Preparation of ortho-hydroxybenzyl alcohols

A yield improved process for the preparation of orthohydroxybenzyl alcohols by esterifying a phenol with boric acid, next condensing the product of esterification with either formaldehyde or a formaldehyde-generating compound, thus effecting formulation of a boric acid ester of the desired ortho-hydroxybenzyl alcohol, and thence decomposing said ester to liberate the ortho-hydroxybenzyl alcohol therefrom, the improvement which comprises preparing the boric acid/phenol esters from at least 1.1 mols of the phenol per mol of boric acid.

BACKGROUND OF THE INVENTION 
1. Field of the Invention: 
The present invention relates to the preparation of ortho-hydroxybenzyl 
alcohols, and, more especially, to the preparation of ortho-hydroxybenzyl 
alcohol, commonly known as saligenol, by the condensation of either 
formaldehyde or a formaldehyde-generating compound with esters derived 
from boric acid and from phenol or substituted phenols. 
2. Description of the Prior Art: 
Ortho-hydroxybenzyl alcohols are desirable intermediates for the 
preparation of the ortho-hydroxymethyl-phenylacetic acids which are useful 
as plant growth regulators. Saligenol itself is an important industrial 
product both for its pharmacological properties and as an intermediate for 
the synthesis of insecticides. 
The presently most valuable industrial process for the manufacture of 
ortho-hydroxybenzyl alcohols consists of reacting formaldehyde or one of 
its derivatives with an aryl metaborate; compare U.S. Pat. Nos. 3,290,352 
and 3,290,393 and French Pat. No. 1,328,945, each hereby expressly 
incorporated by reference in its entirety and relied upon. This process 
provides saligenol in yields on the order of 65%, expressed relative to 
the phenol and the formaldehyde employed in the reaction. Despite its 
value, it has been determined that this process is not without 
disadvantages from an economic point of view. In fact, in a process of 
this kind, the formaldehyde which is not converted to saligenol is lost in 
the form of by-products and/or cannot be recovered from the reaction 
mixture. And insofar as the boric acid is concerned, although same is not 
converted in the reaction process, it too is lost because the recovery of 
same would require the use of expensive isolation techniques. The loss of 
these two products consequently contributes to an increase in the cost of 
saligenol. 
SUMMARY OF THE INVENTION 
Accordingly, a major object of the present invention is to avoid the 
disadvantages of the process described in the aforesaid U.S. Pat. Nos. 
3,290,352 and 3,290,393, and the French Pat. No. 1,328,945 and, more 
particularly, to provide an improved process characterized by enhanced 
yields of ortho-hydroxybenzyl alcohols, relative to the phenol and the 
formaldehyde, and by enhanced efficacy relative to the boric acid 
employed. 
More specifically, the present invention features an improved process for 
the preparation of ortho-hydroxybenzyl alcohols by reacting esters of 
boric acid and of phenols with formaldehyde or a formaldehyde-generating 
substance, thus effecting the in situ formation of the boric acid esters 
of ortho-hydroxybenzyl alcohols, and thence decomposing said latter esters 
in order to liberate the subject ortho-hydroxybenzyl alcohols, and which 
process is characterized in that the boric acid esters of the phenols 
employed for the condensation are obtained by reacting at least 1.1 mols 
of the phenol with one mol of boric acid. 
DETAILED DESCRIPTION OF THE INVENTION 
It has now surprisingly been found that the use, for the condensation with 
formaldehyde, of boric acid esters of phenols obtained by reacting at 
least 1.1 mols of a phenol with 1 mol of boric acid enables substantial 
improvement in the yields of the product ortho-hydroxybenzyl alcohols, 
relative to the phenol converted, and considerably enhances the yield of 
hydroxybenzyl alcohols, relative to the formaldehyde employed in the 
reaction. This results in a simultaneous decrease in the consumption of 
boric acid per kilogram of benzyl alcohols manufactured. 
