl) and 1680 c m - ' (conjugated carbonyl); at 1660 c m - ' ( a , ^ - a ' , jS'-conjugated carbonyl) a very weak absorption (shoulder) is found.
Isolation of reaction products
2-{cyc\ohexen-i-yi}cyclohexanone (i)
A 5 0 % solution o f t h e bicyclic ketone distillation fraction in petroleum ether 40-60° was kept at -20°. The crystals which had formed after some days were used to initiate crystallization in more dilute solutions. After crystallization, the supernatant liquid was rapidly decanted and the residue was dis-solved in afresh portion of the solvent. This procedure was repeated ten times. It was then found that the shoulder in the UV spectrum at 254 m(x (methanol) had completely disappeared; the compound showed only one spot on TLC (methylene chloride); n ^ 1.5056. The m.p., determined in a test tube with the thermometer in the material, was 9°. Calculated for C , j H „ 0 : C 80.83, H 10.20%. Found: C 80.8, H 10.2. Amax (methanol) 291m[i (46). Amax (cyclohexane) 298 m(i (37). IR: See Fig. 1.7a. NMR (CCI4) : 1 proton at ö 5.4 ppm ( - C = C H - ) , 1 proton at d 2.8ppm ( - C = C - C H - C = 0 ) .
Cis-2,6-di(cYclohexen-1-yl)cYclohexanone (8)
As mentioned above, the yellow tricyclic ketone fraction slowly crystallizes on standing. After some days the crystals were separated by a laborious filtration process. Three crystallizations from methanol gave colourless crystals, m.p. 79.5-80°. Lit. (Mleziva, 1953) 79°. Amax (methanol) 290 my. (50), Amax (cyclohexane) 297 my. (50). IR: See Fig. 1.7b. NMR (CSj) : 2 protons at d 5.4 ppm ( - C = C H ) and 2 protons at S 2.6-3.0 ppm ( - C = C - C H - C O ) .
2,6-dicyclohexylidenecyclohexanone (5)
After compound Ö had been filtered from the tricyclic ketone fraction as described above, another crystallization occurred in the clear yellow filtrate. The crystals were filtered off, washed with methanol at room temperature and dissolved in boiling methanol. On cooling a small amount of colourless crystals, m.p. 130-134°, was obtained. Comparison ofthe infrared spectra proved this compound to be identical with 2,6-dicyclohexylidenecyclohexanone, prepared according to Munk and Plesek (1957). Amax (methanol) 285 my (13,500), Amax (cyclohexane) 277 m^ (14,400). IR: See Fig. 1.7e. NMR ( C C g :
No absorption at fields lower than S 2.7 ppm (no vinyl protons).
Trans-2,6-di(cYclohexen-1-yl)cyclohexanone (7)
Preliminary experiments showed that the components of the tricyclic ketone fraction can only be separated by chromatography on a relatively large amount of silica. It was also found that, on a very active silica, isomerlzatlon takes place, as could be seen from TLC o f t h e eluted fractions. The silica, therefore, was deactivated somewhat and the elution was accomplished with a high speed. The column was filled with 900 g silica gel 0.05-0.2 mm (Merck, Darmstadt) suspended in ethyl acetate. The ethyl acetate was replaced by a mixture of petroleum ether 40-60°/ethyl acetate (99/1 v/v); 0.9 g of a mix-ture o f t h e tricyclic ketones was applied (0.1%) and eluted with the petroleum ether/ethyl acetate mixture at a rate of about 5 ml/min. 200 mg of 7 (colourless oil) was obtained. Calculated for C , j H j j O : C 83.65%, H 10.16%. Found: C 83.5%, H 10.2%. Amax (methanol) 299 my (180), Amax (cyclohexane) 301 my (155). IR: See Fig. 1.7c. NMR (CSj): 2 protons at 6 5.5 ppm ( - C = C H ) , 2 protons between 2.7-3.0 ppm (C = C - C H - C = 0 ) .
2-(cyclohexen-1 -yl)-6-cyclohexylidenecyclohexanone (6)
During the chromatographic separation of compound 7 described above also fractions containing only compound 6 were eluted. 116 mg colourless crystals wasobtained, m.p. 37-39°. Calculated for C , , H j 4 0 :
3000 2500
Fig. 1.7a Infrared spertrum of 4 (CCIJ
1500 40
O^rt)
8 0 b _ i I 1 1 i__i L _i I L 3000 2500 2000Fig. 1.7b Infrared spectrum of 8 (CCIJ
1500
1000
• frequency (cnr^)
_L _j 1 i_ J i_ _J 1 L_ _1 I 1 I L.
