Patent Application
20240132430
In at least one aspect, the present invention relates the use of hypohalites in mechanism-based selective dual-radical organic syntheses.
The use of radicals in organic syntheses is abundant in the industry and employs mostly toxic materials that generate harmful by-products
Accordingly, there is a need for safe and effective radical organic syntheses devoid of dangerous by-products.
In at least one aspect, the present invention provides an exemplary use of hypohalites, such as hypochlorous acid, sodium hypochlorite and potassium hypoiodite, as dual-radical reagents for the synthesis of pattern-specific-compounds. In this regard, unlike most synthetic methodologies that use one reagent to produce one chemical action, the method employed in the present invention targets two selective sites of a starting material using the dual-radical reagent to achieve the overall reaction. According to an embodiment, the dual-radical reagent is sequential in nature: first, the hypohalite radical removes a hydrogen atom from an appropriate donor generating hydroxyl radical as the second part of the radical system , where formation of the hydroxyl radical hinges entirely on the reaction of the hypohalite radical. As such, only those compounds containing the correct pattern in the starting material can react. Such reactions will generally be safe and produce no toxic compounds. For example, sodium chloride and water are the usual by-products.
In another aspect, the following chemical transformations with pattern-specific starting materials can be achieved with the exemplary process:
Some aspects of the disclosure are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and are for purposes of illustrative discussion of embodiments of the disclosure. In this regard, the description, taken with the drawings, makes apparent to those skilled in the art how aspects of the disclosure may be practiced.
Reference will now be made in detail to presently preferred compositions, embodiments and methods of the present invention, which constitute the best modes of practicing the invention presently known to the inventors. The Figures are not necessarily to scale. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for any aspect of the invention and/or as a representative basis for teaching one skilled in the art to variously employ the present invention.
Except in the examples, or where otherwise expressly indicated, all numerical quantities in this description indicating amounts of material or conditions of reaction and/or use are to be understood as modified by the word “about” in describing the broadest scope of the invention. Practice within the numerical limits stated is generally preferred. Also, unless expressly stated to the contrary: all R groups (e.g. Ri where i is an integer) include hydrogen, alkyl, lower alkyl, C1-6 alkyl, C6-10 aryl, C6-10 heteroaryl, —NO2, —NH2, —N(R′R″), —N(R′R″R′″)+L−, Cl, F, Br, —CF3, —CCl3, —CN, —SO3H, —PO3H2, —COOH, —CO2R′, —COR′, —CHO, —OH, —OR′, —O−M+, —SO3−M+, —PO3−M+, —COO−M+, —CF2H, —CF2R′, —CFH2, and —CFR′R″ where R′, R″ and R′″ are C1-10 alkyl or C6-18 aryl groups M is a metal atom (e.g., Na, K, Li, etc.) and L− is a counter anion (e.g., Cl−, Br−, tosylate, etc.); single letters (e.g., “n” or “o”) are 1, 2, 3, 4, or 5; in the compounds disclosed herein including compounds described by formula or by name, a CH bond can be substituted with alkyl, lower alkyl, C1-6 alkyl, C1-22 linear or branched alkyl, C6-10 aryl, C6-10 heteroaryl, —NO2, —NH2, —N(R′R″), —N(R′R″R′″)+L−, Cl, F, Br, —CF3, —CCl3, —CN, —SO3H, —PO3H2, —COOH, —CO2R′, —COR′, —CHO, —OH, —OR′, —O−M+, —SO3−M+, —PO3−M+, —COO−M+, —CF2H, —CF2R′, —CFH2, and —CFR′R″ where R′, R″ and R′″ are C1-10 alkyl or C6-18 aryl groups where M is a metal atom (e.g., Na, K, Li, etc.) and L− is a negative counterion (e.g., Cl−, Br−, etc.); percent, “parts of,” and ratio values are by weight; the description of a group or class of materials as suitable or preferred for a given purpose in connection with the invention implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among the constituents of a mixture once mixed; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation; and, unless expressly stated to the contrary, measurement of a property is determined by the same technique as previously or later referenced for the same property.
The term “alkyl” refers to C1-22 inclusive, linear (i.e., “straight-chain”), branched, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 9 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 22 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 carbon atoms.
