Method for preparing di(organo) esters of pyrocarbonic acid

Di(organo) esters of pyrocarbonic acid, e.g., dialkyl pyrocarbonates, such as diethyl pyrocarbonate, are prepared by reaction of the corresponding organohaloformate with aqueous alkali metal hydroxide, e.g., sodium hydroxide, in the substantial absence of an organic solvent and in the presence of a catalytic amount of a bis[poly(oxy(C.sub.2 -C.sub.4)alkylene)] C.sub.6 -C.sub.20 aliphatic amine, e.g., coco bis(polyoxyethylene) amine.

DESCRIPTION OF THE INVENTION 
The present invention relates to a method for preparing di(organo) esters 
of pyrocarbonic acid, e.g., dialkyl dicarbonates, which are also known as 
dialkyl pyrocarbonates. 
Dialkyl pyrocarbonates have found a variety of uses in synthetic chemistry 
and in biological applications. These materials, particularly diethyl 
pyrocarbonate, have been used for the preparation of beta-ketoesters, for 
the protection of amino groups during peptide synthesis, as fermentation 
inhibitors in wines, beer and fruit juices, for stabilizing 
polyurethane-containing polymers against color formation, as blowing 
agents for polymers and as nuclease inhibitors. 
U.S. Pat. No. 3,326,958 describes a process for preparing dialkyl and 
diphenyl pyrocarbonate. In that process, the corresponding chloroformate, 
e.g., ethyl chloroformate, is dissolved in an organic solvent such as 
methylene chloride and reacted with sodium hydroxide in the presence of 
the ethoxylated or propoxylated secondary amine N-methylstearyl amine as 
the catalyst. This method suffers from the disadvantages of using a 
chlorinated organic solvent and in requiring distillation as part of the 
product recovery procedure. Solvents such as methylene chloride give rise 
to increased manufacturing costs because of the possible environmental 
safeguards which must be incorporated into the process to eliminate their 
emission into the air and their contamination of any aqueous effluent 
discharged from the process. Further, since many of the common dialkyl and 
diaryl pyrocarbonates are thermally unstable, the use of distillation 
procedures in the recovery procedure requires special conditions, e.g., 
high vacuum and low temperatures, to avoid loss of product. Generally, it 
is preferable to avoid distillation of the pyrocarbonate products, if at 
all possible. 
U.S. Pat. No. 4,929,748 describes a process of preparing dialkyl 
dicarbonates by reacting an alkyl haloformate and an alkali metal 
carbonate in the presence of a crown ether and a suitable organic solvent, 
e.g., acetonitrile, dichloromethane (methylene chloride), toluene, 
tetrahydrofuran or N,N-dimethyl formamide. This described process also 
suffers from the disadvantage of using an organic solvent. 
It has now been discovered that di(organo) esters of pyrocarbonic acid, 
e.g., dialkyl pyrocarbonates, may be prepared by reacting the 
corresponding organohaloformate with an aqueous solution of alkali metal 
hydroxide, e.g., sodium hydroxide, in the presence of a catalytic amount 
of a bis[poly(oxyalkylene)] C.sub.8 -C.sub.18 aliphatic amine and in the 
substantial absence of an organic solvent. The process of the present 
invention does not suffer from the disadvantage of using an organic 
solvent, i.e., it is free of organic solvent and hence environmentally 
friendly, produces high yields of pyrocarbonate product of excellent 
purity, does not require distillation as part of the product recovery 
process, and eliminates water insoluble by-products.

DETAILED DESCRIPTION 
In accordance with the process of the present invention, di(organo) esters 
of pyrocarbonic acid are prepared by the reaction of the corresponding 
organohaloformate or a mixture of organohaloformate with an aqueous 
solution of alkali metal hydroxide in the presence of the hereinafter 
described catalyst and in the substantial absence of an organic solvent. 