The boric acid esters of phenols obtained by reacting at least 1.1 mols of 
the phenol with 1 mol of boric acid, which esters will hereafter be 
referred to as the "aryl borates" for purposes of convenience, are complex 
mixtures comprising: 
##STR1## 
(in which formulae Ar represents a substituted or unsubstituted phenyl 
radical, as more fully defined below), which mixtures optionally contain 
excess phenol. The proportion of each of the aforesaid boric acid 
derivatives in the esterification mixture obviously varies as a function 
of the molar ratio of phenol/boric acid and/or as a function of the degree 
of esterification. Thus, for molar ratios of phenol/boric acid of between 
1.1 and 1.5, the mixture mainly comprises metaborates, and, for ratios 
which are equal to or on the order of 3, the orthoborates are virtually 
the only components of the mixture. When preparing the aryl borates, it 
was found that it was not necessary to convert all the phenol employed to 
borate, in particular if the molar ratio of phenol/boric acid is on the 
order of 3, in order to obtain good yields of ortho-hydroxybenzyl 
alcohols; it is therefore possible to limit the degree of esterification 
of the phenol in question, but without such degree being less than 70%, 
and preferably 80%, of the phenol employed. In this case, a mixture of 
aryl borates is obtained which contains the unconverted phenol, the acid 
borates of the formula (IV) and the aryl orthoborate. 
The aryl borates are prepared consistent with known processes, by reacting 
a phenol with boric acid in a solvent which forms an azeotrope with the 
water evolved during esterification reaction. The latter is removed by 
azeotropic distillation as it is formed. Aromatic hydrocarbons, such as 
benzene, toluene and xylene, are representative of suitable solvents for 
the preparation of the aryl borates. Any other inert solvent which permits 
the azeotropic distillation of the water can be used. 
The condensation of the formaldehyde with the aryl borate can be carried 
out directly on the anhydrous aryl borate solution thus obtained, 
optionally after dilution with an additional amount of the solvent 
selected. The amount of formaldehyde employed is preferably 1 mol per mol 
of boric acid, although it is possible to deviate to some extent from this 
proportion (same can be, for example, between 0.9 and 1.1 mols per mol of 
boric acid), but without any particular advantage being gained thereby. If 
a formaldehyde generator is used (for example formaldehyde oligomers or 
polymers), the amount is obviously calculated such that the amount of 
formaldehyde available for the reaction is 1 mol per mol of boric acid. 
The phenyl borate/formaldehyde condensation could be carried out in a 
different solvent from that utilized in the stage of preparation of the 
aryl borate, without departing from the ambit of the present invention, 
but this complicates the process without providing any particular 
advantage. 
The temperature for the condensation of the formaldehyde, or its generator, 
with the phenol can be between 20.degree. and 120.degree. C., and 
preferably between 40.degree. and 100.degree. C. 
The condensation reaction mixture is a complex mixture of 
ortho-hydroxybenzyl alcohol borates and mixed aryl/ortho-hydroxybenzyl 
alcohol borates, the composition of which varies with the compositions of 
the mixture of aryl borates selected as the starting material. Regardless 
of the composition of this reaction mixture, the liberation of the 
ortho-hydroxybenzyl alcohols from the condensation products can be carried 
out in accordance with those processes described in the U.S. Pat. Nos. 