It is also to be understood that this invention is not limited to the specific embodiments and methods described below, as specific components and/or conditions may, of course, vary. Furthermore, the terminology used herein is used only for the purpose of describing particular embodiments of the present invention and is not intended to be limiting in any way.
It must also be noted that, as used in the specification and the appended claims, the singular form “a,” “an,” and “the” comprise plural referents unless the context clearly indicates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.
The term “comprising” is synonymous with “including,” “having,” “containing,” or “characterized by.” These terms are inclusive and open-ended and do not exclude additional, unrecited elements or method steps.
The phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. When this phrase appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps, plus those that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.
With respect to the terms “comprising,” “consisting of,” and “consisting essentially of,” where one of these three terms is used herein, the presently disclosed and claimed subject matter can include the use of either of the other two terms.
The phrase “composed of” means “including” or “comprising.” Typically, this phrase is used to denote that an object is formed from a material.
It should also be appreciated that integer ranges explicitly include all intervening integers. For example, the integer range 1-10 explicitly includes 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Similarly, the range 1 to 100 includes 1, 2, 3, 4 . . . 97, 98, 99, 100. Similarly, when any range is called for, intervening numbers that are increments of the difference between the upper limit and the lower limit divided by 10 can be taken as alternative upper or lower limits. For example, if the range is 1.1. to 2.1 the following numbers 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 can be selected as lower or upper limits. In the specific examples set forth herein, concentrations, temperature, and reaction conditions (e.g. pressure, pH, etc.) can be practiced with plus or minus 50 percent of the values indicated rounded to three significant figures. In a refinement, concentrations, temperature, and reaction conditions (e.g., pressure, pH, etc.) can be practiced with plus or minus 30 percent of the values indicated rounded to three significant figures of the value provided in the examples. In another refinement, concentrations, temperature, and reaction conditions (e.g., pH, etc.) can be practiced with plus or minus 10 percent of the values indicated rounded to three significant figures of the value provided in the examples.
In the examples set forth herein, concentrations, temperature, and reaction conditions (e.g., pressure, pH, flow rates, etc.) can be practiced with plus or minus 50 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples. In a refinement, concentrations, temperature, and reaction conditions (e.g., pressure, pH, flow rates, etc.) can be practiced with plus or minus 30 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples. In another refinement, concentrations, temperature, and reaction conditions (e.g., pressure, pH, flow rates, etc.) can be practiced with plus or minus 10 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
The term “weak organic acid” refers to a carboxylic acid, dicarboxylic acid, or tricarboxylic acid having a pKa from 2 to 7.5. In a refinement, refers to a carboxylic acid, dicarboxylic acid, or tricarboxylic acid having a pKa of at least 2, 2.5, 3, 3.5, or 4 and of at most 7.5, 7, 6.5, 6, 5.5 or 5. Examples of weak organic acids include but are not limited to, acetic acid, formic acid, propionic acid, butyric acid, benzoic acid, lactic acid, and oxalic acid. It is noteworthy that acetic acid has a pKa of about 4.76.
In at least one aspect, one of the most abundant radicals in the animal environment is the hydroxyl radical (OH), produced naturally by enzymes but also by the interplay of compounds such as ferric iron (Fe+3) and ascorbic acid (vitamin C). The hydroxyl radical produced by nature is used as a tool to perform essential reactions, it also serves as a signaling molecule of vital conditions and to destroy invading attackers such as viruses and bacteria. It was found that the enzyme catalase, present extensively in the human body to perform the conversion of hydrogen peroxide (H2O2) to molecular oxygen (O2) and water (H2O) as shown as the overall reaction in
In another aspect, by using the reported crystal structures of the enzyme and the hydroxyl radical generator K3HFe(CN)6, which also converts H2O2 to O2 and H2O but through the formation of OH radicals as shown in 21 2, the mechanism of action of catalase has been elucidated.
