Smart solution chemistry: Prolonging the lifetime of ortho-phthalaldehyde disinfection solutions

Article abstract of DOI:10.1002/jhet.5570430216

The oxidation of ortho-phthalaldehyde to phthalic acid in aqueous solutions can be remedied by the addition of various cyclic acetals, which, when reacted with phthalic acid, yields ortho-phthalaldehyde, thus prolonging the lifetime of the ortho-phthalaldehyde disinfection solution.

Full text of DOI:10.1002/jhet.5570430216

Mar-Apr 2006
361
Smart Solution Chemistry: Prolonging the Lifetime of ortho-
Phthalaldehyde Disinfection Solutions
a
a
a
b
Bobby N. Brewer, Keith T. Mead, Charles U. Pittman, Jr., Kaitao Lu
∗
b
and Peter C. Zhu
a
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA.
Fax: 1-662-325-1618; Tel: 1-662-325-3584; E-mail: CPittman@ra.msstate.edu
b
Biocides Research, Advanced Sterilization Products, Johnson & Johnson, 33 Technology Drive, Irvine, CA
92618, USA
Received June 27, 2005
The oxidation of ortho-phthalaldehyde to phthalic acid in aqueous solutions can be remedied by the
addition of various cyclic acetals, which, when reacted with phthalic acid, yields ortho-phthalaldehyde, thus
prolonging the lifetime of the ortho-phthalaldehyde disinfection solution.
J. Heterocyclic Chem., 43, 361 (2006).
Introduction.
amount of acid or the pH of the solution allowed the rate of
hydrolysis of the cyclic acetal to be controlled.
Consequently, the addition of cyclic acetals to an aqueous
solution of OPA leads to a “smart solution” that is capable
of self replenishment. The ability of this solution to replen-
ish OPA in aqueous solutions prolongs the shelf life and
use life of the aqueous OPA solutions.
Dilute solutions of ortho-phthalaldehyde (OPA) have
become preferred over glutaraldehyde for use in hospitals
as high-level disinfectants for instrument processing [1].
The lifetime of OPA, 1, in aqueous media is shortened by
oxidation to 2-carboxybenzaldehyde (CBA, 2) and
phthalic acid (3) (Scheme 1). This decrease in shelf life
can be overcome using “smart solution chemistry.” As
OPA is oxidized in aqueous environments, concentrations
of 2 and 3 increase; by adding cyclic acetals to the solu-
tion, the increased concentrations of 2 and 3 can be used to
replenish OPA concentrations. Treating a variety of cyclic
acetals with phthalic acid in aqueous media readily
hydrolyzed these acetals to OPA (Scheme 1). Varying the
Results and Discussion.
In aqueous environments, OPA is slowly oxidized to
CBA and phthalic acid (see Scheme 1). This oxidation
can be easily followed by monitoring the pH and concen-
tration of OPA in idle aqueous solutions. Over a three
week period, the pH of the OPA solution decreased from a
pH of 6.09 to a slightly more acidic pH of 5.16. The con-
centration of OPA dropped 10% within the first week.
When used as a high-level disinfectant, this oxidation
decreases both the shelf life and use life of the OPA solu-
tion. OPA is converted to phthalic acid when mixed with
hydrogen peroxide at room temperature [2-3]. The poten-
tial for contamination of disinfectant solutions with
hydrogen peroxide is a common problem in hospitals.
Many times instruments are added to disinfection solu-
tions after being in contact with hydrogen peroxide solu-
tions. We have found that when a minimal amount (0.18
mmols) of hydrogen peroxide is added to 30 mL of a 0.5
wt% OPA solution (1.08 mmols), 80% of OPA is oxidized
to phthalic acid in just 3 days.

