U.S. patent number 5,683,668 [Application Number 08/522,405] was granted by the patent office on 1997-11-04 for method of generating nitric oxide gas using nitric oxide complexes.
This patent grant is currently assigned to The United States of America as represented by the Department of Health. Invention is credited to Joseph A. Hrabie, Larry K. Keefer.
United States Patent |
5,683,668 |
Hrabie , et al. |
November 4, 1997 |
Method of generating nitric oxide gas using nitric oxide
complexes
Abstract
The present invention provides a method for the generation of NO
gas by exposing zwitterionic polyamine-nitric oxide adducts of the
formula RN[N(O)NO.sup.- ](CH.sub.2).sub.x NH.sub.2.sup.+ R',
wherein R=C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aminoalkyl, or
cyclohexy, R'=hydrogen or C.sub.1 -C.sub.6 alkyl, and x=2-6, to
suitable conditions to effect the release of NO, such as by contact
with a mildly acidic solvent or water of neutral or slightly
alkaline pH.
Inventors: |
Hrabie; Joseph A. (Frederick,
MD), Keefer; Larry K. (Bethesda, MD) |
Assignee: |
The United States of America as
represented by the Department of Health (Washington,
DC)
|
Family
ID: |
34811922 |
Appl.
No.: |
08/522,405 |
Filed: |
February 2, 1996 |
PCT
Filed: |
March 12, 1993 |
PCT No.: |
PCT/US93/02374 |
371
Date: |
February 02, 1996 |
102(e)
Date: |
February 02, 1996 |
PCT
Pub. No.: |
WO94/20415 |
PCT
Pub. Date: |
September 15, 1994 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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906479 |
Jun 30, 1992 |
5250550 |
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585793 |
Sep 20, 1990 |
5155137 |
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Current U.S.
Class: |
423/405; 534/552;
534/556; 534/569; 570/206 |
Current CPC
Class: |
C01B
21/24 (20130101) |
Current International
Class: |
C01B
21/24 (20060101); C01B 21/00 (20060101); C01B
021/24 () |
Field of
Search: |
;423/400,405 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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900978 |
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Oct 1990 |
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WO |
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9205149 |
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Apr 1992 |
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WO |
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9420415 |
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Sep 1994 |
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WO |
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Other References
Maragos et al. "Complexes of .sup..cndot. NO with Nucleophiles as
Agents for the Controlled Biological Release of Nitric Oxide
Vasorelaxant Effects" Apr. 3, 1991. pp. 3242-3247, Journal of
Medicinal Chemistry vol. 34..
|
Primary Examiner: Langel; Wayne
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.
Parent Case Text
This is a continuation of PCT application Ser. No. US/93/02374,
filed on Mar. 12, 1993, which is a continuation-in-part of U.S.
Ser. No. 07/906,479, filed Jun. 30, 1992, now U.S. Pat. No.
5,250,550, which is a division of U.S. Ser. No. 07/585,793, filed
Sep. 20, 1990, now U.S. Pat. No. 5,155,137.
Claims
What is claimed is:
1. A method of generating NO gas ex vivo, which method comprises
contacting a zwitterionic polyamine/NO adduct of structure
RN[N(O)NO.sup.- ](CH.sub.2).sub.x NH.sub.2.sup.+ R', wherein
R=C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aminoalkyl, or
cyclohexyl, R'=hydrogen or C.sub.1 -C.sub.6 alkyl, and x=2-6, with
a solvent, said solvent having sufficient protonating ability to
cause the release of NO from said zwitterionic polyamine/NO
adduct.
2. The method of claim 1, wherein R=methyl, ethyl, propyl,
isopropyl, cyclohexyl, (CH.sub.2).sub.2 NH.sub.2, (CH.sub.2).sub.3
NH.sub.2, or (CH.sub.2).sub.4 NH.sub.2, R'=hydrogen, methyl, ethyl,
propyl, or isopropyl, and x=2-4.
3. The method of claim 2 wherein R=CH.sub.3, R'=H, and x=2.
4. The method of claim 1, wherein said solvent has a pH of about 5
to about 7.
5. The method of claim 1, wherein said solvent is water and has a
pH of about 7 to about 8.
6. The method of claim 1, wherein said solvent is nonaqueous
organic.
7. A method of carrying out ex vivo a chemical process employing a
reagent that produces nitric oxide in situ in a solvent, wherein
the improvement comprises substituting said reagent with a
zwitterionic polyamine/NO adduct of structure RN[N(O)NO.sup.-
](CH.sub.2).sub.x NH.sub.2.sup.+ R', wherein R=C.sub.1 -C.sub.6
alkyl, C.sub.1 -C.sub.6 aminoalkyl, or cyclohexyl, R'=hydrogen or
C.sub.1 -C.sub.6 alkyl, and x=2-6.
8. The method of claim 7, wherein R=methyl, ethyl, propyl,
isopropyl, cyclohexyl, (CH.sub.2).sub.2 NH.sub.2, (CH.sub.2).sub.3
NH.sub.2, or (CH.sub.2).sub.4 NH.sub.2, R'=hydrogen, methyl, ethyl,
propyl, or isopropyl, and x=2-4.
9. The method of claim 8, wherein R=CH.sub.3, R'=H, and x=2.
10. The method of claim 7, wherein said reagent acts via the
production of a nonaqueous diazotizing agent.
11. The method of claim 7, wherein said reagent is a sodium nitrite
or an alkyl nitrite.
12. The method of claim 7, wherein said chemical process is
selected from the group consisting of a Pschorr ring closure or
modification thereof, a Meerwein arylation reaction or modification
thereof, a process of preparing a monohalide from an amine via a
Sandmeyer reaction or modification thereof, a process of preparing
a dihalide using NO gas, a process of preparing a monohalide using
nitrosyl chloride generated in situ, and a deoximation reaction
using either a sodium or an alkyl nitrite .
Description
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the generation of nitric oxide gas
using solid complexes of nitric oxide, in particular zwitterionic
polyamine-nitric oxide adducts.
BACKGROUND OF THE INVENTION
Nitric oxide (NO) has many important uses in biological,
pharmaceutical, chemical, and industrial applications. For example,
NO is a key bioregulatory molecule that plays critical roles in the
regulation of various biological processes, including the normal
physiological control of blood pressure, macrophage-induced
cytostasis and cytotoxicity, inhibition of platelet aggregation,
and neurotransmission (Moncada et al., Pharmacological Reviews,
43(2), 109-142 (1991)). Many diseases, such as endotoxic shock,
ischemia reperfusion injury, genetic mutations, cancer, male
impotence, and atherosclerosis have been suggested to be caused by
defects in the production and/or regulation of NO (Moncada et al.,
supra; Masini et al., Agents and Action, 33, 53-56 (1991)). The use
of NO-releasing compounds in the treatment of hypertension and
other cardiovascular disorders is disclosed in U.S. Pat. No.
4,954,526, which corresponds to WO 92/05149, U.S. Pat. Nos.
5,039,705, and 5,155,137.
In addition to its role as an important bioeffector molecule, NO
has many other uses, particularly in chemical and industrial
applications. NO is used extensively in both the laboratory and the
industrial plant. For example, NO gas is used to directly effect
desired chemical results, and the NO radical is involved in the
formation of diazotizing/nitrosating agents, which are used to
achieve a variety of chemical results.