In another aspect, the catalase enzyme has in its native state a hydrogenated heme iron (heme-H) in a low oxidation state in close proximity to the oxygen of the phenol tyrosine that is actually a tyrosyl radical. Similar to the synthesis of K3HFe(CN)6 shown in
In another aspect, the mechanism of catalase is shown in
In another aspect, to demonstrate the production and involvement of the hydroxyl radical in the catalase mechanism, the same reaction of
Furthermore, a reaction similar to the one displayed in
In another aspect, despite the fact that
In another aspect, the importance of the result of
In another aspect, the reaction of
Furthermore, since the reaction of
In another aspect, the reaction of
Furthermore, because the reaction is not concerted, the hydroxyl radicals can be observed with ease especially when the concentration of peroxide decreases. Application of the discovered dual radical character of hypochlorite to the reaction of 1,4-aminophenol can be done in a biphasic system of ethyl acetate/water, a method that simplifies purification of the 1,4-iminoquinone of
Furthermore, the formation of dopaminochrome proceeds expeditiously with only two units of hypochlorite as opposed to the 4 units of hydroxyl radicals required with catalase, as shown in
In another aspect, the new discovery of the dual-radical character of hypochlorite in which a hydroxyl radical is involved, ushered a search for the synthesis of compounds that are typically difficult or unattainable by other methods. In that vein, E-quinone, the metabolite of α-tocopherol, one of four vitamin E, which have been successfully produced using the hydroxyl radical was evaluated with this simple method. The reaction of α-tocopherol with one equivalent of hypochlorite in an ethanol/water mixture produces 100% yield of pure red E-quinone with sodium chloride (NaCl) as the only by-product. Following the mechanism outlined before, this synthesis is detailed in
In another aspect, the importance of an easy and inexpensive synthesis of E-quinone lies in the fact that it allows the study of its involvement in the long known toxicity/interaction with vitamin K, a close structural analog. It has been proposed that the α-tocopherol has toxicity not shared by the β, δ and γ analogues, so the hypochlorite synthesis, a possible replication of a natural process, was used to process the 6-analogue, a compound that differs from the α-analogue in the absence of two methyl (CH3) groups flanking the OH phenol. Since radical reactions in the aromatic ring follow the electronic rules for substitution, this reaction presents the possibility of explaining the differences in toxicity of the 4 analogues.
In another aspect, as shown in
In another aspect, the formation of 1,4-iminoquinone and 1,4-benzoquinone represent new dehydrogenations reactions, dopaminochrome synthesis from dopamine represents a cyclization reaction, whereas E-quinone and tococatechol production are examples of new hydroxylation reactions achieved using the dual-radical character of the hypochlorite, subject of the current application. The areas of activity of this dual radical extend besides those three general methods. When phenylalanine and proline are mixed separately with hypochlorite, the known fecal metabolite indole and the semen-smelling 1-pyrroline are formed, respectively as shown in
Furthermore, the simplicity of the syntheses of
In another aspect, the examples given use sodium hypochlorite as the hypohalite of choice due to ample availability, simplicity of product purification, and low cost. Hypochlorous acid, obtained by acidification of sodium hypochlorite typically to a pH of 3-4 is used to produce materials that are more stable as salts such as the hydrochloride of dopaminochrome, and the hypoiodite can also be employed to perform the same reactions, but, because the hypoiodite is unstable, it is generated in the reaction vessel from the reaction between potassium iodide and hydrogen peroxide. Although hypoiodite can be used at any concentration even in catalytic amounts, the drawbacks for its use is the price of the potassium iodide compared to the hypochlorite and the price of purification of the final product due to the fact that iodine (I2) is a by-product in this reaction, and iodine gives a yellow color to final materials. The hypoiodite is generated from the reaction of potassium iodide (KI) with hydrogen peroxide and its catalytic use stems from the fact that after reaction with the hydrogen donors, regenerates the iodide starting material, so the only consumable component is the hydrogen peroxide. As shown in
In another aspect, the requirements for the dual-radical formation process make the reactions: a) very selective, b) prevent the formation of secondary products, and c) releases non-toxic by-products, namely salt and water. Further, the reactions can be completed (with purified products) relatively quickly, making the processes very cost-effective.
