TECHNICAL REVIEW
Cyclohexanone Chlorination Products Eugene C. Gilbert,* Robert E. Jones, Donald C. McLean, and Edward Sherman
Eugene C.
nwr Groul Chemicals tion, Che The Quak ny, Barrin ceived his selm's Cot his Ph.D. 1 After a year or postdoctoral study at tne Jonns H O P kins University, he joined the research staff of The Quaker Oats Company in 1970. His interests lie in the areas of synthesis and characterization of novel mo'nomers and stabilizers for polymer systems as well as the study of structure-property relationships of plastics and elastomers. He is a member of The American Chemical Society and SigmaXi.
If
Y'echnology (1953). His current interests are in the area of synthesis and characterization of chemical intermediates and stabilizers. He is a member of The American Chemical Society.
I
Robert E. Joi ciate Director and Developm, cals Diuision, Oats Company, 111. He receiveu l l L o ".__ degree from Cornell College, Iowa, in 1942, and his M.S. and Ph.D. deerees in orpanic chemistrv from the Uniuersity of I l l k ~ ~in i s 1943 and 1945. H l is the author or coauthor of several publications on varying aspects of organic synthesis and is inventor or coinuentor of 30 issued U.S. patents. Current interests are inuolued with broad chemical opportunities in the foundry and applied industries. Jones is a member of AAAS, Sigma Xi, and The American Chemical Society.
2
Ind. Eng. Chern.. Prod. Res. Dev., VoI. 14. No. 1, 1975
vi
".
is Man.' ager, Planning and Admin- ,,',~''"{ istration, for the Chemical ' Research and Development Department of the Chemicals Division, The Quaker Oats Company, Barrington, Ill. He studied at the University of Illinois (B.S., 1940), Lehigh University (M.S., 1947; Ph.D., 1949), and Northwestern University (M.B.A., 1970). He joined The Quaker Oats Company in 1949 after seruing for one year as a postdoctoral fellow at Illinois Institute of Technology. He is the author or coauthor o f a number of papers and encyclopedic articles and the inventor or coinventor of numerous issued US.and foreign patents. Dr. Sherman is a member of The American Chemical Society, the Society of the Sigma Xi, Delta Mu Delta, and is a fellow of the American Association for the Advancement of Science. Edward Sherman
I
Syntheses have been devised which afford both 2,2,6-trichloro- (V) and 2,2,6,6-tetrachlorocyclohexanone ( V I ) in excellent yield (90 and 99%, respectively) from chlorination of cyclohexanone ( I ) in “neat” systems in t h e presence of certain nitrogen-containing catalysts (or their salts). Compound V I , which was first prepared by Hassel and Lunde (1950), is a very stable material; V, a novel intermediate, is of moderate stability. T h e observed data argue strongly against a simple mechanism for chlorination in t h e presence of nitrogen-containing catalysts or their salts. T h e reactions of V and V I are potentially wide-ranging from both a theoretical and practical viewpoint. T h e derivatives most easily obtained from these chlorinated ketones (90% yield) are isomerically pure o-chlorophenol (VI I ) and 2,6-dichlorophenol ( V I I I ) , respectively.
Introduction As part of a broader program, we recently undertook research on the chemistry of cyclohexanone, and this paper treats mainly the novel processes for its halogenation to a-chlorinated ketones and subsequent thermolysis of these intermediates to isomerically pure o-chlorophenols. More specifically, the work presented outlines the most convenient and economical methods presently available for preparation of both 2,2,6-trichloro- and 2,2,6,6-tetrachlorocyclohexanone, as well as the routes of choice for synthesis of isomerically pure o-chlorophenol and 2,6-dichlorophenol via dehydrochlorination of the respective ketones. Historical Preparation of a-substituted mono, di-, and tetrachlorinated cyclohexanones has been previously described in the literature (34, 41, 4 2 ) . 2,2,6-Trichlorocyclohexanone (V) is a new chemical compound. 2,2,6,6-Tetrachlorocyclohexanone (VI) was first synthesized (but incorrectly characterized) by Hassel and Lunde (26) in 1950 uia chlorination of both cyclohexano1 and cyclohexanone in the presence of light. While the alcohol gave the desired material in fair yield (55%), chlorination of the ketone yielded copious amounts of sidereaction products. A process for the production of VI in about 60% yield uia ultraviolet irradiation of cyclohexanol in the presence of peroxide catalyst appeared in 1951; absolute assignment of structure for this suggested insecticide was not given, however (25). Correct structure proof for VI was first presented by Riemschneider and Rubner in 1953 (44, 45). Along a more independent vein, Corey and Burke (11) prepared VI via a chlorination-decarboxylation scheme using cyclohexanone-2,6-dicarboxylicacid as starting material. Lastly, in 1966, a process ( 2 ) for the preparation of VI in 85 to 90% yield from direct chlorination of cyclohexanol in inert solvent in the presence of an amine or amine salt catalyst and water appeared. This ketone is used today as an intermediate for the commercial preparation of 2,6-dichlorobenzonitrile, a herbicide more familiarly known under the trade name Casoron (38). Discussion
A. Synthesis of Chloroketones. 2,2,6-Trichlorocyclohexanone (V), a colorless liquid of moderate stability, was obtained in 90% yield via chlorination of cyclohexanone (19). The preparation of V was studied mainly as a function of catalyst, solvent, temperature, time, and mode of ketone addition. Highlights of this study are presented in Table I. From the data in Table I, it is seen that V was obtained in approximately 90% yield using the batch process, carboxylic acid solvent, and no added catalyst. Use of inert