The organohaloformate may be represented by the graphic formula, 
##STR1## 
wherein R is selected from the group consisting of C.sub.1 -C.sub.12 
alkyl, C.sub.6 -C.sub.10 cycloalkyl and C.sub.6 -C.sub.9 aryl, and X is 
halogen, i.e., chloro, bromo, or iodo, preferably chloro. More 
particularly, R is selected from the group consisting of C.sub.2 -C.sub.4 
alkyl. Examples of R groups include those such as ethyl, propyl, butyl, 
secondary butyl, pentyl, hexyl tertiary butyl, 2-ethylhexyl, decyl, 
dodecyl cyclohexyl, 4-tertiary butyl cyclohexyl, phenyl and methylphenyl. 
As used in the description and claims, the term "alkyl" when referring to 
dialkyl pyrocarbonates is intended to means and include both linear and 
branched chain alkyls; and the term "cycloalkyl" is intended to mean and 
include both alkyl-substituted and unsubstituted cycloalkyl groups, e.g., 
cyclohexyl and tertiary butyl cyclohexyl. 
The di(organo) esters of pyrocarbonic acid may be represented by the 
following graphic formula, 
##STR2## 
wherein R is as defined herein with respect to graphic formula I. When 
mixtures of organohaloformate are sued, e.g., a 50/50 mixture of ethyl 
chloroformate and isopropyl chloroformate, the resulting product is a 
statistical mixture of the symmetrical and unsymmetrical dialkyl 
pyrocarbonates derived from the starting alkyl haloformates, e.g., diethyl 
pyrocarbonate (25 percent), diisopropyl pyrocarbonate (25 percent) and 
ethyl isopropyl pyrocarbonate (50 percent). The unsymmetrical mixed 
pyrocarbonate may be represented by the graphic formula, 
##STR3## 
wherein R and R' are each as defined with respect to R in graphic formula 
II, provided that R is not the same as R'. 
The organohaloformate is reacted with an aqueous solution of alkali metal 
hydroxide, e.g., sodium hydroxide, potassium hydroxide, or lithium 
hydroxide. Sodium hydroxide is economically preferred. The amount of 
alkali metal hydroxide used is in about equimolar amounts with the 
organohaloformate since the alkali metal hydroxide serves as an acid 
acceptor of the halogen released from the organohaloformate, thereby to 
form the corresponding alkali metal halide salt, e.g., sodium chloride. 
While typically about equimolar amounts of the organohaloformate and alkali 
metal hydroxide are used, an excess of the organohaloformate may be used 
to reduce the opportunity for hydrolysis of the organohaloformate. 
However, an excess of alkali metal hydroxide may also be sued and is 
particularly contemplated. In the present process, ti si preferred that a 
slight excess of the alkali metal hydroxide is used. No undue hydrolysis 
of the organohaloformate has been observed using a slight excess of alkali 
metal hydroxide in the present process. For example, the mole ratio of 
alkali metal hydroxide int eh present process. For example, the mole ratio 
of alkali metal hydroxide to organohaloformate contemplated herein may 
vary from about 1.0:1 to 1:1.10, e.g., 1.01:1 to 1.08:1. 
Suitable examples of dialkyl, diaryl and dicycloalkyl pyrocarbonates 
include dimethyl pyrocarbonate, diethyl pyrocarbonate, di-isopropyl 
pyrocarbonate, di-n-propyl pyrocarboante, di-n-butyl pyrocarbonate, 
di-isobutyl pyrocarbonate, di-secondary butyl pyrocarbonate, di-tertiary 
butyl pyrocarbonate, dipentyl pyrocarbonate, dihexyl pyrocarbonate, 
diheptyl pyrocarbonate, di-2-ethylhexyl pyrocarboante, dinonyl 
pyrocarbonate, didecyl pyrocarbonate, di-dodecyl pyrocarbonate, 
di-cyclohexyl pyrocarboante, di-4-tertiary butyl cyclohexyl pyrocarboante 
and diphenyl pyrocarbonate. Diethyl pyrocarbonate is economically 
preferred. As discussed, unsymmetrical diorgano pyrocarbonates are also 
contemplated, e.g., ethyl isopropyl pyrocarbonate, ethyl secondary butyl 
pyrocarbonate and ethyl n-propyl pyrocarbonate. 