362
B. N. Brewer, K. T. Mead, C. U. Pittman, Jr., K. Lu and P. C. Zhu
Vol. 43
Table 2
The ortho arrangement of the two aldehyde groups in
Conversion of 1,3-dialkyloxyphthalans to OPA by the addition of
various equivalents of phthalic acid
OPA favors the cyclic acetal form in aqueous alcoholic
solutions. This cyclic acetal form could be used to protect
the aldehyde groups. These 1,3-dialkyloxy cyclic acetals
are easily prepared by treatment of OPA with either fuming
sulfuric acid or trifluoroacetic acid [4] in the corresponding
anhydrous alcohol (Scheme 2). Results for the formation of
various 1,3-dialkyloxyphthalans are shown in Table 1.
Alkyl Group
Methyl
Methyl
Ethyl
Acid Equivalents
Conversion Time [a]
2 days
0.1
0.001
0.1
13 days
1 day
Ethyl
Ethyl
Ethyl
0.05
0.01
0.001
2 days
6 days
24 days
[a] Time required to convert >95% of 1,3-dialkyloxyphthalan to OPA by
GC/MS
Scheme 2
phthalan converted to OPA with 89 days required to
hydrolyze 95% of the acetal. These different rates of
conversion can be useful for prolonging the shelf life and
use life of OPA.
Table 3
Conversion of 1,3-diethoxyphthalan to OPA at various pHs.
Table 1
Entry
pH [a]
Conversion Time
Formation of various 1,3-dialkyloxyphthalans from OPA.
1
2
3
4
3.5
5.4
6.9
4 days
20 days
20 days
89 days
Alkyl Group
Acid
H SO
Time
% Yield
Methyl
Ethyl
Isopropyl
Isopentyl
4 h
6 h
24 h
24 h
92 [a]
92 [b]
84 [a]
80 [a]
2
4
4
10.8
H SO
2
TFA
TFA
[a] pH indicates the initial pH of the solution.
[a] GC Yield; [b] Isolated Yield.
In basic solutions, the conversion of the cyclic acetal is
very slow, thus generating a small amount of OPA over a
long period of time. This is desirable if the solution is idle
for long periods of time, and the only concentration loss is
due to oxidation of OPA to phthalic acid. Alternatively, in
acidic environments, the cyclic acetal is converted rapidly
to OPA. This is desirable if the solution is being heavily
used and the concentration of OPA is diminishing due to its
use as a disinfectant.
In order to further evaluate the effect of pH on the solu-
tion, mixtures of OPA and 1,3-diethoxyphthalan were eval-
uated at various pHs in non-buffered solutions (Scheme 3).
The purpose of these experiments was to determine what
affect the presence of OPA in solution and subsequent oxi-
dation to phthalic acid has on the rate of hydrolysis.
Solutions were prepared at concentrations of 0.037 M OPA
and 0.005 M 1,3-diethoxyphthalan in distilled water which
was previously adjusted to a wide range of initial pH values
with either NaOH or HCl. Entries 1 thru 3 in Table 4 show
that all 1,3-diethoxyphthalan is converted to OPA in six
days or less in acidic aqueous media in the presence of
OPA. At more neutral pHs (entries 4, 5 and 6 in Table 4)
conversion times vary from as little as 8 days up to 41 days.
The conversion of 1,3-diethoxyphthalan to OPA is gener-
ally quicker in the presence of OPA due to the simultaneous
oxidation of OPA to phthalic acid, which decreases the pH
The conversion of 1,3-dialkyloxyphthalans to OPA was
first investigated by monitoring the rate of this conversion
after the addition of various equivalents of phthalic acid
(Scheme 1) [5]. By varying the amount of phthalic acid,
the cyclic acetal can be converted to OPA in time periods
ranging from a few hours to a few weeks (Table 2).
Reactions were stirred at room temperature and concentra-
tions were monitored by GC/MS. Conversion of 1,3-
dimethoxyphthalan or 1,3-diethoxyphthalan to OPA with
the addition of 0.1 equivalents of phthalic acid was very
fast, with conversion occuring in 2 days or less. By adding
smaller amounts of phthalic acid, the rate of conversion is
slower and the overall conversion time can be increased to
between 13 and 24 days.
The rate of conversion of 1,3-dialkyloxyphthalans to
OPA can be controlled by varying the pH of the initial
solution. Solutions were prepared by dissolving 1,3-
diethoxyphthalan in distilled water which was previously
adjusted to an initial pH of 3.5, 5.4, 6.9, or 10.8 with either
HCl or NaOH (Table 3). Entry 1 shows that at a pH of 3.5,
virtually all of the 1,3-diethoxyphthalan is converted to
OPA after only 4 days, while at pHs of 5.4 and 6.9 (entries
2 and 3), it takes 20 days to completely convert 1,3-
diethoxyphthalan into OPA. At pH 10.8, 1,3-diethoxy-