solvent as partial or full replacement for carboxylic acid, however, significantly lowers the yield (incomplete conversion). High yields were also derived from incremental ketone addition in “neat” or inert solvent systems in the presence of an appropriate nitrogen-containing compound or its salt. When a nitrogen catalyst is used (“neat” or inert solvent system), incremental ketone addition is preferred because it essentially eliminates side reactions due to self-condensation of cyclohexanone. The batch process, on the other hand, is the method of choice in carboxylic acid solvent. Use of unduly high reaction temperatures in either the solvent or “neat” system diminishes the yield; V is consumed uia further reaction to produce VI. Depending on end-use, one may choose either system (presence or absence of added catalyst) to effect synthesis. Preparation of V in acetic acid is best if one wishes to isolate the ketone; on the other hand, the “neat” system, making use of an appropriate nitrogen catalyst, is preferred if subsequent thermolysis to o-chlorophenol (VII) is to be carried out, since the same catalyst used to foster chlorination can also be employed to effect dehydrochlorination as well. Preparation of VI was achieved in quantitative yield via chlorination of cyclohexanone (21). The white crystalline material obtained was very pure and quite stable ( > 2 years storage without change). A similar approach to that outlined above for V was carried out in our study of the preparation of VI. Highlights of this study are presented in Table 11. Incremental addition of ketone was found to be best in both solvent and “neat” systems. Unlike the preparation of V, both high temperature and catalyst were needed to introduce the fourth chlorine atom into the ring. All circumstances considered, the “neat” system is the preferred mode for synthesis of this compound. The necessity of an appropriate catalyst for the preparation of both chloroketones in good yield under “neat” or inert solvent conditions is clearly seen from the data in Table III. B . Reaction R a t e and Mechanism of Chloroketone Formation. The chlorination of cyclohexanone in acetic acid almost certainly occurs in a step-wise manner as indicated in Scheme I. The rate of chlorination slows up as one, two, and finally three chlorine atoms are introduced into the molecule at room temperature. We thus have the general kinetic scheme operating as shown in Scheme 11. The simplified Scheme I1 is based on the data in Tables I and I1 as well as on semiquantitative heat of reaction data observed in the preparation of V. (a) When incremental addition of I is employed, the reaction is always exothermic as long as the ketone feed is continued; when it is stopped, exothermicity ceases. (b) When 11 is used as starting material in place of I, the reaction is still exothermic, but slightly less than before. Again, when the ketone feed is stopped, exothermicity ceases. Ind. Eng. Chem., Prod. Res. Dev., Vol. 14, No. 1, 1975
3
Table II.2,2,6,6-Tetrachlorocyclohexanone(VI)
Table I. 2,2,6-Trichlorocyclohexanone(V) Preparative Study
Preparative Studya
Solvent
-
~~~
~
Temp, Mode of "C ketone addn
Yield, Catalyst
Solvent
Batcha ... 92 Incrementalb .. . 80 Batch' ... 60 Incrementalb Nitrogen 89 compoundd cc1, 2 5 Incrementalb Nitrogen 87 compoundd a All of cyclohexanone in pot at start of reaction. Cyclohexanone addition concurrent with chlorine feed; chlorine to ketone ratio equal to at least 3.5 throughout the course of the reaction. c 2,2,6Trichlorocyclohexanone used as its own solvent. E.g., collidine hydrochloride. HOAc 25 20 HOAc HOAc/CCl,, 1:l 25 "Neat"c 25
Ub
&.'/
IIIa,
\
I1
?cat., 2
0
V
Scheme I1
-
c1, L
k,
catalyst 1
C1,
fi
C12 -L (7'
E
Zti'C, HOAc; k , > k? > k ,
>>>
h,)
(c) Chlorination of I11 or IV in place of I exhibited essentially no exotherm under our conditions. (d) Very little VI (-2%) was formed a t room temperature (even in systems using nitrogen base catalyst) since heat (70-100°C) is needed to favor substantial introduction of the fourth chlorine atom. Because of the many chlorination reactions occurring simultaneously, the kinetics of such a multistep chlorination are quite complicated. Reproducible rate data were obtained, however, for the preparation of V in acetic acid (no added catalyst) as well as under neat conditions in the presence of collidine hydrochloride catalyst. (These data were obtained from the chlorination reactions with cyclohexanone after enough halogen had been added to ensure almost total conversion of the starting ketone to a t least the dichlorinated species.) The first-order data obtained (kv(H0Ac) = 6.00 x 10-5 sec-1 and kv("Neat," catalyst) = 1.18 x sec-I) indicate very little difference in rate between the two sets of reaction conditions. The mechanism of chlorination of ketones is significantly more complicated than was previously thought. For Ind. Eng. Chem., Prod. Res. Dev., Vol. 14, No. 1, 1975
Temp,"C
-
CataYield, lyst," g Product 96
25 None V 45 25 2 V 68 25 4 V 81 25 20 V 90 VI 15 CCl,, 240 mlc 75-80 None CCl,, 240 mlc 75-80 5 VI 55 CCl,, 240 mlc 75-80 10 VI 94 a Collidine hydrochloride. 100 g of 2,2,6-trichlorocyclohexanone (90% pure) used as solvent, two moles of cyclohexanone concurrently added with chlorine feed (700 g) over a period of 4 hr. CTwo moles of cyclohexanone concurrently added with chlorine feed (850 g) over a period of 5 hr.
IV
4
80-100
"Neat"b "Neat'Ib "Neat"b
u a = cis; h =trans.