Free NO gas is used in the preparation of nitric acid, nitrosyl
chloride, metal nitrosyls, and caprolactam, which, in turn, is used
in the synthesis of nylon (McCleverty, Chem. Rev., 79, 53-76
(1979)). NO gas can be used to produce aryl bromides from aryl
amines by a procedure which was developed as an alternative to
traditional Sandmeyer reaction (Brackman and Smit, Recl. Tray.
Chim. Pays-Bas, 85, 857-864 (1966)). The NO gas is used to produce
cuptic bromide nitrosyl in situ, which converts the amine to a
diazonium salt and then to the bromide. NO is also used
commercially as a polymerization inhibitor during the preparation
of olefins (U.S. Pat. No. 4,040,912 and French Patent 2,478,648)
and to improve the properties of various polymers (German Patent
2,216,844). There are numerous other potential chemical and
industrial uses of NO, such as the synthesis of dyes via diazonium
salts (Brackman and Smit, supra).
The potential uses of NO undoubtedly have been limited by the fact
that NO is a highly poisonous and reactive gas. It is a strong
irritant to the skin and mucous membranes. Moreover, NO is
difficult to store in compact form, has a boiling point of
-152.degree. C., and is dangerous to transport. Also, NO gas cannot
be manipulated in the presence of oxygen and will attack most
metals and plastics. Consequently, NO is a difficult gas to handle,
and the constraints on its use are compounded by the fact that,
generally, NO can only be purchased in relatively low-pressure
cylinders, thereby making its storage and distribution quite
cumbersome and relatively expensive.
Currently, NO is either prepared on-site or shipped in heavy
stainless steel cylinders at a pressure of 500 psig. When prepared
on site, sodium nitrite, which serves as the source of NO, is
reacted with acidified iron sulfate to release NO gas, which then
must be purified to remove higher oxides of nitrogen (Blanchard,
Inorg. Synth., 2, 126-128 (1946)). The method employs a rather
large apparatus to contain the slurry of salts used in the reaction
and to ensure that pure NO gas is obtained. This process suffers
from several disadvantages, including the production of large
volumes of highly acidic (H.sub.2 SO.sub.4), iron-containing waste
and concentrated alkaline waste, given that NaOH is used to remove
NO.sub.2 from the gas before use, and the inability to turn the gas
generation on or off as desired.
The literature is replete with examples of compounds which can be
manipulated to release NO; however, these manipulations have been
generally designed for limited NO release under specialized
conditions. Thus, these manipulations are generally unsuitable for
the larger-scale production of NO for biological, pharmaceutical,
chemical, and, particularly, industrial applications.
In particular, it has been found that many tissues in the body
endogenously release NO (Marietta, Chem. Res. in Toxicology, 1(5),
249-257 (1988); Marietta, Biochemistry, 27, 8706-8711 (1988)).
Also, it has been discovered that drugs, including xenobiotics, can
be metabolized to give NO either as the effector molecule or as a
harmful metabolite (Feelisch, J. Cardiovasc. Pharmacol., 17,
S25-S33 (1991); Ignarro etal., Biochem. Biophys. Res. Comm., 94,
93-100 (1980); Servent et al., Biochem. Biophys. Res. Comm., 163,
1210-1216 (1989); Haussmann et al., In: Relevance of N-Nitroso
Compounds to Human Cancer. Exposures and Mechanisms, Bartsch,
O'Neill and Schulte-Hermann, eds., IARC Sci. Pubs., 84, 109-112
(1987)). The nature of these manipulations to generate NO, while
useful in certain biological processes, does not render these
manipulations suitable for the generation of NO in many
applications.
The reaction of NO with amines to produce salts of the structure
RR'N[N(O)NO.sup.-].RR'NH.sub.2.sup.+ has been known for many years
(German Patent 1,085,166; Drago and Paulik, J. Am. Chem. Soc., 82,
96-98 (1960); Drago and Karstetter, J. Am. Chem. Soc., 83,
1819-1822 (1961); Drago et al., J. Am. Chem. Soc., 83, 4337-4339
(1961); Longhi et al., Inorg. Chem., 1, 768-770 (1962); Ragsdale et
al., Inorg. Chem., 4, 420-422 (1965)). The anionic portions of
these salts spontaneously decompose in solution to regenerate NO
(Ragsdale et al., Inorg. Chem., 4, 420-422 (1965); Maragos et al.,
J. Med. Chem., 34, 3242-3247 (1991)). The more stable examples of
these salts, in particular the diethylamine/NO adduct (DEA/NO,
wherein R=R'=ethyl) and the sodium salt of the isopropylamine/NO
adduct (R=isopropyl and R'=H) have been previously isolated (Drago
et al., J. Am. Chem. Soc., 82, 96-98 (1960); Drago et al., J. Am.
Chem. Soc., 83, 1819-1822 (1961)). Although these salts have proven
to be of value in biological studies where a controlled, gradual
release of NO is required, these salts undergo slow decomposition
even in the solid state unless stored at -78.degree. C. and are
thus unsuitable for the convenient storage and generation of NO gas
in many applications.
Intermolecular salts have been prepared through the reaction of two
diamines with NO (Longhi et al., supra). These compounds, however,
were apparently not stable enough to give good combustion analyses
and therefore are likely unsuitable for the storage and generation
of NO gas.
U.S. Pat. Nos. 3,973,910, 3,996,002, 3,996,003, and 3,996,008
describe the generation of NO for the purpose of measuring the
N-nitrosoamine content of a sample. The NO gas is generated by
heating N-nitrosoamine compounds of formula R.sub.1 R.sub.2 NNO,
wherein R.sub.1 and R.sub.2 are the same or different organic
radicals, including those radicals which together with the
nonnitroso N of N-NO constitute a nitrogen heterocyclic radical.
The heat (200.degree.-300.degree. C.) reportedly breaks the N-NO
bonds but not other molecular bonds, thereby releasing NO gas. This
technique, however, requires significant energy in the form of heat
to yield NO gas.
U.S. Pat. Nos. 4,256,462, 4,303,419, and 4,336,158 also describe
the generation of NO for the purpose of measuring the
N-nitrosoamine content of a sample. Instead of cleaving the N-NO
bond by using heat energy, the N-NO bond is chemically cleaved. In
particular, NO gas is generated by reacting denitrosating agents
with N-nitrosoamines of formula RR.sub.1 NNO, wherein R and R.sub.1
may be organic or substituted organic moieties. The denitrosating
agent is a mixture of glacial acetic acid and a concentrated
inorganic acid, particularly phosphoric or sulfuric acid, in
combination with an inorganic water-soluble bromide or iodide salt.
This process, however, involves the undesirable use of
significantly acidic components and halogen salts for the
generation of NO gas. Moreover, the nitrosoamine-based methods for
the generation of NO suffer from the disadvantages that the amount
of NO contained in any nitrosoamine, as a percent by weight, is
very small.
Yet another process for generating NO gas is disclosed in U.S. Pat.