3,290,352 and 3,290,393, and the French Pat. No. 1,328,945, namely, by 
saponification, alcoholysis or hydrolysis. The saponification process is 
very particularly suitable because it makes it possible, especially in 
those cases where the ratio of phenol/boric acid becomes large, to easily 
recover the excess phenols which can be recycled to a further operation 
for the preparation of aryl borates. This technique is very especially 
attractive if the ratio of phenol/boric acid is between 1.5 and 3, this 
involving the recovery of the phenols. In order to successfully carry out 
such a recovery of the phenol and the separation thereof from the 
ortho-hydroxybenzyl alcohols, it is important, in a first step, to conduct 
the saponification with an amount of alkaline agent in aqueous solution 
(in particular, sodium hydroxide or potassium hydroxide in aqueous 
solution) which is calculated such as to effect formation, from the 
ortho-hydroxybenzyl alcohol borates, of the complexes of the formula: 
##STR2## 
in which Me represents an alkali metal, which complexes are water-soluble, 
without giving rise to the formation of alkali metal phenates from the 
phenols liberated during the saponification. Under these conditions, the 
phenols liberated remain in solution in the organic solvent employed 
during the esterification and condensation stage, and the complex salt of 
the formula (V), derived from the ortho-hydroxybenzyl alcohol formed, 
transfers into the aqueous phase. The organic and aqueous phase are then 
separated by decantation. The organic phase containing the excess phenol 
can be directly re-used for a further operation. In a second step, the 
aqueous phase can in turn be treated in various ways in order to liberate 
the ortho-hydroxybenzyl alcohol from the complex of the formula (V). For 
example, the aqueous solution can be treated with an inorganic acid or the 
ortho-hydroxybenzyl alcohol can be displaced via the action of a compound 
having a greater complexing power than that of said alcohol, for example, 
a polyol, such as mannitol and sorbitol, which form very water-soluble 
complexes with boric acid; the ortho-hydroxybenzyl alcohols liberated are 
extracted with a suitable solvent. After separation of the organic phase 
containing the phenol, it is also possible to treat the aqueous phase with 
an aqueous alkaline solution to liberate the ortho-hydroxybenzyl alcohol 
in the form of an alkali metal salt thereof. In this case, an aqueous 
solution of alkali metal borate and of alkali metal salt of the 
ortho-hydroxybenzyl alcohol is recovered; the alcohol can be recovered 
from this solution by extraction, after acidification, or the solution can 
be directly used for the preparation of ortho-hydroxybenzyl alcohol 
derivatives. For example, the ortho-hydroxybenzyl alcohols, in the form of 
their alkali metal salts, can be oxidized with oxygen or air to provide 
the corresponding hydroxybenzaldehydes. 
The amount of alkali metal base to be employed in the first saponification 
step, in order to separate off the excess phenol at the completion of the 
aryl borate/formaldehyde condensation, is at most 1.2 mols per mol of 
boric acid, preferably 1 mol per mol and at least 0.8, and preferably 0.9, 
mol of alkali metal base per mol of boric acid. The "suitable amount" can 
easily be determined in each particular case by simple experimentation. 
The amount of alkali metal base employed in the second saponification step 
is typically between 0.8 and 1.5 mols per mol of boric acid initially 
employed. 
The phenols which are suitable for conducting the process of the present 
invention are represented by the structural formula: 
##STR3## 
in which n is an integer from 1 to 3 and R represents: an alkyl radical 
having from 1 to 12, and preferably from 1 to 4 carbon atoms, such as 
methyl, ethyl, propyl, butyl, hexyl and octyl; an alkoxy radical having 
from 1 to 12, and preferably from 1 to 4 carbon atoms, such as the 
methoxy, ethoxy, propoxy and butoxy groups; or a halogen atom such as 
chlorine and bromine. If n is greater than 1, at least one of the 
ortho-positions relative to the phenolic hydroxy group must be free of any 
substituents. The phenols of the formula (VI) enable synthesis of 
ortho-hydroxybenzyl alcohols of the general formula 
##STR4## 
in which R and n are as above defined. 
Examples of phenols of the formula (VI) which are representative are 
phenol, cresols, 2,3-xylenol, 3,4-xylenol, monoethylphenols, 
2-methoxyphenol, 3-methoxyphenol, 4-methoxyphenol, 2,3-dimethoxyphenol, 
2-ethoxyphenol, 4-ethoxyphenol and monochlorophenols. 
The process according to the invention is very particularly suitable for 
the preparation of saligenol from phenol.

