Process for the preparation of 3,5-dialkyl-4-hydroxy benzoic acid

An improved process for the preparation of 3,5-dialkyl-4-hydroxybenzoic acid comprising the reaction of 2,6-dialkylphenol and carbon dioxide in the presence of a mono- or polyalkylene glycol ether.

3,5-dialkyl-4-hydroxybenzoic acid and the various esters thereof are well 
known, commercially successful stabilizers of polymers subject to 
oxidative deterioration. 
U.S. Pat. No. 3,330,859 and U.S. Pat. No. 3,681,431 are representative of 
the patents disclosing such compounds. The preparative processes disclosed 
in the patents include esterification procedures from suitable alcohols 
and acids, acid halides or acid anhydrides. 
Other preparative approaches have also been disclosed. For example, the 
carboxylation of alkali metal salts of phenols with carbon dioxide is well 
known for the preparation of p-hydroxybenzoic acids [for a review of the 
Kolbe-Schmitt reaction see A. S. Linsey and H. Jeskey, Chem. Rev., 57, 583 
(1957)]. The use of dipolar aprotic solvents for the carboxylation of 
alkali metal salts of 2,6-dialkyl phenols has also been described [see, 
for example, Meek, U.S. Pat. No. 3,825,593; Lind et al, U.S. Pat. No. 
4,034,006 and Grosso, U.S. Pat. No. 4,072,707]. N,N-Dimethylformamide has 
been the preferred dipolar aprotic solvent for these processes even though 
it has the disadvantages of having a high boiling point (b.p. 153.degree. 
C.) and known human toxicity (see, for example, M. Windholz, The Merck 
Index, Ninth Edition, p. 3236). 
Other solvents have been explored for use in the carboxylation of 
phenoxides but considerably reduced yields have resulted. For example, T. 
Sakakihara and K. Haraquchi (Bull. Chem. Soc. Jpn. 53, 279, 1980) have 
shown that the carboxylation of sodium phenoxide in polyethylene glycol 
dimethyl ethers gives exceedingly poor yields of the hydroxybenzoic acids. 
In fact, there was no benzoic acid formed when sodium phenoxide was 
treated with carbon dioxide in 1,2-dimethoxyethane. 
As a further aspect of the primary reaction approach, Grosso (U.S. Pat. No. 
4,072,707) has described the use of 1 to 5 equivalents of alkali metal 
hydrides relative to the 2,6-dialkyl phenols as a preferred preparation of 
the corresponding alkali metal salts of 2,6-dialkyl phenols, 
notwithstanding the high cost of alkali metal hydrides relative to alkali 
metal hydroxides. The alkali metal salts are treated with carbon dioxide 
in dipolar aprotic solvents to prepare 3,5-dialkyl-4-hydroxy-benzoic 
acids. 
The search for improved processes continues in an attempt to obtain 
increased yields and purity while reducing extreme reaction conditions, 
eliminating toxicity problems and improving reaction economics. 
Accordingly, it is the primary object of this invention to provide an 
improved process for the preparation of 3,5-dialkyl-4-hydroxybenzoic acid. 
Various other objects and advantages of this invention will become apparent 
from the following detailed discussion thereof. 
The present invention describes a new and improved process for the 
preparation of 3,5-dialkyl-4-hydroxybenzoic acids from an alkali metal 
salt of 2,6-dialkyl phenol and carbon dioxide in the presence of a mono- 
or polyalkylene glycol ether solvent. The following advantages are 
particularly relevant to this invention: 
(1) The process prescribes the use of carbon dioxide at atmospheric 
pressure, thereby avoiding the difficulties associated with high pressure 
processes. 
(2) The process requires only moderate temperatures, thereby avoiding the 
problems and cost associated with higher temperature processes. 
(3) The process is conducted in a homogeneous phase by the use of a solvent 
so as to avoid the difficulties associated with heterogeneous gas-solid 
processes. 
(4) The process allows for the partial or complete substitution of metal 
hydroxides for the more costly metal hydrides. 
(5) The process encompasses the use of polyethylene glycol dialkyl ethers 
of low boiling point which avoids the use of higher boiling dipolar 
aprotic solvents. In particular, the use of ethylene glycol dimethyl ether 
(boiling point 85.degree. C.) over the previous use of 
N,N-dimethylformamide (boiling point 153.degree. C.) allows for easier 
recovery of solvent. 
(6) The preferred use of ethylene glycol dimethyl ether also avoids the 
health hazard associated with the known human toxicity of 
N,N-dimethylformamide. 
The general reaction scheme of the instant inventions corresponds to the 
equation 
##STR1## 
wherein R and R.sub.1 independently are alkyl groups of 1 to 30 carbon 
atoms. Thus, branched and straight chain alkyl groups are contemplated 
such as methyl, ethyl, propyl, butyl, tert-butyl, octyl, decyl, dodecyl, 
tetradecyl, octadecyl, eicosyl and the like. Since the hindered phenols 
are preferred as stabilizers, branched alkyls of 4 to 8 carbon atoms, and 
particularly tert-butyl groups are preferred. 
The reaction proceeds by reacting the 2,6-dialkylphenol in the presence of 
a strong base which functions to convert the phenol to a phenolate ion in 
the presence of a mono- or polyalkylene glycol ether solvent and an 
optional aromatic hydrocarbon solvent such as benzene, toluene, xylene, 
and the like. The mixture is heated to a temperature range of 30.degree. 
to 60.degree. C., whereupon the carbon dioxide is introduced below the 
surface of the reaction mixture for a period of generally 0.5 to 2 hours 
to insure complete reaction. Any excess sodium hydride is then destroyed 
by use of an alcohol, the reaction mixture generally adjusted to a pH of 1 
to 2 with mineral acid and the 3,5-dialkyl-4-hydroxybenzoic acid recovered 
by conventional means. 
The strong bases include alkali and alkaline earth metal and ammonium 
hydroxides, hydrides and amides. 
The mono- and polyalkylene glycol ethers correspond to the formula 
##STR2## 
wherein R.sub.5 and R.sub.7 are independently lower alkyl of 1 to 8 carbon 
atoms, 
R.sub.6 is hydrogen or lower alkyl of 1 to 8 carbon atoms, 
n is 0, 1 or 2, and 
m is 1 to 9, and preferably m is 2 to 5. 
Suitable glycol ethers are ethylene glycol dimethyl ether, diethylene 
glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol 
dibutyl ether, tripropylene glycol dimethyl ether, tetraethylene glycol 
dimethyl ether, tetraethylene glycol diethyl ether and pentaethylene 
glycol monoethyl ether. The mono- and polyethylene glycol dialkyl ethers 
are preferred such as the ethylene glycol dimethyl ether, diethylene 
glycol dimethyl ether and tetraethylene glycol dimethyl ether. 
Product yields in excess of 80% are generally obtained. The resulting 
products are readily available for use as stabilizers either in their acid 
or ester form. 
The following examples illustrate the embodiments of this invention.