3000 2500 2000 FIg. 1.7d Infrared spectrum of 3 (CCIJ
100
o
-(y&o
j I I 1 - _i I L _ i 1 I I 1 I 1 1 I I I I 1 1 1
-3000 2500 FIg. 1.7e Infrared spectrum of 5 (CCIJ
1000 100
OT^O
1500 I . I 1 _ 1000 — » - fret^uency (cm-^)C 83.65%, H 10.16%. F o u n d : C 83.6%, H 1 0 . 1 % . Amax (methanol) 256 mjj. (9200), Amax (cyclohexane) 249 my (6100). IR: See Fig. 1.7 f. NMR (CCI^): 1 p r o t o n at d 5.4 ppm ( - C = C H ) . Signals at <5 2.8 (not completely separated).
Isolation of the "Spot H" and "Spot / " products
1.3 g of a m i x t u r e of tricyclic ketones was separated on 260 g silica gel using benzene as eluant. The first fraction contained 16 mg of the " S p o t I " products, t h e infrared spectrum of which shows, in ad-dition t o the C-H stretching bands, absorption maxima at 3035, 1692 and 1645 c m - ' , ascribed t o , respectively, t h e C = C - H , conjugated carbonyl and C = C groups. The second fraction consisted o f 7 mg of the " S p o t H " product. In the infrared spectrum of this product maxima were found at 3050 c m - ' ( C = C - H ) , 2934 and 2856 c m - ' ( C - H ) , and 1712 c m - ' (non-conjugated carbonyl).
Isolation ofthe "Spot S" products
2.0 g o f t h e neutralized reaction m i x t u r e of an alkali-catalyzed azeotropic cyclohexanone condensation was chromatographed on 30 g basic alumina (Fluka), benzene being used as eluant. T w o narrow yellow bands appeared r i g h t at the t o p o f t h e column. After the o t h e r components had been washed o u t w i t h benzene, the yellow products were extracted w i t h acetone. The solvent was evaporated under reduced pressure and 100 mg (5%) o f t h e yellow products was obtained. The infrared spectrum o f t h e " S p o t S" m i x t u r e shows a broad absorption maximum at 3470 c m - ' , assigned t o an associated O H - g r o u p , and three bands in the carbonyl stretching r e g i o n , viz. at 1756,1710and 1680 c m - ' , suggesting the presence o f t h r e e different carbonyl groups in t h e m i x t u r e .
Reference compounds
2-cyclohexYlidenecYclohexanone (3)
Compound 3 was prepared according t o Reese (1942) by elimination of hydrogen chloride f r o m 2-(1-chlorocyclohexyl)cyclohexanone (1) w i t h sodium methoxide at low temperature. Colourless crystals w e r e obtained; yield 5 3 % , m.p. 56-57.5. Lit. (Reese, 1942) m.p. 57°.
O n a thin-layer chromatogram (silica gel/methylene chloride, the only system that separates the iso-meric compounds 3 and 4) this product gives only one spot. Amax (methanol) 254 my (7100), Amax (cyclohexane) 2i7 my (8000). IR: See Fig. 1.7d. NMR ( C C I J : N o absorption at fields higher than
Ó 2.6 ppm (no vinyl protons).
2,6-dicYclohexylidenecyclohexanone (5)
This compound was synthesized according t o Munk and P/esek (1957). A m i x t u r e of tricyclic ketones was dissolved in acetic acid and saturated w i t h hydrochloric acid. The precipitate was dehydrochlori-nated w i t h sodium methoxide in an ethanol/benzene m i x t u r e . Colourless crystals, m.p. 142-143°, were obtained. Lit. 144.5-146.5 (Munk and Plesek, 1957). The UV-spectrum of 5 in the paper of Munk and P/esek shows a shoulder at 350 my. In the UV spectrum o f t h e recrystallized material this shoulder is absent. The crystals are colourless and not yellow as reported by Munk dan Plesek.