No. 5,094,815, which pertains to a process for the
HPLC-chemiluminescence detection of N-nitroso compounds. In
particular, nitric oxide is cleaved from the N-nitroso compounds by
photolysis using ultraviolet radiation. This process, however,
requires a specialized apparatus involving the use of a UV
generator and is unsuitable for the large-scale production of NO
gas.
It is an object of the present invention to provide a method for
the convenient storage and generation of NO gas. It is another
object of the present invention to provide a method for the
controlled release of NO gas from an easily transportable source.
It is a further object of the present invention to provide for the
larger-scale production of NO gas in sufficient quantities for
biological, pharmaceutical, chemical, and industrial uses. It is
yet another object of the present invention to provide for the
generation of NO gas without the need for the expenditure of
considerable energy, the use of significant quantities of
concentrated acids, or the requirement for elaborate apparatus,
such as UV-generators and the like.
The present invention satisfies these long-standing needs for
convenient NO storage, distribution, and generation and provides
for the easy and inexpensive generation of NO gas in sufficient
quantities for a variety of uses. These and other objects and
advantages of the present invention, as well as additional
inventive features, will be apparent from the description of the
invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for the generation of NO
gas by exposing a zwitterionic polyamine/NO adduct to suitable
conditions to effect release of NO, such as by contacting the
adduct with an acidic solvent, water of neutral or slightly
alkaline pH, or a suitable catalyst in an alkaline solvent. The
zwitterionic polyamine/NO adduct has the structure
RN[N(O)NO.sup.-](CH.sub.2).sub.x NH.sub.2.sup.+ R', wherein
R=C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aminoalkyl, or
cyclohexyl, R'=hydrogen or C.sub.1 -C.sub.6 alkyl, and x=2-6. More
preferably, the zwitterionic polyamine/NO adduct is such that
R=methyl, ethyl, propyl, isopropyl, cyclohexyl, (CH.sub.2).sub.2
NH.sub.2, (CH.sub.2).sub.3 NH.sub.2, or (CH.sub.2).sub.4 NH.sub.2,
R'=hydrogen, methyl, ethyl, propyl, or isopropyl, and x=2-4. The
most preferred zwitterionic polyamine/NO adduct is
N-methylethylenediamine, i.e., the compound wherein R=CH.sub.3,
R'=H, and x=2.
Upon exposure to suitable conditions, the zwitterionic polyamine/NO
adducts will release NO gas for any suitable purpose., e.g.,
biological, pharmaceutical, chemical, and industrial applications.
The zwitterionic polyamine/NO adducts can also be used in chemical
processes wherein nitric oxide is generated in situ, by
substituting an adduct for a reagent that produces nitric oxide in
situ in a solvent in the chemical process. The zwitterionic
polyamine/NO adducts used in the present inventive method are very
stable solids and contain as much as 45% NO by weight, which is
capable of being released in solution in amounts and at rates that
vary predictably with structure.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows a suitable apparatus useful in the generation of NO
gas by the method of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of generating NO gas. The
method involves exposing a zwitterionic polyamine/NO adduct to
suitable conditions to effect the release of NO, such as by
contacting the adduct with an acidic solvent, water of neutral or
slightly alkaline pH, or a suitable catalyst in an alkaline
solvent. The zwitterionic polyamine/NO adduct has the formula
wherein R=C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aminoalkyl, or
cyclohexyl, R'=hydrogen or C.sub.1 -C.sub.6 alkyl, and x=2-6.
Preferred zwitterionic polyamine/NO adducts for use in the present
inventive method are those of formula I, wherein R=methyl, ethyl,
propyl, isopropyl, cyclohexyl, (CH.sub.2).sub.2 NH.sub.2,
(CH.sub.2).sub.3 NH.sub.2, or (CH.sub.2).sub.4 NH.sub.2,
R'=hydrogen, methyl, ethyl, propyl, or isopropyl, and x=2-4. Most
preferred for use in the present inventive method is the
zwitterionic polyamine/NO adduct of formula I, wherein R=CH.sub.3,
R'=H, and x=2, namely the N-methylethylenediamine derivative of
formula CH.sub.3 N[N(O)NO.sup.- ](CH.sub.2).sub.2
NH.sub.3.sup.+.
In general, those zwitterionic polyamine/NO adducts of low
molecular weight are preferred since such adducts, as compared to
higher molecular weight adducts, typically have a higher
water-solubility and a higher % NO yield by weight. Also, the lower
molecular weight adducts typically are less expensive and have
lower molecular weight by-products after release of NO which can be
more readily disposed. In addition, zwitterionic polyamine/NO
adducts which are diamines and triamines are preferred inasmuch as
adducts with fewer amine-groups will be generally less
cross-reactive with other possible species.
The zwitterionic polyamine/NO adducts may be prepared by any
suitable process. The synthesis of the NO adducts is described in
U.S. Pat. No. 5,155,137, as well as in Example 1 herein.
The appropriate polyamines are preferably prepared first and then
reacted with nitric oxide under suitable conditions to give the
desired zwitterionic polyamine/NO adduct. Many of the polyamines
needed to prepare NO adducts using such a synthesis route are
commercially available (e.g., from Aldrich Chemical Co., Milwaukee,
Wis.). Polyamines useful in preparing the NO adducts can also be
synthesized utilizing procedures well known by those of ordinary
skill in the art (see, e.g., Garrido et al., J. Org. Chem., 49,
2021-2023 (1984); Bergeron, Accts. Chem. Res., 19, 105-113 (1986);
Bergeron et al., J. Org. Chem., 49, 2997-3001 (1984); Bergeron et
al., J. Org. Chem., 53, 3108-3111 (1988); Carboni et al., Tet.
Lett., 29, 1279-1282 (1988)). The NO adducts can be prepared by
reacting these suitable polyamines with nitric oxide in a method
similar to that taught in Drago et al., J. Am. Chem. Soc., 83,
1819-1822 (1961). It is generally important that the amine starting
materials are uncontaminated by absorbed CO.sub.2 so as to optimize
reaction yields and the stability or shelf-life of the products.
There does appear to be a preference for NO attachment at secondary
amines. Compounds which have primary and secondary nitrogen sites
will typically react with NO gas so as to primarily result in the
production of secondary amine/NO adducts.
The use of dilute solutions in virtually any aprotic solvent will
prevent the formation of intermolecular salts; however, more polar
aprotic solvents may be necessary to prevent formation of
alternative intermolecular products. For example, reaction of
N-isopropyl-1,3-propanediamine with NO can result in the formation
of either an intermolecular salt (isopropyl-N(O)NO.sup.-
(CH.sub.2).sub.3 NH.sub.2.isopropyl-NH.sub.2.sup.+ (CH.sub.2).sub.3
NH.sub.2) or a zwitterion (isopropyl-N[N(O)NO.sup.-
](CH.sub.2).sub.3 NH.sub.3.sup.+). Mostly the salt (86%) forms in
dilute ether solution, whereas mostly the zwitterion (96%) forms in
dilute tetrahydrofuran (THF). The zwitterion forms exclusively in
dilute acetonitrile. Not all of the polyamine/NO reactions exhibit
such a dramatic variation with respect to the solvent used. Some of
the polyamine/NO reactions form pure zwitterionic products in
dilute ether solution. Given that the amines, themselves, are small
polar protic molecules, which can alter the character of the
solvent, acetonitrile is used as the solvent of choice, since
reactions in this solvent appear to be less subject to
complications arising from the effect of the amine on the character
of the solvent.