C1,
Yield, %
Nitrogen 50 compoundb 80-100 Nitrogen 60 HOAc/CCl,, 1:l compoundb 80-100 Nitrogen 94 cc1, compound 80-100 Nitrogen 99 compoundb a Cyclohexanone addition concurrent with chlorine feed; chlorine to ketone ratio of at least 4.5 maintained throughout the course of the reaction. E.g., collidine hydrochloride. 2,2,6,6-Tetrachlorocyclohexanone serves as its own solvent. HOAc
Solvent
k,
Catalyst
Table 111. Yield of Chloroketones as a Function of Catalyst Concentration
Scheme Ia
c1,
Temp,"C
%
example, classical work on the chlorination of acetone led to the general belief that enolization occurs more readily a t nonhalogenated carbon atoms ( 2 4 ) . Though the conclusion is a bit tenuous, it is possible to predict from anomeric and conformational effects that cis-2,6-dichlorocyclohexanone (IIIa) should be the main dichloro intermediate formed from chlorination of cyclohexanone under our reaction conditions in acetic acid. Although IIIa was indeed isolated as the major isomer (>60%) in several cases; Caujolle and g u a n (8) have recently shown that under similar conditions, this thermodynamically more stable intermediate forms mainly from equilibration of the more kinetically favored 2,2-dichlorocyclohexanone(IV) rather than via direct chlorination of 2-chlorocyclohexanone (11) (see Scheme III). Further experimental results on our part bear them out on this point. One is thus led to the concluScheme I11
IIb
sion that either acetone and cyclohexanone are significantly different in their chlorination preference (perhaps due to conformational differences) or that the earlier work with acetone was erroneously based on isolation of the thermodynamically more stable 1,3-dichloroacetone formed via fast rearrangement of the kinetically more favored 1,l-dichloroacetone, An investigation of the earlier work on acetone chlorination has shown the latter actually to be the case (15, 4 3 ) . That the mechanism of chlorination is indeed quite complex and highly dependent on reaction conditions is even more evident from the recent work of Teo and Warnhoff (53) in which a novel concerted mechanism was postulated as competitively operating during the chlorination of cyclohexanone in aprotic nonpolar solvents. The independence of the reaction rate on the concentration of halogen under “neat” and acetic acid solvent conditions does not eliminate such a mechanism for the preparation of V or VI from either IIIa or b. (See Scheme IV.) Scheme IVa
-,
V
IIIa, b
0
VI
From a conformational standpoint (14), introduction of a third chlorine atom into the dichloroketone (IIIa) would be accompanied by both increased eclipsing and van der Waals strain (syn-axial interactions) (see Scheme V.) This would manifest itself in a significant rate reduction. Insertion of the fourth chlorine atom, while perhaps comparable on electronic grounds to introduction of the third one, is made significantly more difficult due to the presence of a greater steric interaction (14) in both chair conformations (2-syn-axial chlorine atoms). Compare the conformational equilibria shown in Scheme V. Scheme V C1-CI syn-axial interaction can be avoided
0
H+-41
Table IV. Catalyst Study: Preparation of VIa VI, % yield pK, ( I , 9, 1 6 )
Catalyst
Collidine; “21 salt 99; 99 7.45 Tetramethylurea 94 0.40 Dimethylacetamide 81 0.10 T r i -n-butylamine 72 9.93 Diethylaniline; HC1 salt 10; 3 6.56 Dimethylaniline 5 5.06 tert-Butylamine; HC1 salt 2; 1 10.68 a Reactions carried out in inert solvent (cyclohexane or carbon tetrachloride) at 80-90°C; incremental addition of cyclohexanone concurrent with chlorine feed. Whereas acid catalysis is operating in those chlorinations utilizing no nitrogen compounds, it was unclear as to whether acid or base catalysis was prevailing in the chlorinations which did employ them; therefore, a limited study was undertaken in the hope of determining their role in the reaction to produce VI. These results are presented in Table IV. Examination of the data in Table IV indicates that there is no simple correlation of catalytic activity with basicity in the preparation of VI. What is clear, however, is that the highest yields of VI occurred with catalysts which are not very strong bases for abstraction of hydrogen from V, either because of steric (collidine, tri-n-butylamine) or electromeric interactions (dimethylacetamide, tetramethylurea) (see Scheme VI). While the poor yields achieved with the dialkylanilines and tert-butylamine may be due to competitive reactions of these catalysts with chlorine in the presence of cyclohexanone, it is difficult to reconcile their efficacy in the preparation of VI (80-9) from cyclohexanol as precursor ( 2 ) . The decreased basicity of these effective catalysts lends strong credence to the hypothesis that the nitrogen salts (and not the nitrogen compounds themselves, per se) are the true catalysts for chlorination under these conditions. In “neat” and inert solvent systems, the effective nitrogen compounds used could then be simply postulated as forming salts which provide for more facile enolization through a salt effect whereby the increased ionic strength leads to a faster rate in a polar transition state ( 2 4 b ) . It is also possible to conceive a more direct interaction with either the carbonyl group, in much the same way that HCl, for example, can foster enolization, or with chlorine SO as to facilitate chloronium ion formation (analogous to push-pull mechanisms postulated for halogenation of aromatic compounds in the presence of a catalyst) (24c) followed by subsequent chlorination.