2-(1-hydroxYcyclohexyl)cyclohexanone (2)
Synthesis from cyclohexanone, using KOH as the catalyst. 200 g cyclohexanone and lO.Og powdered
potassium hydroxide (0.18 moles) w e r e mixed while cooling w i t h tap water. The m i x t u r e was stirred for 45 minutes at room t e m p e r a t u r e , 150 ml benzene was added and the solution was washed neutral w i t h water. The benzene and cyclohexanone were evaporated at a pressure of 2 m m . The residue (38 g, 0.19 moles) crystallized on cooling. It was recrystallized f r o m petroleum ether 40-60°, giving colourless crystals w i t h a m.p. of 32-33°. The melting point could be raised neither b y f u r t h e r crystalli-zations nor by distillation. This distillation was carried o u t at 0.1 mm in an apparatus originally designed for vacuum sublimation, the heating bath being kept at 45° and the receiver at —20°, thus minimizing
dehydration ofthe ketol. Calculated for C „ H j „ 0 : C 73.41%, H 10.29%, O 16.30%. Found: C 73.5%, H 1 0 . 2 % , O 16.4%. Amax (methanol) 290 mfjt (21), Amax (cyclohexane) 295 m(j. (31). IR: maxima at 3 5 2 8 c m - ' (H-bonded O - H ) , 1 6 9 5 c m - ' (H-bonded carbonyl). NMR ( C C I J : singlet (1 proton) at
Ö 3.2 ppm ( O H ) , disappearing on protonation with trifluoroacetic acid.
Synthesis from cyclohexanone using N-methyl aniline magnesium bromide. The synthesis was performed
according to Cologne (1934). Asolution of 35 g N-methyl aniline in 100 ml benzene was added dropwise to a solution of a Grignard compound made from 9 g magnesium turnings and 50 g ethyl bromide in 120 ml ether. The solution thus obtained was added dropwise to a stirred solution of 66 g cyclo-hexanone in 50 ml benzene at 20-30°. The reaction mixture was treated with ammonium chloride, washed neutral with water and distilled under reduced pressure; b.p. 117-120°/2-3 mm. It was shown by TLC that in addition to 2 also cyclohexanone, 3 and 4 were present in the slightly yellow distillate. Crystallization from petroleum ether 40-60° gave 13.0 g of colourless crystals, m.p. 32-33°. Lit. 56° (Co/ogne, 1934). judging from TLC the compound was pure. The infrared spectrum showed it to be identical with the product which had been prepared by condensation of cyclohexanone, as described above. A mixed melting point of the two samples did not show a depression. The oxime of 2 has a m.p. of 114.3-114.7. Lit. 113° {Cologne, 1934).
Sym. dodecahydrotriphenylene (12)
This compound was prepared from cyclohexanone and sulfuric acid in boiling methanol according to
Mannich (1907). The compound has a m.p. of 232-232.5°. Lit. 232-233° (Mannich, 1907). Asymmetric condensation products
Synthesis of 10 by low-temperature condensation of cyclohexanone
The asymmetric condensation product 10 {Svetozarskli et al., 1959, Razuvaev, 1961) was obtained by keeping a mixture of 200 g cyclohexanone and 20 g powdered sodium hydroxide at 0° for 72 h, with occasional stirring. The gel thus formed was washed with water until neutral and crystallized by the addition of methanol, yielding 141 g (71%) of crystalline product. 40 g of it was recrystallized from 1 I benzene. It was observed that the melting point ofthe recrystallized product depends on the rate of heating o f t h e samples. Slowly heated it melts at 173-174°. (Lit. 175°) but when the sample is brought into a Gallenkamp melting point apparatus that has been preheated to 165° and then quickly heated, the m.p. is 191°. This may be due to the easy dehydration ofthe compound.
It appeared that compound 10 decomposes on silica gel thin layers to products with a higher as well as to products with a lower Rp than 10. This decomposition can be avoided by introducing a small amount of gaseous ammonia into the elution vessel. Using benzene/methanol 5/1 v/v as the eluant, the recrys-tallized product then gives only one spot on the thin-layer. Calculated for C,8H3o03 : C 7 3 . 4 1 % , H 10.29%. Found:C 73.7%, H 10.2%. IR: (CSJ 3590 c m - ' ( f r e e O H ) and 3520 c m - ' (intramolecularly bonded O H ) . 2935 and 2855 c m - ' ( C - H ) . N o absorption was found in the carbonyl region.