Under an NO pressure of 70-80 psig, the zwitterionic polyamine/NO
adducts used in the present inventive method form at room
temperature in excellent yields with short (less than one day)
reaction times. The NO adducts are stable as solids for weeks at
room temperature in closed containers and yet will release NO
rapidly in acidic solutions or more slowly in buffered near-neutral
media.
Contacting a zwitterionic polyamine/NO adduct of formula I with an
acidic solvent or water (neutral or even slightly alkaline) allows
for the spontaneous release of NO gas as desired with no
contamination by other oxides of nitrogen. There is no need to heat
the solution, subject it to other reagents, or utilize UV-radiation
to generate the NO gas. The acidic solvent may be any suitable
organic solvent, preferably containing at least a minor amount of a
mineral acid (e.g., hydrochloric acid, sulfuric acid, or the like)
or a Lewis acid (e.g., CuBr.sub.2 or the like). The acidic solvent
is preferably only mildly acidic and has a pH of about 5 up to
about 7. The water of slightly alkaline pH preferably has a pH of
from about 7 to about 8. The solvent may be any suitable solvent
which is capable of wetting the zwitterionic polyamine/NO adduct.
It is not necessary that the adduct dissolve fully for NO to be
produced, although full dissolution is preferable. The preferred
solvent for the generation of NO is water.
The zwitterionic polyamine/NO adduct will also release NO gas when
contacted with a suitable catalyst, such as copper, even in an
alkaline solvent. Such catalyzed release of NO gas in an alkaline
medium is particularly useful in the in situ generation and
reaction of NO. For the in situ generation and reaction of NO, as
set forth, for example, in Example 3 herein, the preferred solvent
is acetonitrile, although other organic solvents (such as ether,
tetrahydrofuran, and the like) will suffice.
The present invention also provides an improved method of carrying
out a chemical process that employs a reagent that produces NO in
situ in a solvent, wherein the improvement comprises substituting
for the reagent a zwitterionic polyamine/NO adduct of formula I.
For example, these zwitterionic polyamine/NO adducts can substitute
for a reagent that acts via the production of a nonaqueous
diazotizing agent and, in particular, can be useful substitutes for
the sodium nitrite or alkyl nitrites in any one of the following
reactions:
the Pschorr ring closure (Abramovitch, Adv. Free-Radical Chem., 2,
87-138 (1966)) or modification thereof (Chauncy and Gellert, Aust.
J. Chem., 22, 993-995 (1969)),
the Meerwein arylation reaction (Rondestvedt, Org. Reactions, 24,
225-259 (1976)) in its modern form (Doyle et al., J. Org. Chem.,
42, 2431-2436 (1977)),
the preparation of monohalides from amines via an alternative to
the Sandmeyer reaction (Brackman et al., Recl. Trav. Chim.
Pays-Bas, 85, 857-864 (1966)), the preparation of dihalides using
NO gas (Doyle et al., J. Amer. Chem. Soc., 98, 1627-1629 (1976)),
the preparation of monohalides using nitrosyl chloride generated in
situ (Doyle et al., J. Org. Chem., 43, 4120-4126 (1978)), and
a deoximation reaction using either sodium or alkyl nitrites (Lee
et al., Tet. Lett., 31, 6677-6680 (1990)).
Those compounds which are most preferred for use in the present
invention are those NO complexes which contain the highest
percentage of NO by weight. Such complexes are formed from the
lowest molecular weight amines. Especially preferred examples of
these NO complexes are set forth in Table I.
TABLE I ______________________________________ Compound % NO By Wt.
______________________________________ CH.sub.3 N(N.sub.2
O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.3.sup.+ 44.7 CH.sub.3
N(N.sub.2 O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.2.sup.+ CH.sub.3
40.5 CH.sub.3 CH.sub.2 N(N.sub.2 O.sub.2.sup.-)CH.sub.2 CH.sub.2
NH.sub.3.sup.+ 2 40.5 CH.sub.3 CH.sub.2 N(N.sub.2
O.sub.2.sup.-)CH.sub.2 CH.sub.3.Na.sup.+ 38.7 H.sub.2 NCH.sub.2
CH.sub.2 N(N.sub.2 O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.3.sup.+
36.8 EtN(N.sub.2 O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.2.sup.+ Et
34.1 ______________________________________
The NO complexes contain as much as 45% NO by weight and are
capable of releasing NO in amounts and at rates that vary in a
predictable way with structure. Accordingly, the selection of an
appropriate zwitterionic polyamine/NO adduct allows for a wide
range of desired NO generation rates to be achieved. The NO
released from the various adducts can be very rapid, such as 1-2
minutes, or very slow, such as several days. An appropriate NO
adduct, therefore, can be chosen for a desired rate of release for
most applications.
In particular, the release rate of NO can be varied by altering the
length of the alkyl chain separating the nitrogen atoms, i.e., the
value of x in the general structural formula I of the zwitterionic
polyamine/NO adducts of interest. Generally, the rate of release of
NO may be increased by increasing the value of x. For example,
1-hydroxy-2-oxo-3-(N-methyl-2-aminoethyl)-3-methyl-1-triazene, in
which x=2, has a half-life of 36.1 min, whereas
1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene, in
which x=3, has a half-life of 10.1 min. This decrease in half-life
is believed to be the result of the decreasing importance of
hydrogen bonding as x increases.
The release rate of NO can be also varied by altering the size of
the R group in the general formula I of the zwitterionic
polyamine/NO adducts. For example,
1-hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene, in which R is
methyl, has a half-life of 40 min, whereas
1-hydroxy-2-oxo-3-(2-aminoethyl)-3-ethyl-1-triazene, in which R is
ethyl, has a half-life of 333 min. In general, half-lives in
buffered aqueous solution at pH 7.4 and 22.degree. C. vary from
extremely short (1.3 min for MeN[N(O)NO.sup.- ](CH.sub.2).sub.4
NH.sub.2.sup.+ Me) to very long (56 h for H.sub.2 NCH.sub.2
CH.sub.2 N[N(O)NO.sup.- ]CH.sub.2 CH.sub.2 NH.sub.3.sup.+) with the
longest half-lives being achieved by triamine/NO adducts, in
particular 1-hydroxy-2-oxo-3,3-di(2-aminoethyl)-1-triazene which
has a half-life over 200 times that of the diethylamine/NO adduct.
Stabilization of the zwitterionic polyamine/NO adducts by the R
group may be due to changes in the electron distribution within the
[N(O)NO.sup.- ] system.
When increasing the size of the R group to increase the stability
of the NO adducts in solution, and thereby lengthen the half-lives
of those NO adducts, it is important to take into consideration
steric effects with respect to substitutions at the R group. If the
R group is too large, the derivative which results may fail to
react with NO under low pressure conditions and the desired NO
adduct may be more difficultly prepared.
In contrast to R, R' does not appear to have any influence on
half-life. For example,
1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (R=i-Pr,
R'=H) and
1-hydroxy-2-oxo-3-(N-isopropyl-3-aminopropyl)-3-isopropyl-1-triazene
(R=i-Pr, R'=i-Pr) have similar half-lives.