4
0-3 ‘ ........ gHR3C1@
Va C1-C1 syn-axial interaction cannot be avoided
p
A chlorine-hydrogen syn-axial interaction has -AGoa+e equal to approximately 0.4 to 0.6 kcal/mol; the free energy value for a chlorine-chlorine interaction, while not presently available in the current literature, will probably be significantly higher than this (3, 18).
c1 (acid-catalysis by conjugate acid of amine)
All things considered, while the actual mechanistic role of the nitrogen salts is not certain at this time, their necessity in the preparation of VI (in good yield) is, nevertheless, quite clear. It is also worthy of note that there is a distinct difference in the reactivity, and perhaps mechanism, of cyclohexanol (vis-a-vis cylohexanone) chlorination to VI under these conditions. That this is the case is indicated by the following: (a) while some catalysts (e.g., collidine) give good to excellent yields of VI with either system, other catalysts (e.g., diethylaniline and tert-butylamine) give Ind. Eng. Chern., Prod. Res. Dev., Vol. 14, No. 1, 1975
5
Scheme VI. Interactions Reducing Basicity 1. Steric: Y
Table V. Thermolysis Catalyst Study: Preparation of VIII from VI
.--.
% VIIP Catalyst bp, "Cb
Catalyst
Y
2. Electromeric:
nS
dH,
good yields with the alcohol (80-go%), but not with the ketone (0 to lo%), precursor; (b) use of water is essential to high yields with cyclohexanol, but detrimental in the case of cyclohexanone. These facts may argue against a simple oxidation of cyclohexanol to cyclohexanone by chlorine followed by halogenation (Scheme W).They also serve again to reinforce the fact that mechanistic interpretation of halogenation in general is not as simple as previously thought (24), being highly dependent on reaction conditions (53).
None 14 ... Pyridine 100 116 100 165 Dimethylacetamide 100 216 Tri -n-butylamine 100 217 Diethy laniline T et ramet hy lur e a 99 166 Collidine 94 176 83 105 Di-n-propylamine n-Butylamine 74 78 tert-Butylamine 49 44 Formamide 49 111 NH4C1 11 ... Acetonitrile 8 81 H3PO4 0 ... KHSO, 0 ... QComparison of proportion of WI us. VI from gas chromatographic analysis. 760 mm; "Handbook of Chemistry and Physics," R. C . Weast, Ed., 55th CRC Press, Cleveland, Ohio, 1974.
Scheme IX OH
0
V
Scheme VI1
VI1
n
OH
n
OH
+
C1
2HC1
VI I
VI
C. Preparation of o-Chlorophenols via Thermolysis of V and VI. Compounds V and VI are potentially useful as intermediates leading to new families of chlorinated compounds including phenol, thiophenol, and aniline derivatives (via appropriate pyrolyses), as well as products arising from hydrolysis and solvolysis (20, 44, 45, 47) (see Scheme VIII). Scheme VI11
vhydro'ysis, solvolysis
I
A
cl&z
A
X = OH (SH, NH2,NHR) Z = H,C1
C y y OH
VI
I
!ztO$!'
0
, etc.
The route to isomerically pure o-chlorophenols is the most straightforward of these reactions. Hassel and Lunde (26) previously isolated 2,6-dichlorophenol (VIII) in very low yield on pyrolysis of VI in the absence of catalyst. Pyrolysis of V and VI a t 200 to 250°C in the presence of a suitable nitrogen containing catalyst has now been found to give isomerically pure VI1 and VIII, respectively, in greater than 90% yield (Scheme IX). 6
Ind. Eng. Chern., Prod. Res. Dev., Vol. 14, No. 1, 1975
The results of a catalyst study for the preparation of 2,6-dichlorophenol (VIII) from thermolysis of 2,2,6,6-tetrachlorocyclohexanone (VI) is presented in Table V. While our dehydrochlorination studies were not basically of a fundamental nature, it was, nevertheless, still possible to glean some mechanistic information from the data in Table V. Perusal of these data shows several trends quite clearly. ( a ) Amines, amides, and ureas can all function quite well as dehydrochlorination catalysts. (b) Substituted catalysts (alkyl us. H) seem to function more effectively in this regard (increased basicity). (c) There seems to be a respectable correlation between catalyst efficiency and boiling point. This would indicate that the more volatile catalysts tend to remove themselves more quickly from the reaction site. As basicity decreases, diminished volatility becomes more important. While few data are available for substantiation, solubility factors could also be important. The data can support the operation of a basic mechanism for the preparation of VI1 and VI11 from the respective chloroketones; this may well be of the nature of simple dehydrohalogenatioln followed by isomerization to the chlorophenol (Scheme X). The operation of a basicity cycle involving a free basesalt equilibrium could well form the heart of a mechanism involving catalyst efficacy as a function of structure. @I
0
-
+
RJJHC1 R,N HCl This would explain the leveling effect in catalyst type observed in Table V, which clearly shows that several moderately strong bases ( e . g . , pyridine, tri-n-butylamine, etc.)
Table VI. Distillation of 2,2,6-Trichlorocyclohexanone(V)
Scheme X n
r
o
1
Distillation no. 1 2 3 4 5 6
work as well as significantly weaker ones ( e . g . , dimethylacetamide, tetramethylurea). In an equilibrium of this type, the strongest bases would form salts with relative ease and be less prone to dissociation; the weaker bases, however, would be available in higher concentration due to their relative sluggishness toward salt formation (and hence ease of dissociation). The catalysts used could either abstract hydrogen directly or complex with it to allow for facile isomerization in a concerted mechanism. While not to be ruled out, undesirable side reactions of a Haller-Bauer nature (40) could also complicate the picture. From the known reactivity of VI, however, the likelihood of such an unwanted diversion of starting material is probably fairly small (26, 43, 4 5 ) . Commercial preparation of isomerically pure VI1 and VIII by the classical routes is not an easy task. o-Chlorophenol (VII), for example, has been produced both by chlorination of phenol and hydrolysis of o-dichlorobenzene. Each method is encumbered with purification problems; the first because of unwanted isomers, the second because overhydrolysis leads to the dihydroxybenzene derivative (32). In the preparation of VIII by chlorination of VI1 in nonpolar media, the product obtained invariably is a mixture of 2,4- and 2,6-dichlorophenol contaminated with small amounts of o-chlorophenol and 2,4,6-trichlorophenol. The separation of isomerically pure VI11 from such a mixture by conventional methods is difficult and tedious (6, 32).
