Patent Application
20240228507
The present invention relates to the use of xylose derivatives as solvent, preferably as polar for chemical reactions or for recrystallizations or for extractions.
In recent decades, the gradual depletion of fossil fuel resources, increase in global energy consumption, and environmental issues have driven the development of new materials and technologies that utilize renewable biological sources such as biomass or food waste. One of the cutting-edge topics in this area is the development of bio-based solvents that are considered as greener alternatives to petroleum-derived solvents. In principle, bio-based solvents do not result in a net increase of carbon dioxide in the atmosphere at the end of their lifetimes and thus ensure less environmental damages. In a further aspect, bio-based solvents are typically less toxic. This creates efficiency savings due to the reduced costs of hazardous waste disposal and safety management.
The development of viable replacements for conventional polar aprotic solvents (PAS) has recently been identified as a key green chemistry research area according to ACS Green Chemistry Institute® Pharmaceutical Roundtable. This class of organic solvents is considered as one of the most difficult to replace solvents due to their unique solubilizing properties and the ability to provide strong interactions with the active pharmaceutical ingredients. Research in this field is also highly driven by regulatory initiatives. For instance, European Union REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) recently has restricted the industrial use of N-methylpyrrolidinone (NMP), and listed others of the most common PAS like N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF) as substances of very high concern due to their severe reproductive toxicity.
Up to now, a number of bio-based solvents that offer a potential to replace highly toxic PAS have been developed and some of them commercialized. Typical examples of bio-based alternatives to PAS include 2-methyltetrahydrofuran (2-MeTHF) and γ-valerolactone (GVL).
2-MeTHF is a solvent that can be produced through two-step hydrogenation of furfural, which is a renewable furan that can be obtained from biomass-derived carbohydrates (C. J. Clarke, W. C. Tu, O. Levers, A. Brohl and J. P. Hallett, Chem. Rev., 2018, 118, 747-800). Usage of this solvent grew rapidly in past decades and now 2-MeTHF is mostly used as a renewable alternative to THF due to its lower toxicity and greatly reduced solvent emissions and waste streams. 2-MeTHF has also proved to be a suitable alternative to some PAS, such as DMSO, acetonitrile, acetone in a series of reactions. However, due to its high flammability, the use of 2-MeTHF is problematic.
γ-valerolactone is biorenewable and (GVL) another biodegradable solvent that can be produced from cellulose or hemicellulose via levulinic acid pathway (E. Ismalaj, G. Strappaveccia, E. Ballerini, F. Elisei, O. Piermatti, D. Gelman and L. Vaccaro, ACS Sustain. Chem. Eng., 2014, 2, 2461-2464). Although being a good alternative, it has a limited stability which of course limits its use. Furthermore, GVL has limited applications at an industrial scale due to high production costs, which is associated with its many production steps form biomass.
Schmidt and Nieswandt, Chemische Berichte, 82, No. 1, 1949, pages 1 to 94 disclose the determination of the molecular weight by cryoscopy of a specific lacton by using dimethylen-xylose as a solvent because of its structural similarity. A chemical reaction was not involved, i.e. dimethylen-xylose has not been used as solvent for chemical reactions.
Y. M. Questell-Santiago, R. Zambrano-Varela, M. Talebi Amiri and J. S. Luterbacher, Nat. Chem. 2018, 10, 1222-1228 discloses that Diformylxylose (DFX) can be directly synthesized from D-Xylose in the presence of 37 wt % aqueous solution of formaldehyde and 37 wt % aqueous solution of HCL using 1,4 dioxane as solvent. N-hexane is used as extraction solvent.
The problem of the present invention is to provide bio-based solvents with different properties for the replacement of hazardous and/or petroleum-based conventional analogues.
The problem is solved by the solvent compounds according to claim 1 as well as by the method according to claim 17 as well as by a compound according to claim 23. Further preferred embodiments are subject of the dependent claims.