EXAMPLE 1 
A reaction vessel was charged with a suspension of 4.74 grams (0.198 mol) 
of sodium hydride in 150 ml of dry ethylene glycol dimethyl ether to which 
was added dropwise at 20.degree.-25.degree. C. a solution of 20.6 grams 
(0.10 mol) of 2,6-di-tert-butylphenol in 150 ml of ethylene glycol 
dimethyl ether. After the addition was complete, the reaction mixture was 
warmed to 50.degree. to 60.degree. C. for a period of 1.5 hours and then 
carbon dioxide was introduced through a gas-disparging tube below the 
surface of the reaction mixture for 20 hours. The reaction mixture was 
cooled to 5.degree. C. and the excess of sodium hydride was destroyed 
carefully with 30 ml of methyl alcohol. After hydrogen evolution ceased, 
the reaction mixture was adjusted to a pH of 2 with 1N hydrochloric acid 
and then was diluted with 1.6 liters of water. The resultant precipitate 
was collected by filtration and was dried in vacuo. 
The solid was triturated with 150 ml of petroleum ether at reflux to give 
22.6 grams (90.4%) of an off-white solid, m.p. 205.degree.-209.degree. C. 
EXAMPLE 2 
The procedure of Example 1 was repeated using 4.74 grams (0.198 mol) of 
sodium hydride, 20.6 grams (0.10 mol) of 2,6-di-tert-butylphenol and 300 
ml of tetraethylene glycol dimethyl ether to give 21.0 grams (84%) of an 
off-white solid, m.p. 205.degree.-208.degree. C. 
EXAMPLE 3 
A reaction vessel was charged with a stirred mixture of 20.6 grams (0.10 
mol) of 2,6-di-tert-butylphenol, 4.0 grams (0.10 mol) of sodium hydroxide 
in 3.9 grams of water and 250 ml of toluene. The reaction mixture was 
heated at reflux under nitrogen and the water was collected in a 
Dean-Stark trap. After 4.7 ml of H.sub.2 O was collected, the mixture was 
cooled and 300 ml of tetraethylene glycol dimethyl ether was added to the 
reaction mixture. The mixture was heated in vacuo during which time 220 ml 
of toluene was removed by distillation. The cooled reaction mixture was 
admixed with 0.24 grams (0.01 mol) of sodium hydride. The mixture was 
heated to 60.degree. C. and then carbon dioxide was introduced through a 
gas-disparging tube below the surface of the reaction mixture for 20 
hours. The reaction mixture was cooled to 5.degree. C. and any residual 
sodium hydride was destroyed with 5 ml of methyl alcohol. After hydrogen 
evolution ceased, the reaction mixture was adjusted to a pH of 2 with 1N 
hydrochloric acid and then was diluted with 1 liter of water and 
sequentially extracted with two-100 ml portions of ether and one 100 ml 
portion of chloroform. The organic extracts were combined and dried over 
Na.sub.2 SO.sub.4. The solvent was removed in vacuo and the residue was 
triturated with 150 ml of petroleum ether at reflux to give 17.3 grams 
(69%) of an off-white solid, m.p. 205.degree.-209.degree. C. 
EXAMPLE 4 
The procedure of Example 3 was repeated using 20.6 grams (0.10 mol) of 
2,6-di-tert-butylphenol, 6.2 grams (0.11) of potassium hydroxide in 7.3 
grams of water, 250 ml of toluene and 250 ml of tetraethylene glycol 
dimethyl ether. After trituration with 125 ml of petroleum ether at 
reflux, 10.8 grams (43%) of an off-white solid was obtained, m.p. 
206.degree.-208.degree. C. 
Summarizing, it is seen that this invention provides an improved process 
for preparing 3,5-dialkyl-4-hydroxybenzoic acid. Variations may be made in 
proportions, procedures and materials without departing from the scope of 
the invention as defined by the following claims.