Experimental Section Melting points were obtained on a Mel-Temp melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer Model 521 spectrophotometer in carbon tetrachloride solution and were calibrated with respect to polystyrene film. Nmr spectra were obtained in carbon tetrachloride on a Varian A-60 spectrometer; chemical shifts in hertz were measured from internal tetramethylsilane. Microanalyses were performed by Micro-Tech Laboratories of Skokie, Ill. Cyclohexanone (technical grade, Columbia Chemicals) was distilled prior to use. Product purity was ascertained by thermolysis (220°C, 1 hr) to phenols of a 2-g sample containing 0.1 g of collidine hydrochloride, and subsequent vpc analysis of the thermolyzate. Proper standards were used for reference. 2,2,6-Trichlorocyclohexanone(V). (a) Glacial Acetic Acid Solvent: Method of Choice for Isolation of V. At 15 to 30”C, 709.1 g (9.9 mol) of chlorine was introduced with agitation over a 5-hr period into a mixture of 800 ml of glacial acetic acid and 294 g (3 mol) of cyclohexanone. The mixture was stirred for an additional hour to complete the reaction and then concentrated on a rotary evaporator to strip HOAc, excess chlorine, and HC1. The yield
Best pressure obtained 0.30 mm
1
0.01 mm (50°C)
Av purity of best fractions 91% 95% 95% 96% 98% 99%
of crude product was 588.8 g (89% trichlorocyclohexanone content by vpc; 86% yield). The crude trichloroketone was passed through a column containing anhydrous polystyrenesulfonic acid ion-exchange resin ( H f ) to eliminate ions which lead to decomposition. The trichloroketone was then meticulously purified by six successive distillations under reduced pressure, taking heart cuts of increasing purity. The first three distillations were performed using a small column (few theoretical plates); the last three were performed using a large 3-ft column filled with small glass beads (several theoretical plates) for better fractionation. In each case, distillation was carried out under reduced pressure with careful heating to prevent decomposition of the pot contents. Although decomposition did occur to a small extent, it became considerably less of a problem with each successive distillation, as evidenced by better pressure control (lesser HC1 evolution) (see Table VI). The final material obtained (48 g) was a clear, colorless liquid: UZ5D 1.5142; dZ54 1.4365; ir spectrum, 5.72 p (s), 13.72 p (S); nmr spectrum, T 8.00 (multiplet, l H ) , 7.45 (multiplet, 2H), 7.15 (multiplet, 3H), and 4.80 (multiplet, l H ) , MRd, Calcd: 42.3; Found: 42.2. Anal. Calcd for CeH7C130: C, 35.77; H, 3.50; C1, 52.74. Found: C, 36.00; H, 3.65; C1, 52.58. ( b ) “Neat” System: Preferred Method for Subsequent Thermolysis of V to VII. At 15 to 2 5 T , 300 g of chlorine (4 mol) and 98 g of cyclohexanone (1 mol) were incrementally and concurrently added to a solution consisting of 75 g of trichlorocyclohexanone (90% pure) and 6.0 g of collidine hydrochloride over a period of 2 hr. After stirring for an additional hour to complete the reaction, the mixture was stripped of HC1 and other volatiles to yield 274 g of crude product containing 89% trichloroketone. This material was used for thermolysis to o-chlorophenol (VII) as described in the appropriate section below. 2,2,6,6-Tetrachlorocyclohexanone(VI). (a) “Neat” System. At 80-95”C, 1120 g (15.6 mol) of chlorine and 310 g (3.16 mol) of distilled cyclohexanone were continuously fed over an 8-hr period into a mixture of 250 g of 2,2,6,6tetrachlorocyclohexanone and 16 g of collidine‘ hydrochloride which had been previously swept with nitrogen. Feed was in the ratio of 4.5 mol of chlorine to 1 mol of cyclohexanone throughout the reaction. After addition of chlorine and cyclohexanone was completed, the reaction mixture was maintained a t 80-95°C for 2 hr. The solution was diluted with 2000 ml of n-hexane, filtered hot, and then allowed to cool. Crystals of 2,2,6,6-tetrachlorocyclohexanoneformed and were separated from the solvent by filtration. The air-dried crystalline product weighed 955 g (96% yield) mp 80-84°C; lit. ( 2 )82-83°C. (b) Carbon Tetrachloride Solvent. The reaction conditions and work-up were similar to those employed in the “neat” system, except for stripping of solvent prior to recrystallization. From 310 g of cyclohexanone and 1120 g of Ind. Eng. Chem., Prod. Res. Dev., Vol. 14, No. 1, 1975
7
Numbers in parentheses are minimum yields (%) attainable. Those below 90% have not been optimized. starting material where R = H.