Alkali metal hydroxide aqueous solutions of varying concentrations may be 
sued in the described process. Contemplated are concentrations of rom 
about 7 to about 50 weight percent, preferably, from about 35 to about 50 
weight percent. It has been found that higher concentrations of alkali 
metal hydroxide result in higher yields of product. 
In accordance with the present invention, a catalytic amount of a 
bis[poly(oxy(C.sub.4 -C.sub.4)alkylene)] C.sub.6 -C.sub.20 aliphatic amine 
is uses as the catalyst for the above-described process. In one 
embodiment, such amines may be represented by the following graphic 
formula, 
##STR4## 
wherein R.sub.1 is a C.sub.6 -C.sub.20 alkyl or C.sub.6 -C.sub.20 alkenyl, 
n is an integer of from 2 to 4, and x and y are each average numbers 
ranging from about 2 to about 24, the sum of x and y being a number of 
from about 4 to about 48. Preferably, R.sub.1 is a C.sub.8 -C.sub.18 
alkyl, n is the integer 2 or 3, more preferably 2, and x and y are each 
numbers of from about 2 to 14, the sum of x and y being a number of from 4 
to 28, e.g., 5 to 15. 
It is also contemplated that the oxyalkylene group may be a block copolymer 
resulting from the successive alkoxylation of the starting aliphatic 
primary amine with different C.sub.2 -C.sub.4 alkylene oxides, e.g., a 
successive ethoxylation and propoxylation of the base amine material. Such 
amines may be represented, for example, by the graphic formula, 
##STR5## 
wherein R.sub.1 is as defined with respect to graphic formula III, a and b 
are different and are each integers of from 2 to 4, x and y are each 
numbers averaging from 1 to 24, and x' and y' are each numbers averaging 
from 0 to 23, the sum of x, x', y and y' being a number of from about 4 to 
48, preferably 4 to 28, e.g., 5 to 15. 
Examples of bis[poly(oxyalkylene)] C.sub.6 C.sub.20 aliphatic amine 
catalysts contemplated include the following compounds. The CTFA adopted 
name (if known) is also reported. 
______________________________________ 
COMMON NAME CTFA NAME 
______________________________________ 
polyoxyethylene (5)* cocoamine 
PEG-5 cocamine 
polyoxyethylene (10) cocoamine 
PEG-10 cocamine 
polyoxyethylene (15) cocoamine 
PEG-15 cocamine 
polyoxyethylene (5) octadecylamine 
PEG-5 stearamine 
polyoxyethylene (10) octadecylamine 
PEG-10 stearamine 
polyoxyethylene (15) octadecylamine 
PEG-15 stearamine 
polyoxyethylene (5) tallowamine 
PEG-5 tallow amine 
polyoxyethylene (15) tallowamine 
PEG-15 tallow amine 
polyoxyethylene (5) oleylamine 
PEG-5 oleamine 
polyoxyethylene (15) oleylamine 
PEG-15 oleamine 
polyoxyethylene (5) soyaamine 
PEG-5 soyamine 
polyoxyethylene (10) soyaamine 
PEG-10 soyamine 
polyoxyethylene (15) soyaamine 
PEG-15 soyamine 
polyoxyethylene (5) hexylamine 
-- 
polyoxyethylene (5) octylamine 
-- 
polyoxyethylene (10) decylamine 
-- 
polyoxypropylene (15) cocoamine 
-- 
polyoxybutylene (10) octadecylamine 
-- 
polyoxypropylene (5) tallowamine 
-- 
polyoxybutylene (10) soyaamine 
-- 
______________________________________ 
*indicates the average number of oxyalkylene groups in the compound. 
Preferably, the catalyst is in liquid form an is light in color, e.g., has 
a Gardner color of less than 8, preferably 6 or less. 