In another aspect, five types of general reactions are covered by this dual radical method in which the basic series of events are outlined in the general diagram of
The mechanistic diagram of
H—X—RB—RA—RC—OH
wherein:
RA is an optionally substituted aromatic ring, or an optionally substituted aromatic ring fused to a second ring structure, wherein RA is optionally substituted with one or more C1-20 alkyl, hydroxyl, or C1-20 alkoxy groups;
RB is absent, a C1-20 alkyl group or a carboxyl group;
RC is absent, a C1-20 alkyl group or a carboxyl group; and
X is absent, O or NH. As set forth above, the starting compound is cyclized when the starting compound includes a phenol group and an amino group; the starting compound is dehydrogenated when the starting compound includes two phenol groups in the same ring or when a phenol and amino group in the same ring; the starting compound hydroxylated when the starting compound described includes a phenol group and a hydrogen on an adjacent carbon to the phenol (ortho position) or two carbons apart (para position); or the starting compound is decarboxylated when the starting compound includes an amino group and a carboxyl (acid) group attached to the same carbon.
In another aspect, a method for making p-quinones via a dehydrogenation reaction as depicted in
wherein R is selected from linear or branched C1-22 alkyl, HC═O, or carboxy. In a refinement, the molar ratio of the hypochlorite salts to the 5,7,8-trimethyl-6-chromanol is about 1:1.
In another aspect, a method for making aminochromes via a cyclization reaction as depicted in
wherein R1, R2 are each independently H, alkyl, or alkoxy. In a refinement, the molar ratio of the hypochlorite salt or the hypochlorous acid to the catecholamine described by formula 3 is about 1:1.
In another aspect, a method for making catechols via a hydroxylation reaction as depicted in
wherein R is selected from linear or branched C1-22 alkyl, HC═O, or carboxy. In a refinement, the molar ratio of the hypochlorite salt or the hypochlorous acid to the chromanol described by formula 5 is about 1:1.
In another aspect, a method for making p-imino quinone via a dehydrogenation reaction as depicted in
wherein R1, R2, R3 and R4 are each independently H, alkyl, or alkoxy. In a refinement, the molar ratio of the hypochlorite salt or the hypochlorous acid to the p-aminophenol described by formula 7 is about 1:1.
In another aspect, a method for making trichloromethyl ketones as depicted in
wherein R is linear or branched C1-22 alkyl. In a refinement, R is methyl. In a refinement, the molar ratio of the hypochlorite salt to the ketone described by formula 9 is about 3:1.
In another aspect, a method for making a dehydroascorbic acid via a dehydrogenation reaction as depicted in
In a refinement, the molar ratio of the hypochlorite salt or hypochlorous acid to the ascorbic acid described by formula 11 is about 1:1.
To a solution in water, or water/alcohol of the substrate (i.e., the compound to undergo the reaction) is added the number of equivalents of sodium hypochlorite required to produce the reaction. The number of equivalents of the hypochlorite are calculated from the balanced equation of the process based on the conditions of the dual radical system established above. After completion of the reaction, estimated by the disappearance of the starting material which can be observed using thin layer chromatography (TLC), the product is isolated by extraction or by concentration followed by extraction with a solvent of appropriate polarity. If hypochlorous acid is indicated for stability of the final product, as in the synthesis of dopaminochrome, the reactions above are run on a weak organic acid pre-acidified (e.g., pH 3 to 4) solution.
For compounds that are soluble in nonpolar solvents, a biphasic system of ethyl acetate/water is also appropriate. As such, the substrate is dissolved in the ethyl acetate with the mixture set above the water solution of sodium hypochlorite and shaken until completion (about 1-2 hours) as judged by TLC. The mixture can be separated using a separatory funnel and the organic phase is passed through a short silica gel or alumina plug and concentrated.
Typically, the reactions are carried out at ambient temperatures and pressure. For example, the reaction can be carried out at a temperature from 20 to 30° C. (e.g. room temperature) and a pressure of about 0.8 to 1.2 atm. It should be appreciated that the hypochlorite salts used in each of the methods can be replaced with other hypohalite salts such as potassium hypoiodite.
2.1 Synthesis of Indole: To a solution of phenylalanine in water are added two equivalents of sodium hypochlorite in water. After the evolution of carbon dioxide (CO2) has subsided, the indole produced is isolated by extracting it with ethyl acetate. The purity of the material was verified by melting point, nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Yield is 90%.