It was found that a compound selected from the group consisting of the general formula (I), (II), (III), (IV), (V) and/or (VI)
wherein R1 and R1′, R21 and R21′, R31 and R31′ are the same and are hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C2 to C18 alkenyl, a linear or branched C1 to C10 alkoxy, a linear or branched C1 to C9 alkanoyloxy, a linear or branched C1 to C9 alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C9 alkoxyalkyl, an unsubstituted cycloalkyl, a linear or branched C1 to C6 alkyl substituted cycloalkyl, preferably an unsubstituted cyclohexyl, an unsubstituted C6 to C12 aryl, a linear or branched C1 to C4 alkyl substituted C6 to C12 aryl, or C7 to C12 aralkyl,
R2 and R2′, R22 and R22′, R32 and R32′ are the same and are hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkoxyalkyl, or R2 and R2′ form together with R1 and R1′ respectively, R22 and R22′ form together with R21 and R21′ respectively, R32 and R32′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated or saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms,
X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C9 alkanoyloxy, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl,
Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C2 to C10 alkenyl, a sulfonate, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl,
R60 is selected from the group consisting of hydrogen, hydroxy and C1 to C18 alkoxy and
R61 is selected from the group consisting of hydrogen, hydroxy, C1 to C10 alkylsulfonyl-C1 to C5 alkenyl (preferably methylsulfonylmethylenyl) and C1 to C18 alkyl.
can be used as solvent, preferably as polar for chemical reactions or for recrystallizations.
The term “linear C1 to C9 alkoxyalkyl” denotes a group of the formula —(CH2)q—O—CrH2r+1, wherein q, r and r′ are independently from each other 1 to 9. Preferred embodiments of linear C1 to C9 alkoxyalkyl are —CH2OCH3, —CH2CH2OCH3, —CH2OCH2CH3, —CH2CH2OCH2CH3. In case of a branched C1 to C9 alkoxyalkyl it denotes a corresponding branched residue such as for example —(CH2)q-1—(CH)—(O—CrH2r+1)2 or —(CH2)q-1—(CH)—(O—CrH2r+1) (Cr′H2r′+1). Preferred embodiment of such a branched C1 to C9 alkoxyalkyl are —CH(OCH3)2, —CH(OCH2CH3)2 and —CH(OCH3)(CH3).
The term “oxo” denotes a C═O bond.
The term “alkanoyloxy” denotes an ester group —OC(O)R, R being an organyl residue, preferably an alkyl or aryl.
The term “Hydroxycarbonyl” means a C(O)OH radical or a carboxylic acid —CO—OH. The term “Aminocarbonyl” or “Carbamoyl” denotes a —C(O)NR2 radical, wherein R1 and R1′, R21 and R21′, R31 and R31′ are independently from each other hydrogen or C1 to C18 alkyl, preferably both hydrogen.
The term “Alkoxycarbonyl” means a —C(0)OR radical wherein means a —C(0)OR radical where R is alkyl or aryl.
The term “sulfonate” denotes an ester of sulfonic acid such as mesylate and tosylate.
The term “carboxy” denotes a carboxylate or a carboxylic acid depending on the pH.
The term “C1 to C9 alkoxyalkyl” denotes a group of the formula —(CH2)q—O—CrH2r+1, wherein q and r are independently from each other 1 to 9.
According to a preferred embodiment of the present invention the compound is selected from the group of the general formula (I)
wherein R1 and R1′ are the same and are a linear or branched C1 to C10 alkyl,
R2 and R2′ are the same and are a linear or branched C1 to C10 alkyl or
R2 and R2′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated or saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms,
preferably wherein R2 and R2′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated or saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms.
One aspect of the present invention relates to the use of compounds of the general formula (I), (II), (III), or (IV), (V) or (VI) as polar aprotic solvents, thus solvents which do not contain at least one hydrogen atom connected directly to the electronegative oxygen atom. In other words, this aspect of the present invention relates to the compounds of formula I and II, as well as to compounds of the formula III, wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C9 alkanoyloxy, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl and to compounds of the formula IV, V, VI Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl and a linear or branched C1 to C9 alkylcarbonyl, and
R60 is selected from the group consisting of hydrogen, hydroxy and C1 to C18 alkoxy and
R61 is selected from the group consisting of hydrogen, hydroxy, C1 to C10 alkylsulfonyl-C1 to C5 (preferably methylsulfonylmethyl), alkenyl and C1 to C18 alkyl.