chlorine in 240 g of carbon tetrachloride containing 25 g of collidine hydrochloride, there was obtained 745 g (90%) of product (mp 8243°C). Reaction Rates and Exotherm Measurements. The progress of the above reactions was monitored by removing aliquots at prescribed periods from the reaction mixture, stripping excess chlorine from the solution on a rotary evaporator, and then pyrolyzing to phenols for vpc analysis. Qualitative heats of formation were obtained from reactions carried out in an insulated Dewar flask using an identically insulated Dewar alongside as a reference to monitor normal heat loss to the environment. Precalibration of the flasks showed them to lose heat a t identical rates. Prior to the actual run, 3800 ml (3670 g) of water was placed in each Dewar. One was set under the preheated reaction pot and the other was set alongside as a reference. Both were allowed to equilibrate for 30 min prior to the start of chlorination. Correction factors were applied to account for the heat needed to raise incoming chlorine (and ketone for incremental addition) to reaction temperature as well as the heat consumed due to the cooling effect caused by the exit flow of gases. 2,6-Dichlorophenol (VIII). A charge of 281.8 g (1.19 mol) of 2,2,6,6-tetrachlorocyclohexanone(VI) and 5.6 g of collidine hydrochloride was introduced into a dropping 8
Ind. Eng. Chem., Prod. Res. Dev., Vol. 14, No. 1, 1975
Yields based on
funnel. The dropping funnel was warmed with a heating liquified. lamp until the 2,2,6,6-tetrachlorocyclohexanone The 2,2,6,6-tetrachlorocyclohexanonecontaining catalyst was swept with nitrogen and introduced dropwise into a 24-in. coIumn &-in. 0.d.; 9hs-in. i.d.) packed with 4-mm diameter glass beads. The packed column was heated to about 200°C along its entire length by means of an electric tube furnace. The dehydrochlorination was continued for 1.5 hr until all of the 2,2,6,6-tetrachlorocyclohexanone had been passed through the heated column and converted to product. The thermolyzate was recovered and distilled under reduced pressure' (10 mm, 105°C). The recovered distilled product yielded 177 g (1.09 mol) (91% by weight) of 2,6dichlorophenol, melting point 64-65°C. (lit. (26) 64-65°C). o-Chlorophenol (VII). Following the above procedure, 165.4 g of crude (89% pure) 2,2,6-trichlorocyclohexanone (V) containing 3.0 g of collidine hydrochloride was dehydrochlorinated to the phenol. (Because V is a liquid a t room temperature, it was unnecessarv to heat the dropping funnel.) The distilled product (40 mm, 85°C) weighed 86 g (91% yield). Commercial Applications. The use of VI as a herbicide intermediate has been mentioned earlier. Of the derivatives of V and VI mentioned above, o-chlorophenol (VII) and 2,6-dichlorophenol (VIII) are perhaps the most impor-
tant from a commercial viewpoint. While VI1 has been available on a large scale for some time, VIII has not. The novel method of synthesis of isomerically pure VI11 in high yield from VI could now also make it readily available at reasonable cost, A representation of practical intermediates available from VI11 is given in Scheme XI. An outline of the utility of these chemicals either for direct chemical applications or as monomers for polymer synthesis follows. A. Chemical Intermediates. In addition to its use in synthesis, 2,6-dichlorophenol (VIII) has shown activity as both a plant-growth regulator (56, 57) and as a sex attractant for the lone star tick ( 4 ) . 3,5-Dichloro-4-hydroxybenzenesulfonic acid (50) has utility as an inhibitor in the acid treatment of metals; it also has reported potential as an antiseptic, antiperspirant, bleaching aid, and printing aid to mention a few (33). 2,6-Dichloro-4-nitrophenol has been described as a defoliant, desiccant, herbicide, pesticide, anthelmintic drug, and photosensitive ingredient (12, 27, 28, 29, 51, 5 4 ) . 2,6-Dichloro-4-aminophenol is a potential dye intermediate, photographic developer, and antipyretic intermediate (31). The sulfone and methylene bisphenols of VI11 show utility as chemotherapeutic agents, in extreme pressure lubricants, and as intermediates in the preparation of mosquitocides and insecticides in general (35, 36, 37, 39). The variety of chemicals easily available from VIII, as well as the previously unexplored, or inadequately explored, utilit y of such intermediates provide a fertile field for future applied research. B. Polymer Intermediates. 1. From Bisphenols and Derivatives. An easy access to 2,6-dichlorophenol (VIII) also provides a base for many monomers with significant potential in polymer synthesis. The most common perhaps are bisphenols and some of their derivatives [ e . g . , diglycidyl ethers, di-(2-hydroxyethyl ethers) and di-(2-hydroxypropyl ethers)]. c1 Cl \