2.2 Synthesis of aminochromes: As depicted in
3.1 Synthesis of 1,4-Benzoquinone: To a hydro/alcoholic solution of hydroquinone is added one equivalent of sodium hypochlorite in water. The mixture is stirred for 30 minutes, concentrated, and the solid produced extracted with alcohol, filtered through a plug of silica gel and concentrated to produce pure p-Quinone in 100% yield.
3.2 Synthesis of 1,4-Iminoquinone: As depicted in
3.3 Synthesis of 1,4-Iminoquinone: An ethyl acetate solution of p-aminophenol is suspended in water containing one equivalent of sodium hypochlorite. After approximately 2 hours and verification of reaction completion by TLC, a red 1,4-benzoquinone imine thereof can be isolated, passed through a plug of silica gel, and concentrated to produce 70% yield of pure material as verified by NMR and MS (mass calculated, M+H=108.0439, mass observed, M+H=108.0444).
3.4 Synthesis of dehydroascorbic acid: As depicted in
3.5 Synthesis of p-quinones: As depicted in
4.1 Synthesis of E-Quinone: In an aqueous alcoholic solution of α-tocopherol (a vitamin E), one equivalent of sodium hypochlorite in water was added. The mixture was stirred for 30 minutes and the E-quinone was extracted with ethyl acetate and concentrated to produce 100% yield of a reddish oil that gave MS of 447.3835 observed vs. MS of 447.3833 calculated. The carbon NMR in CDCl3 shows two peaks at 187.11 and 187.50 ppm corresponding to the ketone groups formed and absent in the α-tocopherol.
4.2 Synthesis of catechols: As depicted in
4.3 Synthesis of Trolox Quinone: Trolox and sodium hypochlorite in a 1:1 mixture in alcohol/water were stirred for 30 minutes. The yellow solution produced was concentrated, extracted with alcohol, and passed through a plug of silica gel to give, after concentration, 100% of Trolox Quinone as a yellow solid. The carbon NMR in DMSO shows two peaks at 186.73 and 187.38 ppm corresponding to the ketone groups formed and absent in the original Trolox compound.
Crystal Data Trolo-Quinone: C14H18O5 (M=266.28 g/mol): monoclinic, space group P21/c (no. 14), a=22.5724(14) Å, b=5.6734(4) Å, c=10.2326(6) Å, β=101.6500(10)°, V=1283.41(14) Å3, Z=4, T=100.00 K, β(Cu Kα)=0.870 mm−1, Dcalc=1.378 g/cm3, 42133 reflections measured (7.998°≤2Θ≤158.64°), 2769 unique (Rint=0.0257, Rsigma=0.0125) which were used in all calculations. The final R1 was 0.0331 (I>2σ(I)) and wR2 was 0.0894 (all data).
5.1 Synthesis of 1-Pyrroline: A solution of proline in water was mixed with one equivalent of sodium hypochlorite in water and, after 5 minutes, the mixture was extracted with ethyl acetate, cooled to 5° C., passed through a plug of silica gel, and concentrated to produce 70% of the unstable 1-pyrroline. MS found of M+H=70.0652 vs. M+H calculated of 69.0651.
5.2 Synthesis of Indole: To a solution of phenylalanine in water, two equivalents of sodium hypochlorite in water were added. After the evolution of carbon dioxide (CO2) had subsided, the indole produced was isolated by extracting with ethyl acetate. The purity of the indole was verified by melting point, nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Yield was 90%.
5.3 Synthesis of 2,3,4,5-tetrahydropyridine: To a solution of lysine in water, two equivalents of sodium hypochlorite in water were added. After the evolution of carbon dioxide (CO2) had subsided, the 2,3,4,5-tetrahydropyridine produced was isolated by extracted with ethyl acetate. The purity of 2,3,4,5-tetrahydropyridine was verified by melting point, nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Yield was 90%.
Synthesis of trichloromethyl ketones: As depicted in
While exemplary embodiments are described above, it is not intended that these embodiments describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the invention. Additionally, the features of various implementing embodiments may be combined to form further embodiments of the invention.
This application is a continuation-in-part of U.S. application Ser. No. 17/394,680 filed Aug. 5, 2021, the disclosure of which is hereby incorporated in its entirety by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17394680 | Aug 2021 | US |
| Child | 18390314 | US |