In order to further illustrate the present invention and the advantages 
thereof, the following specific examples are given, it being understood 
that same are intended only as illustrative and in no wise limitative. 
EXAMPLE 1 
155.92 g of 98.6% pure phenol (1.634 mols), 33.48 g of 100% pure boric acid 
(0.542 mol) and 40 ml of toluene were introduced into a 1,000 ml glass 
round-bottomed flask equipped with a central stirrer, a thermometer, 
heating means and a system for separating off the water entrained by 
azeotropic distillation, and the mixture was heated at its boiling point, 
and under stirring, until the amount of water removed by azeotropic 
distillation corresponded to 82% of the amount of water resulting from 
complete esterification. The temperature in the reaction mixture attained 
a value of 160.degree. C. 
After cooling to about 100.degree., the toluene solution thus obtained, 
which contained essentially phenyl orthoborate, was diluted with 200 ml of 
anhydrous toluene and then heated to 90.degree. C. 
Paraformaldehyde (16.94 g of 95.9% pure material, i.e., 0.542 mol) was then 
introduced over the course of 30 minutes and stirring was continued at the 
same temperature for 1 hour 30 minutes. 
The reaction mixture was subsequently cooled to about 20.degree. and then 
run into ice-cold water (290 g) over the course of 20 minutes, while 
stirring same thoroughly. 123.16 g of dilute sodium hydroxide solution of 
17.59% strength by weight (i.e., 0.542 mol of NaOH) were added to this 
mixture and the resulting mixture was stirred for 20 minutes at ambient 
temperature. Stirring was discontinued and the mixture was then left to 
separate. 
The upper toluene phase was recovered. 
The aqueous phase was washed with toluene (2 times, 100 ml). 
The toluene layers were combined; same contain the excess phenol, namely, 
1.087 mols, which was determined by liquid phase chromatography. The 
degree of conversion of the phenol, therefore, was 33.5%. 
165.05 g of an aqueous sodium hydroxide solution of 17.59% strength by 
weight (i.e., 0.72 mol of NaOH) were added to the aqueous phase from which 
the phenol had been removed; this solution contained sodium borate and 
sodium saligenate which was determined by liquid phase chromatography in a 
column having an internal diameter of 4 mm and a length of 15 cm, which 
was packed with an octadecyl trimethoxy silane grafted onto silica phase, 
having a particle size of 5 mm (a product marketed by Societe MERCK under 
the designation RP 18). The eluant consisted of an aqueous alcoholic 
solution obtained by mixing 25% by volume of ethanol and 75% by volume of 
an aqueous solution, buffered to pH=3.4, which was obtained by diluting to 
1,000 ml a mixture of 0.923 g of sodium acetate trihydrate and 7 ml of 
acetic acid. In this manner, 0.528 mol of saligenol was determined and 
this corresponded to a yield of 97.6%, relative to the formaldehyde 
employed. The yield relative to the uncovered phenol was 97%. 
EXAMPLES 2 to 4 
Example 1 was repeated, the molar ratio of phenol/boric acid being varied. 
The following results were obtained: 
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Yield of Yield of 
Degree of saligenol/ 
saligenol/ 
conversion 
formaldehyde 
unrecovered 
EX- Phenol/ of phenol employed phenol 
AMPLE H.sub.3 BO.sub.3 
% % % 
______________________________________ 
2 1.2 79 82.5 87 
3 1.5 67 91.4 91 
4 2 51.5 93.3 90.6 
______________________________________ 
Note: 
The degree of esterification was 97, 93 and 98% in Examples 2, 3 and 4, 
respectively. 
While the invention has been described in terms of various preferred 
embodiments, the skilled artisan will appreciate that various 
modifications, substitutions, omissions, and changes may be made without 
departing from the spirit thereof. Accordingly, it is intended that the 
scope of the present invention be limited solely by the scope of the 
following claims.