/
6 X = CH, SO? CH-CC1, CH,OCH, CH2-K-CH?
I
\
c1
(TCBF)
mxs)
(TCBC) (TCBF-0) (TCBF-MA)
CH, For convenience in the subsequent discussion, abbreviations for these bisphenols are given in parentheses. Melting points for these materials together with those of bisphenol A (BA), bisphenol S (BS), and some of their halogenated analogs are collected in Table VI1 for comparative purposes. While melting points need bear no direct relationship to polymer morphology, they may, with knowledge of monomer structure, provide some insight as to what might be expected in various systems. TCBF does not form a workable homopolycarbonate ( I O ) due to its high symmetry (and hence very crystalline nature). Copolymerization with bisphenol A a t 30 and 70% levels by weight, however, leads to polycarbonates having significantly higher Ta’s and tensile strengths, superior overall base, solvent, and stress cracking resistance, as well as greater hydrolytic, thermal and uv resistance than the commercial bisphenol A polycarbonate (17). Disruption of the symmetry in polymer chains prepared from TCBF by use of isomeric chlorinated bisphenols also produces a suitable polycarbonate which, in addition to the property advantages mentioned above for the TCBF-BA
Table VII. Comparison of Melting Points for Various Bisphenols and Selected Derivativesa
Bisphenol
Di-(2Di-(2hydroxyhydroxy - isopropyl ethyl ether) ether)
TCBAb 130 103 80 TCBF-O 132 TC BC 145 BA 157 TBBA‘ 165 TCBF-MA 175 142 105 TCBF 195 TCBF-MA 218 (DMS salt) BSd 2 43-2 48 TCBF-MA 245 (HC1 salt) TCBS 295 162 140 a Melting points in “C. Tetrachlorobisphenol A. Tetrabromobisphenol A . Mixture of isomers. copolymers, has extraordinary stress cracking resistance to chlorinated solvents ( I 7 ) . The di-(2-hydroxyethyl ether) and di-(2-hydroxypropyl ether) derivatives of TCBF and TCBS have also been claimed to produce polycarbonates with superior properties (46).Both TCBS and TCBF have been used in the preparation of polysulfones and thermostable polyesters (wholly aromatic), imparting an excellent combination of mechanical and physical properties to these polymers (52, 55). Quite recently, the reaction of TCBS with aliphatic dicarboxylic acids has been claimed to produce polyesters of superior solvent resistance ( 5 ) .In like manner, employment of the di-(2-hydroxyethyl ether) and di-(2-hydroxypropyl ether) derivatives of TCBF and TCBS would be expected to provide similar materials exhibiting desirable electrical and mechanical properties, toughness, and solvent resistance (23). In the area of thermosets ( e . g . , epoxy resins and crosslinked polyesters), appropriate derivatives of these bisphenols might find use in the fabrication of polymers having excellent strength, solvent resistance, flame retardant, and heat distortion properties (48). The uses suggested above for the various bisphenols and their derivatives are by no means complete but merely serve to give an indication of the potential of these materials. 2. From Other Monomers Based on 2,6-Dichloropheno1 (VIII). Several types of polymer systems have been synthesized using nonbisphenolic intermediates based on VIII. These include polyphenylene oxides from 2,6-dichlorophenol or its 4-bromo analog (49), as well as polysulfonates from 2,6-dichloro-4-benzene sulfonyl chloride (7). Polymerization of 3,5-dichloro-4-hydroxybenzoicacid to yield the corresponding polyester has also been accomplished (13).More recently, poly(3,5-dichloro-4-methylenephenylene ether), a polymer having excellent thermal stability and hydrolytic resistance, was prepared by selfcondensation of 3,5-dichloro-4-hydroxybenzylchloride (30). Lastly, p-aminophenol has been reacted with both terephthaloyl chloride and phosgene to give polyester amide and polycarbonate ureas, respectively. Consecutive reaction with terephthaloyl chloride and phosgene produces diamide carbonate copolymers (22).Use of 2,6-dichloro-4amino phenol in such formulations could give high strength, flame-resistant polymers. Ind. Eng. Chem., Prod. Res. Dev., Vol. 14, No. 1, 1975
9
Conclusions 2,2,6-Trichloro- and 2,2,6,6-tetrachlorocyclohexanone can be synthesized in excellent yield via chlorination of cyclohexanone. An acidic mechanism appears to be operating in these reactions, even in the presence of nitrogen base catalysts. A multitude of intermediates is possible from these chloroketones; at the present time, isomerically pure 2,6-dichlorophenol appears to be the one with the greatest commercial potential. As a result of the easy access to this phenol, a family of chemicals which was previously economically unattractive is now potentially available. Literature Cited ( 1 ) Adelman. R. L., J. Org. Chem., 29, 1837 (1964). (2) Arnoldy, H. (to N. V. Philips' Gloeilampenfabrieken), Neth. Appl. 6,409,256 (Feb 14, 1966); U.S. Patent 3,360,565 (Dec 26, 1967). (3) Bailey, D. S..Walder. J. A.. Lambert, J. R.. J. Amer. Chem. SOC.,
94, 177 (1972) (4) Berger, R S , Soence, 177, 704 (1972) (5) Borman, W F H (to General Electric Co ) , U S Patent 3 652,499 (Mar28 19721 (6) Bradley, K. B. (to Dow Chemical Co.), U.S. Patent 3,336,400 (Aug 15, 1967). (7) Campbell, R. (to Phillips Petroleum Co.). U.S. Patent 3,549,595 (Dec22. 1970). (8) Caujolle, F., Quan, D. Q., C. R. Acad. Sci., Paris, Ser. C. 265, ( 4 ) , 269 (1 967). (9) "The Chemistry of the Amino Group," S. Patai, Ed., lnterscience Publishers, New York, N.Y., 1968. (10) Conix, A. J. (to Gevaert Photo-Production) U.S. Patent 3,185,664 (May25. 1965). (11) Corey, E. J., Burke, J. H . , J . Amer. Chem. SOC., 77, 5415 (1955). (12) (To Eastman Kodak Co.) French Patent 1,517,412 (Mar 15, 1968). (13) (To Eastman Kodak Co.) U.S. Patent 2,600,376 (June 17, 1952). (14) Eliel, E. L., et a/., "Conformational Analysis," lnterscience Publishers, New York, N.Y., 1965. (15) Fuhrmann, R., Allied Chem. Corp., private communication. (16) Gero, A., Markham, J. J., J. Org. Chem., 16, 1835 (1951). (17) Gilbert, E. C., Brindell, G. D . , "Copolycarbonates of Bisphenol A - I
and Tetrachlorinated Methylene Bisphenols," to be published.