1-Hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene (R=Me, R'=H)
and 1-hydroxy-2-oxo-3-(N-methyl-2-aminoethyl)-3-methyl-1-triazene
(R=Me, R'=Me) have similar half-lives.
1-Hydroxy-2-oxo-3-(2-aminoethyl)-3-ethyl-1-triazene (R=Et, R'=H)
and 1-hydroxy-2-oxo-3-(N-ethyl-2-aminoethyl)-3-ethyl-1-triazene
(R=Et, R'=Et) have similar half-lives. This lack of an effect may
be due to the fact that R' is remote from the .pi. electron system
and is relatively incapable of exerting either a steric or
electronic effect. Similarly, the presence of a tertiary amine
group elsewhere in the molecule does not appear to have an effect
on the half-life of the NO adducts.
The overall amount of NO released can be also varied by choice of
adduct. For example,
1-hydroxy-2-oxo-3-(3-aminopropyl)-3-propyl-1-triazene, spermine/NO
adduct, 1-hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene,
1-hydroxy-2-oxo-3-(N-methyl-2-aminoethyl)-3-methyl-1-triazene,
1-hydroxy-2-oxo-3-(N-ethyl-2-aminoethyl)-3-ethyl-1-triazene, and
1-hydroxy-2-oxo-3,3-di(2-aminoethyl)-1-triazene all release two
equivalents of NO at 22.degree. C.
These zwitterionic polyamine/NO adducts, therefore, are
particularly useful for the storage and generation of NO gas. These
NO adducts are stable powders which may be shipped in glass or
plastic bottles, in contrast to the steel cylinders used to ship NO
gas. The NO adducts not only can be handled in air without fear of
exposure to toxic vapor, they provide a remarkably compact storage
medium for NO gas. For example,
1-hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene is 45% NO by
weight, and a 50 g bottle of this compound is equivalent to an
entire lecture bottle of NO. In fact,
1-hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene can be used in
a Kipp type generator to produce a steady stream of NO in the same
way that zinc is used in the production of hydrogen.
Thus, the present invention also provides for a kit for the
generation of NO gas. Such a kit comprises one or more of the
zwitterionic polyamine/NO adducts and a suitable apparatus for
contacting an adduct with an appropriate solvent such as an acidic
solvent or water. Such an apparatus will typically contain a
reservoir to hold the adduct, a vessel in which to contact the
adduct with solvent to effect generation of nitric oxide gas, means
to direct the flow of the nitric oxide gas (such as appropriate
tubing and valves), means for drying the nitric oxide gas (such as
a drying tower or use of appropriate desiccants), means for
preventing backflow (such as a check-valve), and means for
measuring the output of the nitric oxide gas (such as a flowmeter).
Preferably, such a kit includes a mildly acidic solvent or a more
concentrated acid which can be diluted with water prior to contact
with the adduct.
The following examples further illustrate the present invention
and, of course, should not be construed as in any way limiting its
scope.
EXAMPLE 1
This example illustrates the preparation of various zwitterionic
polyamine/NO adducts for use in conjunction with the present
invention by using different amines as starting materials in the
following general procedure.
A Parr hydrogenation bottle was incorporated into a specially
constructed reactor, which was modeled after the standard Parr 3911
hydrogenation apparatus (Parr Instrument Co., Moline, Ill.),
because stainless steel is required for prolonged exposure to NO
gas and amines degrade most types of stoppers and gaskets. The
reservoir was replaced by a type 304 stainless steel gas sampling
cylinder equipped with stainless steel fittings, which are
available from any valve and fitting plumbing supply company.
Diaphragm-seal, packless type valves (Aldrich), and stainless steel
pressure gauges (Air Products) were employed. The Parr bottle,
along with the usual Parr clamp, were used but were connected to
the gas reservoir using a Teflon tube and were mounted so as to
allow for stirring with a magnetic stirrer.
Unless otherwise indicated, amines were purchased from either
Carbolabs, Inc. (Bethany, Conn.) or Aldrich Chemical Co.
(Milwaukee, Wis.). Reaction solvents were anhydrous grade (Aldrich)
but all others were reagent grade. NO was obtained from Matheson
Gas Products and was used as received.
A solution of the appropriate amine in the desired solvent was
placed into the standard Parr hydrogenation bottle. Nitrogen was
passed through the apparatus and bubbled through the solution for
5-10 minutes. The bottle was clamped, and NO gas was admitted to a
pressure of 5 atm . The solution was stirred for the indicated time
with addition of NO as needed during the first 5-6 h to maintain
the reservoir pressure. The reactions, which were neither heated
nor cooled, appeared to warm only very slightly for the first hour,
and then returned to room temperature. Excess NO was then vented,
and N.sub.2 was bubbled through the resulting white slurry for 5
min. The product was isolated by filtration, washed with the
reaction solvent, washed with ether, and then dried in vacuo for
several hours. All of the products were amorphous, voluminous
powders which, except as indicated, were air-stable.
Analytical data were obtained using the products as isolated
directly from the reaction mixtures. The NMR spectra of all
compounds were obtained in D.sub.2 O (.sup.1 H at 200 MHz; .sup.13
C at 50 MHz) at the natural pD of their solutions. Due to the
finite time required for data acquisition, the .sup.13 C spectra of
the shorter half-lived compounds often displayed small peaks
attributable to the parent amines, which are not set forth herein.
Elemental analysis data for each of the compounds were also
obtained and compared to the calculated values expected for such
compounds.
Ultraviolet data were obtained in 0.01M NaOH to avoid this
degradation problem. Melting points were obtained on a hot stage
and are uncorrected. Kinetic data were obtained by diluting stock
solutions (0.01M NaOH) of each compound with pH 7.4 phosphate
buffer (0.1M) as needed to produce final solutions having compound
concentrations in the range of 90-120 .mu.M. The rate of NO release
was determined by following the disappearance of the characteristic
UV absorption (.lambda..sub.max =250-252 nm), which all of these
compounds exhibit. In each case, a plot of 1/(A-A.sub..infin.) vs.
time was linear and was used to calculate the rate constant. The
temperature in the spectrophotometer cavity was
22.degree..+-.2.degree. C. and was not thermostated. Compound 14
was too stable to permit monitoring over a sufficient number of
half-lives to guarantee the accuracy of the value obtained for its
half-life. No mass spectral data are provided since these compounds
display the spectra of the parent amines due to rapid dissociation
in high vacuum. Elemental analyses were performed by Atlantic
Microlab, Inc. (Norcross, Ga.). All compounds are named in the
neutral form, which would result if the site of proton attachment
was assumed to be the same as the preferred site of alkylation.
1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (1).
Prepared by treating N-isopropyl-1,3-propanediamine (10.0 g, 86.0
mmol) in 200 ml of THF with NO for 74 h. Yield 0.66 g (4.5%); mp
114.degree.-115.degree. C. dec; .sup.1 H NMR .delta. 1.07 (6H, d,
J=6.3 Hz), 1.68 (2H, m), 3.02-3.14 (4H, m), 3.22 (1H, septet, J=6.3
Hz); .sup.13 C NMR .delta. 22.2, 27.2, 40.6, 50.1, 57.1.