Dehydration of compound 10
Several attempts to prepare the crystalline compound 11 by dehydrating 10 according to the methods described in the literature (Svetozarskli, 1959) were unsuccessful because o f t h e reluctance o f t h e ma-terial to crystallize. Crystalline mama-terial could be prepared as follows. Asolution of 6 g of 10 and 20 ml concentrated sulfuric acid in 300 ml methanol was refluxed for 10 minutes. The clear red solution was poured on ice, taken up in ether and neutralized, after which the solvents were evaporated under re-duced pressure. The remaining light-yellow oil was dissolved in a few ml petroleum ether 40-60°. Cooling to -30° gave 1.5 g of colourless crystals (29%). After two more recrystallizations from petro-leum ether 40-60° the m.p. was 43-45°. Lit. 44° (Svetozarsk//, 1959). Calculated for CjaHj^O : C 83.65%, H 10.16%. Found: C 8 3 . 6 % , H 1 0 . 1 % .
By TLC on silica gel/petroleum ether 40-60° (when benzene is used as the eluant only one spot is obtained on the thin-layer chromatogram) it appeared that the product consists of a mixture of two
compounds.Judging from the identical Rp-vaiueson thin-layer chromatograms,these compounds were also obtained when the reaction was carried out according to Svetozarskli (1959). An attempt to separate the mixture by column chromatography (1.8 g on 200 g silica gel 0.2-0.5 mm) was unsuccessful. The spectroscopic data of the mixture are as follows: Amax (ether) 263 my (12,800) shoulders at 257, 273 and 295 my, Amax (cyclohexane) 263 my (12,900) shoulders at 257, 273 and 295 my, Amax (methanol) 260 my (12,200) shoulders at 271 and 295 my. IR: 2930, 2855 and 2832 c m - ' ( C - H ) , 1660 c m - ' (w) and 1640 c m - ' (s). NMR ( C C I J : "0.6 protons" at 5.4 ppm.
Hydrogenation of "compound 11"
The starting material was prepared in advance by dehydration of 10 with concentrated sulfuric acid according t o Svetozarskii (1959). It was used without further purification. A mixture of 26 g of 10 and 20 ml of concentrated sulfuric acid was kept at room temperature for 16 hours, poured into water and extracted with petroleum ether 40-60°. The extract was washed neutral and dried. The volume was increased to 500 ml by addition of petroleum ether. 125 mg of 1 0 % platinum on carbon was added and the whole was hydrogenated at atmospheric pressure. About 4.5 I of hydrogen was taken up. After the catalyst was filtered off, TLC showed that the reaction mixture consisted of several components which could not be separated by vacuum distillation (b.p. 88°/0.05 mm). 2.0 g of the distillate was chromatographed on 225 g silica gel in a multibore column according to Fischer and Kabara (1964), with petroleum ether 40-60° as the eluant. Three major fractions were eluted: A. 105 mg colourless crystals, m.p. 60-61°. Calculated for Ct.HjoO : C 82.36%, H 11.54%. Found:
C 8 2 . 3 % , H 1 1 . 6 % ;
B. 251 mg of a colourless viscous liquid. Found: C 82.6%, H 11.6%; C. 358 mg of a colourless semi-solid product. Found: C 82.5%, H 11.4%.
There is a great resemblance between the infrared spectra of these three com pounds.They show maxima at 2935 and 2850 c m - ' ( C - H stretching), 1445 c m - ' ( C - H deformations) and also strong bands at 1040 and 1015 cm"'. One of these last bands-and possibly b o t h - c a n be ascribed to C - O stretching. In the NMR spectra ( C C I J of all the three compounds the absorption of 1 proton was found at <5 3.7-3.8 ppm ( C - C H - O R ) .
Azeotropic dehydration of dihydroxy ketone 10
The dehydration of 10 under the conditions o f t h e azeotropic condensation of cyclohexanone was accomplished as follows: 98 g of 10, 450 ml toluene and 1.5 g K O H were refluxed in a l I reaction vessel equipped with a DeanStark apparatus. Initially no water was collerted, problaby due to the low t e m -perature (114°) in the reaction vessel, which was caused by the great excess of toluene necessary to dissolve the dihydroxy ketone. During the removal ofthe excess toluene the temperature in the vessel slowly rose to 127° and water separated in the distillate. After 2 hours, 350 ml toluene and 8 ml water were collected, the temperature in the reartion vessel being 127°. During the reaction samples were drawn, which were analyzed by TLC. A photograph ofthe thin-layer chromatogram is shown in Fig. 1.5.
Gas-liquid chromatography
Two columns were applied in the gas chromatography mentioned in this chapter. Column A was used to analyze the course of the azeotropic condensation of cyclohexanone. Column B was used to ascertain the presence of compounds 10, 12 and 13 in the condensation mixture, distillation frartions and distillation residue.