(18) Gilbert, E. C., Koskimies, J., J. Org. Chem., 38, 4214 (1973). (19) Gilbert E. C.. et ai. (to The Quaker Oats Company), Belgian Patent 777,966 (July 13, 1972);other patents pending. (20) Gilbert, E. C., et a/. (to The Quaker Oats Company), Belgian Patent 777,967 (July 13, 1972);other patents pending. (21) Gilbert, E. C., et a/. (to The Quaker Oats Company), Belgian Patent 777,968 (July 13, 1972);other patents pending. (22) Giori, C.. Polym. Prepr., 11, ( l ) , 326 (1970);11, ( 2 ) , 1023 (1970). (23) (To Goodyear Tire and Rubber Co.), British Patent 877,539 (Sept 13, 1961). (24) (a) Gould, E. S.."Mechanism and Structure in Organic Chemistry," Holt, Rinehart and Winston, pp 382-383, 1959; (b) ibid., pp 185187: (c) ibid., pp 442-443.
10
Ind. Eng. Chem., Prod. Res. D e v . , Vol. 1 4 , No. 1 , 1975
(25) Gundel, W., Scherff, W., (to Henkel and Cie G. m. b. H.), German Patent 832.449 (Dec 3, 1951): U.S. Patent 2,674,572 (Apr 6, 1954). (26) Hassel, O., Lunde, K., Acta Chem. Scand., 4, 200 (1950). (27) Hensel, J., Gier, D. W.. (to Chemagro Corp.), U.S. Patent 3,416,911 (Dec 17, 1968). 128) Hensel, J., Gier, D. W . ( t o Chemagro Corp.), U.S. Patent 3,463,838 (Aug 26, 1969). (29) (To I . C. I. Ltd.) British Patent 1,137,539(Dec27, 1968). (30) Izawa, S.,Tanabe, M. (to Asahi Chemical Industry Co.) Japanese Patent 72 13,074 (Apr 20, 1972). (31) "Kirk-Othmer Encyclopedia of Chemical Technology," I nterscience Publishers, 2nd ed, Vol. 2, p 213, 1963. (32) "Kirk-Othmer Encyclopedia of Chemical Technology," I nterscience Publishers, 2nd ed, Vol. 5. p 325, 1963. (33) "Kirk-Othmer Encyclopedia of Chemical Technology," I nterscience Publishers, 2nd ed, Vol. 19, p 208, 1963. (34) Kurmann, A,, eta/., Compt. Rend., 248, 418 (1959). (35) Kramer, P. E., et a/,, J. Pharmacoi. Exptl. Therap., 113, 262 (1955), (36) Lovell, J. E., Baer, R. W. (to American Cyanamid Co.) U S . Patent 3,390,209 (June 2 5 , 1968). (37) Matson, H . J . , Nelson, J. W. (to Sinclair Research Inc.) U.S. Patent 3,239,464 (Mar 8, 1966). (38) (To N. V. Philips' Gloellampenfabrieken), French Patent 1,397,573 (Apr 30, 1965). (39) Nelson, J. W. (to Sinclair Research i n c . ) , U.S.Patent 3,159,533 (Dec 1, 1964). (40) "Organic Reactions," Wiley, New York, N.Y., Vol 9 , pp 1-36, 1957. (41) Org. Syn., 25, 22 (1945). (42) Quan. D . 0 . . Compt. Rend., 249,426 (1959). (43) Rappe, C., Arkiv. Kemi, 24, (17),321 (1965). (44) Riemschneider, R . , Monatsh., 85, 417 (1954). (45) Riemschneider. R., Rubner, H., Z. Nafurforsch, 86, 161 (1953). (46) Rinke, H.. et ai. (to Farbenfabriken Bayer) U S . Patent 3,062,780 (Nov 6, 1962). (47) Rustad, N., Sherman, E.,The Quaker Oats Company, Barrington, Ill., unpublished results, 1969. (48) Spitsbergen, J. C., eta/., J. Appi. Poiym. Sci., 15, 1851 (1971). (49) Stamatoff, G. S. (to E. I . duPont de Nemours and Co.), U S . Patent 3,257,358 (June 21, 1966) (50) Strauss, W . , et a/. (to Deutsche Hydriewerke), German Patent 962,489 (Apr 25, 1957). (51) Sutherns, E. A., Holsted. C. (to Eastman Kodak Co.) U.S. Patent
3,498,789 (Mar 3 , 1970). (52) Sweeny, W (to E. I . duPont de Nemours and Co.), U.S. Patent 3,234,167 (Feb 8, 1966). (53) Teo, K. E., Warnhoff, E. W., J. Amer. Chem. Soc., 95, 2728 (1973). (54) Thorson, R. E., et a/. (to American Cyanamid Co.) U.S. Patent 3,081,224 (Mar 12, 1963) (55) (To Union Carbide Corp.), British Patent 1,078,234 (Aug 9, 1967). (56) Wain, R . L., Harper, D. L., Nature, 213, 1156 (1967). (57) Wain, R. L., Taylor, H. F.. Nature, 207, 167 (1965).
Receiued f o r review M a r c h 25, 1974 Accepted N o v e m b e r 21,1974 Presented in p a r t a t t h e D i v i s i o n of Organic Chemistry, 166th N a t i o n a l M e e t i n g of t h e A m e r i c a n C h e m i c a l Society, Chicago,
Ill., Aug 1973.