Mar-Apr 2006
363
Prolonging the Lifetime of ortho-Phthalaldehyde Disinfection Solutions
as more CBA and phthalic acid are formed. In basic envi-
ronments (entries 8 and 9), 1,3-diethoxyphthalan is still
present even after 91 days at room temperature. By varying
the initial pH of the solution, the rate of conversion of 1,3-
diethoxyphthalan to OPA can be controlled.
Table 5
Formation of OPA from a solution of mixed acetals.
Time Methyl [a]
Ethyl [a]
32.5
15.1
Isopropyl [a] OPA [a]
Table
4
1 h
24 h
48 h
42.6
18.6
4.4
23.8
6.3
1.1
60
92
Conversion of 1,3-diethoxyphthalan to OPA in aqueous solutions
at a variety of pHs.
0.8
2.8
[a] Values reported are relative percents of each component in solution
determined from the GC/MS chromatogram. Each component had a
starting concentration of 0.02 M.
Entry
pH [a]
Conversion Time
1
2
3
4
5
6
7
8
9
3.03
3.96
5.08
6.03
6.95
8.04
8.9
1 day
5 days
6 days
8 days
General Procedure.
23 days
41 days
54 days
> 84 days
> 84 days
OPA (136 mg, 0.829 mmol) was dissolved in 4.2 mL of
pure anhydrous ethanol and fuming sulfuric acid (4
drops) was added to the solution dropwise. The reaction
was then stirred at room temperature for 6 h and moni-
tored by GC/MS. The reaction was quenched with the
addition of a few drops of saturated aqueous sodium
bicarbonate. The mixture was then extracted with ether
9.84
11.01
[a] pH indicates the initial pH of the solution.
A mixture of cyclic acetals (methyl 0.02 M, ethyl 0.02 M,
and isopropyl 0.02 M) was monitored to evaluate their dif-
ferent rates of conversions to OPA in aqueous environ-
ments with the addition of 0.01 equivalents of phthalic acid
(Scheme 4). Table 5 shows that the relative percentages of
1,3-dimethoxyphthalan and 1,3- diethoxyphthalan drop by
56.3% and 53.5%, respectively, in the first 24 hours, while
the relative percentage of 1,3-diisopropoxyphthalan drops
by as much as 73.5%. All of the cyclic acetals are readily
converted to OPA in just 48 hours.
In conclusion, we have demonstrated that the addition of
cyclic acetals to an aqueous solution of OPA, leads to a self-
replenishing “smart solution” with no adverse effects on the
OPA solution. The ability of cyclic acetals to be used as
OPA precursors in aqueous disinfection solutions prolongs
both the shelf life and use life of the aqueous OPA solutions.
and the organic phase was washed with H O and brine.
2
The organic layer was collected and dried over MgSO .
4
Pure 1,3-diethoxyphthalan was isolated by silica gel
chromatography (hexane:EtOAc, 15:1) as a colorless oil
(160 mg, 92%).
REFERENCES AND NOTES
∗
PCZ current (correspondence) address: E-TRANS Drug
Delivery, ALZA Corporation, Johnson & Johnson, 1900 Charleston
Road, Mountain View, CA 94043, USA, Tel: (650)564-5894; E-mail:
PZhu1@alzus.jnj.com.
[1] P. C. Zhu, C. G. Roberts and M. S. Fervaro, Current Org.
Chem., 9, 1155 (2005).
[2] J. J. Gan, P. C. Zhu, S. D. Aust, A. T. Lemley, Editors.
Pesticide Decontamination and Detoxification. In: ACS Symp. Ser.,
2003; 863; 51-64; Publisher ACS, Washington, D. C.
[3] P. Zhu, US 6531634.
Acknowledgements.
[4] S. Mirsadeghi and B. Rickborn, J. Org. Chem., 52, 787
(1987).
[5] The concentration of all 1,3-diethoxyphthalan solutions
was 0.03 M in distilled water for each of the acid and pH studies.
We would like to thank William E. Holmes of the
Mississippi State Chemical Laboratory for the use of instru-
mentation and assisstance with the GC/MS experiments.