The amount of catalyst used in the above-described reaction is that amount 
which catalyzes the formation of the di(organo) ester of pyrocarbonic 
acid, i.e., a catalytic amount. More particularly, the amount of catalyst 
sued will be from about 0.1 to about 1.0 mole percent, based on the amount 
of organohaloformate used. 
The reaction temperatures that may be sued to prepare the di(organo)esters 
of pyrocarbonic acid in accordance with the present process will be in the 
rang of 0.degree. C.-20.degree. C., more usually 5.degree. C.-10.degree. 
C. 
In carrying out the process of the present invention, the organohaloformate 
and catalyst are charged to a suitable cooled reactor, and the aqueous 
alkali metal hydroxide solution slowly added to the reactor while 
agitating the reactor contents. After all of the alkali metal hydroxide 
has been added, and the reaction completed, additional water is added to 
the reaction flask to achieve a reaction mixture containing a theoretical 
amount of about 25 to 30 percent solids. The reaction mixture is agitated 
again to dissolve the solids (salt co-product) and the mixture allowed to 
separate into a top organic phase and a bottom aqueous phase. 
The aqueous phase is drawn off and the remaining organic phase dried, e.g., 
over magnesium sulfate. The resultant crude product is purified by 
removing volatile components remaining therein, e.g., unreacted 
organohaloformate and any di(organo) carbonate by-product, by, for 
example, a rotary evaporator. 
The present invention is more particularly described in the following 
examples which are intended as illustrative only, since numerous 
modifications and variations therein will be apparent to those skilled in 
the art. 
EXAMPLE 1 
This example describes the preparation of diethyl pyrocarbonate with PEG 15 
stearamine as the catalyst. 
A solution of ethyl chloroformate (114.2 grams (95%) 1.00 mole) and PEG-15 
stearamine (1.88 grams (99%) 0.002 mole) was introduce to a 1000 
milliliter, three-necked reaction flask with a bottom stopcock. The 
reaction flask was equipped with a mechanical teflon blade stirrer, sodium 
hydroxide solution inlet, vent and thermowell for a thermocouple, which 
was connected to a temperature control unit. Sodium hydroxide was charged 
to the reaction flask through a Masterflex addition pump. The temperature 
control unit activated a cooling water pump which directed ice water 
against the reaction flask and also controlled the Masterflex pump so as 
to maintain the reaction temperature at below 15.degree. C. 
When the temperature in the reaction flask was below 15.degree. C., sodium 
hydroxide solution was charged to the flask. When the temperature rose 
above 15.degree. C., the Masterflex pump was shut off and ice water 
sprayed on the reaction flask to cool the contents of the reaction flask. 
Aqueous sodium hydroxide solution (82 grams (50%) 1.025 moles) was charged 
to the reaction flask over a period of approximately 60 minutes. 
Semi-solids which remained on the sides of the flask were rinsed into the 
liquid reaction mixture with a small amount of water and the reaction 
mixture post stirred at 15.degree. C. for 30 minutes. 125.5 grams of water 
(including the amount of rinse water) was added tot he reaction flask so 
that the theoretical percent solids in the aqueous phase was about 25 
percent. The reaction mixture was agitated from 10 seconds to dissolve all 
solids before phase separation was performed. 
The top organic phase (82.7 grams) was dried over 6.2 grams of magnesium 
sulfate to give a light yellow clear liquid (77.2 grams). Volatiles in the 
yellow liquid product were removed by a rotary evaporator under water 
aspirator vacuum (40 mm/Hg) for 60 minutes at 60.degree. C., and then 
under vacuum pump (&lt;2 mm/Hg) for 60 minutes at 60.degree. C., thereby to 
obtain a final liquid product (71.8 grams). This product was a clear, 
light yellow liquid having an APHA color of 100. The conversion of 
chloroformate to chloride anion (C1.sup.-) was found to be 100 percent 
based on the analysis for (C1.sup.-) in the aqueous phase. The infrared 
spectrum of the product matched the literature infrared spectrum for 
diethyl pyrocarbonate with a characteristic band at 1823 cm.sup.-1. Both 
.sup.1 H (proton) and .sup.13 C nuclear magnetic resonance analysis 
supported the product as being diethyl pyrocarbonate with a minor amount 
of diethyl carbonate. The product has an assay of 96 percent as determined 
by gas chromatograph analysis. 