The conditions of the analyses are summarized in the following table: Column A Column B Apparatus Detection Column Stationary phase Solid support Carrier gas Column temperature Injertor temperature Detector temperature F & M 810 Flame ionization 1 m ; ' / / ' ; S S 1 0 % Carbowax 20 M; 5 % K O H Gaschrom Z 60/70 N j ; 45 ml/min 40-220° at 10°/min 235° 340° Aerograph 1520 Flame ionization 2 m ; ' / / ' ; S S
2 0 % GE X E ; 60 silicone gum (nitriie) Gaschrom Z 60/70
N j ; 45 ml/min 200°
260° 240°
Under these conditions compound 2 is instantaneously converted into cyclohexanone, while com-pound 10 is dehydrated to 13 (and isomers).
Chapter 2
ISOMERIZATION OF SOME OF THE
CYCLOHEXANONE CONDENSATION PRODUCTS *)
2.1 INTRODUCTION
It was found in Chapter 1 that the azeotropic KOH-catalyzed condensation of cyclo-hexanone can yield a mixture o f t h e unsaturated tricyclic ketones 5, 6, 7 and 8. The main purpose o f t h e experiments to be described in the present chapter was to effect the isomerlzatlon of these tricyclic ketones to the isomeric compound 2,6-dicyclo-hexylphenol (37).
It is known from the literature that several unsaturated alicyclic ketones can be isomerized to the isomeric phenols (Horning, 1943). An example of these reactions is the conversion of carvone to carvacrol (Linstead et al., 1940).
OH
CH3
Even more closely related to the reaction system discussed is the isomerlzatlon of 2,6-dibenzalcyclohexanone to 2,6-dibenzylphenol (Horning, 1945; Weiss and Ebert, 1935).
Isomerizations of unsaturated compounds are known to take place under widely different conditions. They can be effected, e.g., by acids, bases, heat treatment, irra-diation, halogens (with or without photochemical activation) and by metals, salts or complexes or Group VIM or the periodic table (Asinger and Fell, 1966 a).
The experiments to be described in this chapter were restricted, however, t o some acid-, base- and transition-metal-catalyzed reactions, and to the thermal isomerlzatlon ofthe tricyclic ketones.
The metal-catalyzed reaction was expected to be of particular interest, as it might give useful information about the initial stage of the dehydrogenation of the tricyclic ketones, which is also effected by transition-metal catalysts, although at a higher temperature (Chapter 3). For this reason the palladium-catalyzed reactions of
*) The formulas of the compounds to be discussed in this chapter can be found on the back-cover foldout.
CM l o m o o w m T- n o
Jill ••:!!
0°CrO' CrCxQ^ Crö-Q' Cr<X)s
1 h 25 h 49 h 1 h 25 h 49 h 1 h 25 h 49 h 1 h 25 h 49 h
Fig. 2.2 isomerlzatlon o f t h e tricyclic ketones catalyzed by potassium methoxide at 20°
• H • •
m •
#
30 3 8 24 6
min hours hours hours days 30 3 8 24 6 min hours hours hours days
• 8 , 7 • 6 • 5
0 & ^
• • • •
30 3 8 24 6min hours hours hours days
30 3 8 24 6 min hours hours hours days
n • • •
•
A:s^ ö. 30 U
i(-''
1 Peak' ' ' '
No. 1 1__^.-""^
1—
23 and 24 30 20 10-/
i / Peak No. 2 ~^*^- — ~~*~ " ~ ~ ~ ~ - — - ^ I I I and isomers 29. 30. 31 and 32 and isomers 5, 6, 7 and 8 30 20 10 Peak No. 4-"""'"''*"
y ^ , , , 1
OÓTQ)
25 and 2b reaccion time ( h )unidentified products OH 38 unidentified products
on no,
27 and 28 OH 37 OHconènoj
39 -^ reaction time (h)Fig. 2.^ Formation of products during the reactions of 5 (full lines) and 8 (broken lines) with palladium on carbon, as shown by GLC
Peak Nos. « » ^
•
i
a. Reaction t i m e : 2 min Peak Nos.ê
b. Reaction t i m e : 45 minj*J-'7>^ï-'.ïï:V.*-'"»\'*".*''IN 1 2 3
«P
m0^
m
4 5 6 7•
«r
8 9 • • 104
m
1}
c. Reaction time: 2 h _ 1 2 3 4 5 6 7 8 9 10 " Peak N o s ,l li
k J
\pM,K
Peak N o s . 7 2b 34 > 33 >d. Identification of reaction products
Fig. 2.5 Chromatograms obtained by the combined GLC-TLC-technique during the palladium-catalyzed reaction of 8
two ofthe tricyclic ketones were investigated in more detail with the aid of a com-bined GLC-TLC-technique, which will be described in this chapter. In addition a comparison was made between the catalytic activity of platinum and that of palladium in these reactions.