Anal. Calc'd for C.sub.6 H.sub.16 N.sub.4 O.sub.2 : C, 40.90; H,
9.15; N, 31.79. Found: C, 40.98; H, 9.15; N, 31.79.
When this preparation was repeated using a solution of 10 g of the
amine in 150 ml of ether and a 4 day reaction time, there was
obtained 0.88 g of white solid, which NMR showed to be 86%
intermolecular salt (isopropyl-N(O)NO.sup.- (CH.sub.2).sub.3
NH.sub.2.isopropyl-NH.sub.2 (CH.sub.2).sub.3 NH.sub.2). This
material was not stable enough to obtain combustion analytical
data. mp 98.degree.-101.degree. C. dec; .sup.1 H NMR .delta. 1.07
(6H, d, J=6.3 Hz), 1.26 (6H, d, J=6.7 Hz), 1.68 (2H, m), 1.86 (2H,
m), 2.87 (2H, t, J=7.3 Hz); 3.02-3.14 (6H, m), 3.16-3.35 (2H, m);
.sup.13 C NMR .delta. 21.7, 22.2, 27.2, 30.1, 40.5, 40.6, 45.4,
50.1, 53.0, 57.1.
1-Hydroxy-2-oxo-3-(N-methyl-2-aminoethyl)-3-methyl-1-triazene (2).
Prepared by reacting N,N'-dimethylethylenediamine (5.00 g, 56.7
mmol) in 200 ml of THF with NO for 47 h. Yield 3.87 g (46%); mp
116.degree.-117.degree. C. dec; .sup.1 H NMR .delta. 2.73 (3H, s),
2.82 (3H, s), 3.05 (2H, m, M.sub.2 portion of an AA'M.sub.2
system), 3.27 (2H, m, AA' portion of an AA'M.sub.2 system); .sup.13
C NMR .delta. 35.8, 44.9, 48.5, 53.1.
Anal. Calc'd for C.sub.4 H.sub.12 N.sub.4 O.sub.2 : C, 32.43; H,
8.17; N, 37.82. Found: C, 32.53; H, 8.23; N, 37.75.
1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (3).
Prepared by treating N,N'-dimethyl-1,3-propanediamine (9.78 g, 95.7
mmol) in 200 ml of THF with NO for 27 h. Yield 5.37 g (35%); mp
111.degree.-112.degree. C. dec; .sup.1 H NMR .delta. 1.70 (2H, m),
2.68 (3H, s), 2.76 (3H, s), 3.00-3.13 (4H, m); .sup.13 C NMR
.delta. 25.8, 35.8, 45.3, 50.1, 54.4.
Anal. Calc'd for C.sub.5 H.sub.14 N.sub.4 O.sub.2 : C, 37.02; H,
8.69; N, 34.55. Found: C, 37.12; H, 8.74; N, 34.45.
1-Hydroxy-2-oxo-3-(N-methyl-4-aminobutyl)-3-methyl-1-triazene (4).
Synthesized by reacting N,N'-dimethylputrescine (Pfaltz and Bauer,
5.00 g, 43.0 mmol) in 150 ml of CH.sub.3 CN with NO for 23 h. Yield
6.47 g (85%); mp 112.degree.-114.degree. C. dec; .sup.1 H NMR
.delta. 1.40 (2H, m), 1.74 (2H, m), 2.67 (3H, s), 2.74 (3H, s),
2.97 (4H, m); .sup.13 C NMR .delta. 26.0, 26.2, 35.6, 45.2, 51.7,
56.7.
Anal. Calc'd for C.sub.6 H.sub.16 N.sub.4 O.sub.2 : C, 40.90; H,
9.15; N, 31.79. Found: C, 41.18; H, 9.20; N, 31.63.
1-Hydroxy-2-oxo-3-(N-methyl-6-aminohexyl)-3-methyl-1-triazene (5).
Synthesized by treating N,N'-dimethyl-1,6-hexanediamine (5.00 g,
34.7 mmol) in 150 ml of CH.sub.3 CN with NO for 22 h. Yield 6.08 g
(86%); mp 108.degree.-110.degree. C. dec; .sup.1 H NMR .delta.
1.25-1.45 (6H, m), 1.55-1.72 (2H, m), 2.67 (3H, s), 2.72 (3H, s),
2.85-3.01 (4H, m); .sup.13 C NMR .delta. 28.2 (2 C), 28.3, 28.4,
35.6, 45.1, 52.0, 57.3.
Anal. Calc'd for C.sub.8 H.sub.20 N.sub.4 O.sub.2 : C, 47.04; H,
9.86; N, 27.43. Found: C, 47.26; H, 9.94; N, 27.29.
1-Hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-1-triazene (6). Prepared
by treating N-methylethylenediamine (10.0 g, 135 mmol) in 150 ml of
CH.sub.3 CN with NO for 27 h. Yield 14.8 g (82%); mp
115.degree.-116.degree. C. dec; .sup.1 H NMR .delta. 2.82 (3H, s),
3.00 (2H, m, M.sub.2 portion of an AA'M.sub.2 portion of an
AA'M.sub.2 system), 3.24 (2H, m, AA' portion of an AA'M.sub.2
system); .sup.13 C NMR .delta. 39.2, 45.0, 54.1.
Anal. Calc'd for C.sub.3 H.sub.10 N.sub.4 O.sub.2 : C, 26.86; H,
7.51; N, 41.77. Found: C, 27.10; H, 7.58; N, 41.80.
1-Hydroxy-2-oxo-3-(2-aminoethyl)-3-ethyl-1-triazene (7).
Synthesized by treating N-ethylethylenediamine (5.00 g, 56.7 mmol)
in 150 ml of CH.sub.3 CN with NO for 26 h. Yield 5.51 g (66%); mp
105.degree.-106.degree. C. dec; .sup.1 H NMR .delta.0.99 (3H, t,
J=7.1 Hz), 2.97-3.08 (4H, m), 3.25 (2H, m, AA' portion of an
AA'M.sub.2 system); .sup.13 C NMR .delta. 14.0, 39.2, 51.5,
53.0.
Anal. Calc'd for C.sub.4 H.sub.12 N.sub.4 O.sub.2 : C, 32.43; H,
8.17; N, 37.82. Found: C, 32.52; H, 8.19; N, 37.88.
1-Hydroxy-2-oxo-3-(N-ethyl-2-aminoethyl)-3-ethyl-1-triazene (8).
Prepared by reacting N,N'-diethylethylenediamine (5.00 g, 43.0
mmol) in 150 ml of CH.sub.3 CN with NO for 21 h. Yield 6.80 g
(90%); mp 127.degree.-128.degree. C. dec; .sup.1 H NMR .delta. 0.99
(3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.3 Hz), 2.97-3.08 (4H, m), 3.11
(2H, q, J=7.3 Hz), 3.27 (2H, m, AA' portion of an AA'M.sub.2
system); .sup.13 C NMR .delta. 13.4, 13.9, 45.8, 46.5, 51.5,
52.1.
Anal. Calc'd for C.sub.6 H.sub.16 N.sub.4 O.sub.2 : C, 40.90; H,
9.15; N, 31.79. Found: C, 41.00; H, 9.23; N, 31.73.