EXAMPLE 2 
The procedure of Example 1 was followed to synthesize diethyl 
pyrocarbonate, except that PEG-5 cocamine (0.85 grams, 0.002 mole) was 
used a the catalyst. The reaction gave a product of 95 percent assay in 
82.4 percent yield. The final product was a colorless liquid having an 
APHA color of 15. 
EXAMPLE 3 
The procedure of Example 1 was followed except that the concentration of 
sodium hydroxide was varied from 7 percent to 50 percent. Results are 
tabulated in Table I. 
TABLE I 
______________________________________ 
% Chloroformate 
% Color 
Run % NaOH Conversion Purity 
(APHA) % Yield 
______________________________________ 
1 7 97 92 100 52 
2 35 95 96 100 71 
3 50 99 96 100 85 
______________________________________ 
The data of Table I illustrate that the yield of diethyl pyrocarbonate 
increases with increasing concentration of sodium hydroxide. 
COMATIVE EXAMPLE 
Into a tared 500 ml four-necked reaction flask was added ethyl 
chloroformate (58.2 g, 0.525 mole, 99.1 percent assay), 42 ml of methylene 
chloride and 0.714 g (0.002 mole) of propoxylated N-methyl stearylamine 
catalyst. The catalyst, IMPRAFIX BU, was found to contain by analysis 1.26 
moles of propylene oxide per mole of N-methyl stearylamine and had a 
molecular weight of 356.9. To the stirred reaction mixture was added 
dropwise sodium hydroxide (20.0 g, 0.50 mole) over one hour. The 
temperature of the reaction was maintained at 18.degree.-20.degree. C. by 
immersing a portion of the flask in an ice-water bath. 
At the end of the addition of the sodium hydroxide, stirring was 
discontinued and two colorless phases formed almost immediately. The 
reaction mixture was stirred for another 15 minutes to insure completion 
of the reaction. Analysis of an aliquot of the aqueous phase for C1.sup.- 
showed that the reaction product was 98 percent of theoretical. 
The reaction mixture was phase separated in a 500 ml separtory funnel, and 
the aqueous phase extracted with 50 ml of methylene chloride. A 
considerable amount of cruddy, white interface was present. This emulsion 
was broken by passing it through glass wool in a gravity funnel. 
The methylene chloride solution was dried overnight with anhydrous sodium 
sulfate. The solution was decanted, the sodium sulfate extracted twice 
with 25 ml portions of methylene chloride, decanted and the methylene 
chloride solutions combined. The colorless methylene chloride solution was 
distilled from a 100 ml three-necked flask through a 4-inch Vigreux-type 
Claisen adapter. Methylene chloride wad removed at atmospheric pressure by 
heating in a stirred 60.degree.-63.degree. C. oil bath. Additional 
methylene chloride, unreacted ethyl chloroformate and diethyl carbonate 
were collected by reducing the pressure to 20 mm Hg while heating in a 
60.degree. C. oil bath. The pressure was reduced to 5 mm Hg and the oil 
bath temperature increased to 91.degree.-102.degree. C. Diethyl 
pyrocarbonate distilled off at 76.degree. C. at 5.5 mm Hg as a colorless 
liquid. The yield of diethyl pyrocarbonate was found to be 84 percent 
based on GLC analysis of foreshots from the distillation. 
Although the present invention has been described with reference to the 
specific details of particular embodiments thereof, it is not intended 
that such details be regarded as limitations upon the scope of the 
invention, except insofar as and to the extend that they are included in 
the accompanying claims.