2.2 RESULTS
Thermal Isomerlzatlon of the tricyclic ketones 5 and 8 was accomplished at 200° in a nitrogen atmosphere. The reaction was followed on thin-layer chromatograms, photos of which are shown in Fig. 2.1. From these it can be seen that under the conditions of thermal isomerlzatlon the compounds 5 and 8 are converted into a mixture of tricyclic compounds that strongly resembles the mixture of tricyclic ketones obtained on distillation o f t h e condensation product (Fig. 1.6). In both cases compound 6 appears to be the first product to be formed from the starting material.
The base-catalyzed isomerlzatlon of 5, 6, 7 and 8 was effected at 20° in a 0.14 molar solution of potassium methoxide in methanol. The thin-layer chromatograms of these experiments are shown in Fig. 2.2. It can be seen that there is a rather slow conversion of the compounds 5 and 6 into the other tricyclic ketones (and some unidentified compounds). Just as in the thermal isomerlzatlon compound 6 appears t o be the inter-mediate product; 7 and 8 are interconverted rapidly without an interinter-mediate. The acid-catalyzed isomerlzatlon of 5, 6, 7 and 8 was accomplished in a solution of hydrogen chloride in chloroform/ether at 20°. The results are shown in Fig. 2.3. As can be seen, 6 is initially converted into 8, 5 is converted into 6 and later also into 8, while 7 is converted directly into 8. The reverse reaction, viz. the isomerlzatlon of 8 to 7, is much slower and possibly goes via 6 as the intermediate. It appears that after a reaction time of six days equilibrium has not yet been attained.
It can be seen from the photos that the thermal, the acid-catalyzed and the base-catalyzed isomerlzatlon do not yield more than a trace of 2,6-dicyclohexylphenol (37), for this compound has an Rp-value which is higher than that of 8 (see Fig. 2.5). A com-pound with such a high Rp-value is found only in Fig. 2.1, and there merely in traces.
The acid-catalyzed isomerlzatlon can be used for the preparation of compound 8, as is shown by the fact that from a mixture o f t h e tricyclic ketones 5, 6, 7 and 8, dis-solved in methanol and treated with hydrogen chloride, more 8 crystallizes than was present in the original mixture (yield 82%, m.p. 75-79°).
Quite different results are obtained in isomerlzatlon experiments made with palladium or platinum as the catalyst. Fig. 2.4 shows the course ofthe isomerlzatlon ofthe tricyclic ketones 5 and 8 in boiling methylcyclohexane (100°) and catalyzed by palladium on carbon. The reaction was followed by means of a combined GLC-TLC-analysis, which will be described in the next section of this chapter. It appears from the graphs that
70% of 5 is converted by simple double-bond shifts into its isomer 2,6-dicyclohexyl-phenol (37). The remaining 30% is converted into a number of other 2,6-disubstituted cyclohexanones and phenols. When 8 is the starting material, it is almost completely converted into these compounds, viz. cis- and trans-2-(cyclohexen-1-yl)-6-cyclohexyl-cyclohexanone (29 and 30), 2,6-dicyclohexyltrans-2-(cyclohexen-1-yl)-6-cyclohexyl-cyclohexanone (23 and 24), phenyl-6-cyclohexylcyclohexanone (25 and 26), 2,6-diphenylcyclohexanone (27 and 28), 2-phenyl-6-cyclohexylphenol (38) and 2,6-diphenylphenol (39).
The formation of aromatic rings in a number of these products cannot be entirely due to dehydrogenation, for, as can be seen from Fig. 2.6, the amount of hydrogen evolved during the isomerlzatlon reaction is insufficient to account for all the aromatic products. A part of these aromatic compounds must result from disproportionation of cyclo-hexenyl rings.
Palladium on carbon is a more active catalyst for this disproportionation reaction than
moles o f hydrogen evolved „ » moles of tricyclic ketone
40 20
•^
isomerliation of S ^ — — ~ --'^ ^•^ Isomerlzation of 5 —•- time (h)Fig. 2.6 Evolution of hydrogen in the palladium-catalyzed isomerization
- time (h)