1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-methyl-1-triazene (9). Prepared
by treating N-methyl-1,3-propanediamine (10.0 g, 113 mmol) in 150
ml of CH.sub.3 CN with NO for 22 h. Yield 15.9 g (94%); mp
117.degree.-118.degree. C. dec; .sup.1 H NMR .delta. 1.61 (2H, m),
2.76 (3H, s), 3.02 (2H, t, J=4.8 Hz), 3.07 (2H, t, J=6.7 Hz);
.sup.13 C NMR .delta. 27.1, 40.5, 45.3, 54.5.
Anal. Calc'd for C.sub.4 H.sub.12 N.sub.4 O.sub.2 : C, 32.43; H,
8.17; N, 37.82. Found C, 32.57; H, 8.23; N, 37.59.
1-Hydroxy-2-oxo -3-(N-ethyl-3-aminopropyl)-3-ethyl-1-1-triazene
(10). Synthesized by reacting N,N'-diethyl-1,3-propanediamine (5.00
g, 38.4 mmol) in 150 ml of CH.sub.3 CN with NO for 24 h. Yield 6.71
g (92%); mp 114.degree.-116.degree. C. dec; .sup.1 H NMR .delta.
0.97 (3H, t, J=7.2 Hz), 1.27 (3H, t, J=7.3 Hz), 1.71 (2H, m), 2.96
(2H, q, J=7.2 Hz), 3.00-3.14 (6H, m); .sup.13 C NMR .delta. 13.4,
13.8, 25.8, 45.7, 48.0, 51.7, 53.5.
Anal. Calc'd for C.sub.7 H.sub.18 N.sub.4 O.sub.2 : C, 44.19; H,
9.54; N, 29.45. Found: C, 44.23; H, 9.47; N, 29.39.
1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-propyl-1-triazene (11).
Prepared by treating N-propyl-1,3-propanediamine (10.0 g, 86.1
mmol) in 300 ml of CH.sub.3 CN with NO for 23 h. Yield 12.4 g
(82%); mp 98.degree.-99.degree. C. dec; .sup.1 H NMR .delta. 0.90
(3H, t, J=7.3 Hz), 1.34 (2H, sextet, J.sub.1 =J.sub.2 =7.3 Hz),
1.69 (2H, quintet, J.sub.3 =J.sub.4 =6.8 Hz), 2.88 (2H, t, J=7.3
Hz), 3.03 (2H, t, J=6.8 Hz), 3.06 (2H, t, J=6.8 Hz); .sup.13 C NMR
.delta. 13.6, 22.3, 26.9, 40.6, 53.8, 58.9.
Anal. Calc'd for C.sub.6 H.sub.16 N.sub.4 O.sub.2 : C, 40.90; H,
9.15; N, 31.79. Found: C, 40.93; H, 9.21; N, 31.85.
1-Hydroxy-2-oxo-3-(N-isopropyl-3-aminopropyl)-3-isopropyl-1-triazene
(12). Prepared by reacting N,N'-diisopropyl-1,3-propanediamine
(5.00 g, 31.6 mmol) in 150 ml of CH.sub.3 CN with NO for 42 h.
Yield 3.52 g (51%); mp 114.degree.-116.degree. C. dec; .sup.1 H NMR
.delta. 1.07 (6H, d, J=6.2 Hz), 1.30 (6H, d, J=6.4 HZ), 1.67 (2H,
m), 3.06-3.14 (4H, m), 3.22 (1H, septet, J=6.2 Hz), 3.38 (1H,
septet, J=6.4 Hz); .sup.13 C NMR .delta. 21.1 (2 C), 22.2 (2 C),
26.1, 45.8, 50.1, 53.4, 57.1.
Anal. Calc'd for C.sub.9 H.sub.22 N.sub.4 O.sub.2 : C, 49.52; H,
10.16; N, 25.66. Found C, 49.59; H, 10.21; N, 25.59.
1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-cyclohexyl-1-triazene (13).
Prepared by reacting N-cyclohexyl-1,3-propanediamine (5.00 g, 32.0
mmol) in 150 ml of CH.sub.3 CN with NO for 42 h. Yield 4.06 g
(59%); mp 116.degree.-117.degree. C. dec; .sup.1 NMR .delta.
1.05-1.38 (5H, m), 1.55-1.80 (7H, m), 2.88 (1H, m), 2.98-3.15 (4H,
m); .sup.13 C NMR .delta. 27.0 (2 C), 27.1, 28.1, 32.5 (2 C), 40.7,
49.6, 64.4.
Anal. Calc'd for C.sub.9 H.sub.20 N.sub.4 O.sub.2 : C, 49.98; H,
9.32; N, 25.91. Found: C, 50.54; H, 9.43; N, 25.41.
1-Hydroxy-2-oxo-3,3-di (2-aminoethyl)-1-triazene (14). Prepared by
treating diethylenetriamine (5.00 g, 48.5 mmol) in 150 ml of
CH.sub.3 CN with NO for 23 h. Yield 7.14 g (90%); mp
109.degree.-110.degree. C. dec; .sup.1 H NMR .delta. 2.82 (4H, m,
M.sub.2 portion of an AA'M.sub.2 system), 3.18 (4H, m, AA' portion
of an AA'M.sub.2 system), .sup.13 C NMR .delta. 39.7 (2 C), 55.8 (2
C) .
Anal. Calc'd for C.sub.4 H.sub.13 N.sub.5 O.sub.2 : C, 29.44, H,
8.03; N, 42.92. Found: C, 29.50; H, 8.05; N, 42.96.
1-Hydroxy-2-oxo-3,3-di(3-aminopropyl)-1-triazene (15). Prepared by
reacting 3,3'-iminobispropylamine (5.00 g, 38.1 mmol) in 150 ml of
CH.sub.3 CN with NO for 23 h. Yield 6.87 g (94%); mp
99.degree.-100.degree. C. dec; .sup.1 H NMR .delta. 1.60 (4H, tt,
J=7.0, 7.3 Hz), 2.88 (4H, t, J=7.3 Hz), 3.00 (4H, t, J=7.0 Hz);
.sup.13 C NMR .delta. 29.1 (2 C), 40.8 (2 C), 54.2 (2 C).
Anal. Calc'd for C.sub.6 H.sub.17 N.sub.5 O.sub.2 : C, 37.69; H,
8.96; N, 36.62. Found: C, 37.59; H, 8.97; N. 36.52.
1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-(4-aminobutyl)-1-triazene (16).
Prepared by treating spermidine (5.00 g, 34.4 mmol) in 150 ml of
CH.sub.3 CN with NO for 23 h and isolating the hygroscopic product
by the usual method but in a glove bag under N.sub.2. Yield 6.19 g
(88%); mp 92.degree.-94.degree. C. dec; .sup.1 H NMR .delta.
1.32-1.47 (2H, m), 1.51-1.71 (4H, m), 2.79-2.88 (4H, m), 2.91-3.02
(4H, M); .sup.13 C NMR .delta. 26.0, 29.0, 29.7, 40.9, 42.5, 54.3,
56.3.
Anal. Calc'd for C.sub.7 H.sub.19 N.sub.5 O.sub.2 : C, 40.96; H,
9.33; N, 34.12. Found C, 40.91; H, 9.40; N, 34.05.
The ultraviolet and kinetic data for compounds 1-16 were obtained
as previously detailed and are set forth in Table II below.
TABLE II ______________________________________ Synthesized
Zwitterions of the Form RN[N(O)NO.sup.- ](CH.sub.2).sub.x
NH.sub.2.sup.+ R' UV .lambda..sub.max .epsilon. .times. 10.sup.-3
t.sub.1/2 Cmpd x R R' (nm).sup.a (M.sup.-1 cm.sup.-1).sup.a
(min).sup.b ______________________________________ 1 3 i-Pr H 250
7.44 93.0 2 2 Me Me 250 7.31 36.1 3 3 Me Me 250 7.68 10.1 4 4 Me Me
250 8.59 1.3 5 6 Me Me 250 7.25 2.7 6 2 Me H 252 7.80 40 7 2 Et H
252 7.96 333 8 2 Et Et 252 7.61 327 9 3 Me H 250 7.77 13.7 10 3 Et
Et 250 8.55 71.8 11 3 Pr H 250 8.05 76.6 12 3 i-Pr i-Pr 250 7.89
88.5 13 3 cyclohexyl H 250 9.13 115 14 2 (CH.sub.2).sub.2 NH.sub.2
H 252 7.64 3,400 15 3 (CH.sub.2).sub.3 NH.sub.2 H 252 7.86 284 16 3
(CH.sub.2).sub.4 NH.sub.2 H 250 9.42 165
______________________________________ .sup.a Measured in 0.01M
NaOH .sup.b Determined at 22.degree. C. and pH 7.4 in 0.1M
phosphate buffer
EXAMPLE 2
This example describes a preferred method of releasing NO gas from
various zwitterionic polyamine/NO adducts.
NO gas was generated from compounds 2, 6, 10, 11, and 14 of Example
1, as well as H.sub.2 N(CH.sub.2).sub.3 N[N(O)NO.sup.-
](CH.sub.2).sub.4 NH(CH.sub.2).sub.3 NH.sub.3.sup.+, using the
procedure set forth below. The percent NO yield was then calculated
for each of these NO adducts.
Each of these complexes was used to generate NO gas utilizing the
apparatus shown in FIG. 1. The apparatus comprises a first vessel
10 having an inlet 11 and an outlet 12 and contains mineral oil (or
other heavy liquid) to prevent backflow. The outlet 12 of vessel 10
is connected to a first inlet 21 of second vessel 20, which also
has a second inlet 22 and an outlet 23. The second vessel 20
contained either the solid NO complex or an aqueous solution of the
NO complex. An addition funnel 30 is connected to the second inlet
22 of second vessel 20 so as to provide a means of introducing
dilute aqueous HCl into second vessel 20. The outlet 23 of second
vessel 20 is connected to the inlet 41 of condenser 40, and the
outlet 42 of condenser 40 is connected to the inlet 51 of third
vessel 50. The condenser 40 and third vessel 50 function to capture
any mist carried through the apparatus in the gas stream. The
outlet 52 of third vessel 50 is connected to drying towers 60 and
70 which contain desiccant such as calcium chloride or molecular
sieves and contain an outlet 71 for gas passage.
In use, nitrogen gas was passed through the apparatus through the
inlet 11 of first vessel 10 to flush oxygen from the apparatus.
Acidic solution was then introduced into second vessel 20 by way of
addition funnel 30, and NO gas was generated in second vessel 20.
The thus generated NO gas flowed through the outlet 23 of second
vessel 20, through the condenser 40, into the third vessel 50, into
the drying towers 60 and 70, and out the condenser outlet 71.
The NO gas released through the outlet 71 of drying column 70 was
fed into a thermal energy analyzer (TEA), which generates a signal
proportional to the quantity of NO gas present. The yield of NO
gas, as a weight percent of the theoretical maximum, obtained for
each of the compounds tested is given in Table III.
TABLE III ______________________________________ Compound % NO
Yield ______________________________________ CH.sub.3
N[N(O)NO.sup.- ]CH.sub.2 CH.sub.2 NH.sub.2.sup.+ CH.sub.3 98
H.sub.2 NCH.sub.2 CH.sub.2 N[N(O)NO.sup.- ]CH.sub.2 CH.sub.2
NH.sub.3.sup. + 97 EtN[N(O)NO.sup.- ]CH.sub.2 CH.sub.2 CH.sub.2
NH.sub.2.sup.+ Et 100 CH.sub.3 N[N(O)NO.sup.- ]CH.sub.2 CH.sub.2
NH.sub.3.sup.+ 110.sup.a CH.sub.3 CH.sub.2 CH.sub.2 N[N(O)NO.sup.-
]CH.sub.2 CH.sub.2 CH.sub.2 NH.sub.3.sup.+ 110.sup.a H.sub.2
N(CH.sub.2).sub.3 N[N(O)NO.sup.- ](CH.sub.2).sub.4 NH(CH.sub.2).su
b.3 NH.sub.3.sup.+ 95 ______________________________________ .sup.a
Values greater than 100% result when the gas release is slow,
resulting in some drift in the instrument's baseline being included
in th integration.
In a separate series of experiments, the generated gas was also
collected in a gas buret and the yields were measured
volumetrically. Yields ranged from 70-90% of theoretical. For
example, when 1.0 g of CH.sub.3 N(N.sub.2 O.sub.2.sup.-)CH.sub.2
CH.sub.2 NH.sub.3.sup.+ was added to 5 ml concentrated H.sub.2
SO.sub.4, 285 ml NO gas (85%) was trapped in the buret.
EXAMPLE 3
This example illustrates the use of a zwitterionic polyamine/NO
adduct in a chemical process, specifically the conversion of
2,3-dimethylaniline to 3-bromo-o-xylene.
A solution of 44.67 g CuBr.sub.2 (0.20 mole) in 300 ml Ch.sub.3 CN
was cooled in an ice bath and 8.5 g Ch.sub.3 N(N.sub.2
O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.3.sup.+ (0.063 mole) were
added. Then 18.2 g 2,3-dimethylaniline (0.15 mole) were added, and
the resulting solution was stirred, while an additional 4.0 g
CH.sub.3 N(N.sub.2 O.sub.2.sup.-)CH.sub.2 CH.sub.2 NH.sub.3.sup.+
were added in portions over 2 hours. The reaction was allowed to
warm to room temperature and was stirred for 20 hours. The solution
was acidified with 2N HCl and extracted with pentane. The combined
organic layers were dried over MgSO.sub.4, filtered through a short
column of alumina, and distilled to yield 8.2 g (30%) of
3-bromo-o-xylene.
EXAMPLE 4
This example illustrates the extended shelf-life and long-term
stability of the zwitterionic polyamine/NO adducts used in the
present invention.
Samples of compound 11 of Example 1 were stored in a refrigerator
over the course of several months. Combustion analysis data were
obtained several times over the course of the storage period, and
no change in elemental composition was observed during that
time.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference to the same extent as if each
individual document were individually and specifically indicated to
be incorporated by reference and were set forth in its entirety
herein.
While this invention has been described with emphasis upon
preferred embodiments, it will be obvious to those of ordinary
skill in the art that the preferred embodiments may be varied. It
is intended that the invention may be practiced otherwise than as
specifically described herein.
* * * * *