A second aspect of the present invention relates to the use of compounds of the general formula (III) or (IV) as polar protic solvents, thus solvents which contain at least one hydrogen atom connected directly to the electronegative oxygen atom. In other words, this aspect of the present invention relates to the compounds of formula III, wherein X is OR50, wherein R50 is hydrogen and to compounds of the formula IV, wherein Y is OR50, wherein R50 is hydrogen.
In a further aspect of the present invention X is hydroxy leading to a particularly good solubility of the compounds with ability to form hydrogen bonding.
The polar aprotic solvents according to the present invention demonstrate similar performance to conventional polar aprotic solvents (like DMF, NMP and DMSO) in chemical reactions. This is remarkable as the compounds of the general formula (I) or (II) do not contain any nitrogen or sulfur heteroatoms, which are typically found in polar aprotic solvents. Those heteroatoms are known to lead to environmental pollution, and their absence is potentially beneficial. Further, it was found that said compounds have a non-mutagenic and non-volatile nature indicating that this solvent could be safe for human health, which would make it truly “green”. Furthermore, as they can be produced directly from lignocellulosic biomass, their production is likely to be both sustainable and economically feasible.
The polar aprotic solvents according to the present invention, and in particular the compounds of formula (I) or (II) have a unique combination of solvent properties such as polarity, boiling point, melting point, viscosity and poor miscibility with water and can therefore be easily implemented in industry and laboratory routine. Polarity controls both the solubility of different components and the productivity of a reaction through kinetic and thermodynamic effects, whereas physical properties are responsible for separation, handling, and disposal of solvent. Due to their solvent properties, polar aprotic solvents according to the present invention, and in particular the compounds of formula (I) or (II) can satisfy different needs over a variety of chemical sectors. Due to their overall efficacy, toxicity, and sustainability, they can positively influence the cost of the final product.
The polar protic solvents according to the present invention demonstrate similar performance to conventional polar protic solvents (like DMF, NMP, DMAc, dimethyl sulfoxide (DMSO)) in chemical reactions. Since they are strong hydrogen-bond donors, they are very effective at stabilizing any ions. In addition, they can also be used as industrial solvents to help create inks, resins, adhesives, and dyes.
The compounds as defined in claim 1 can be used as solvents, preferably as polar solvents for chemical reactions, for recrystallizations or for extractions since they have high boiling points and do not react with the starting compounds in chemical reactions.
According to a preferred embodiment of the invention, the compounds (I) to (VI) as defined in claim 1, in particular Diformylxylose, can be used as solvent, in particular as polar solvent, for chemical reactions like
Moreover, the compounds (I) to (VI) as defined in claim 1, in particular Diformylxylose, can be used
In one embodiment of the present invention, the compound of formula (I) is a compound of formula (Ia)
wherein R1a and R1a′ are the same and are hydrogen, a linear or branched C1 to C18 alkyl and R2a and R2a′ are the same and are hydrogen, or a linear or branched C1 to C10 alkyl. Preferably, each of R2a and R2a′ is hydrogen.
The term linear C1 to C18 alkyl stands for an alkyl chain which is preferably selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. In a branched alkyl chain, branching occurs preferably either directly in α-position adjacent to the ring system or in Q-position, that is at the end of the alkyl chain. Compounds of formula (Ia) are moderately stable and can withstand harsh reaction conditions.
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (Ib)
wherein wherein R1b and R1b′ are both linear or branched C2 to C10 alkenyl and R2b and R2b′ are both hydrogens. These structures are preferred for reactions requiring ether solvent of medium polarity (e.g. Wurtz reaction, Grignard reaction, etc.).
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (Ic)
wherein R3 and R3′ are both a linear or branched C1 to C10 alkyl. The term linear C1 to C10 alkyl stands for an alkyl chain as defined above. Thus, in other words, compounds of formula (Ic) stand for compounds of formula (I), wherein R1 and R1′ are a linear or branched C1 to C10 alkoxy and each of R2 and R2′ are hydrogen. Higher oxygen content of such solvents increases their hydrogen-bond accepting ability or basicity, which makes them advantageous solvents for Michael addition, specifically.
Also, high basicity of solvent is typically required for solubilization of complex targets such as lignin and cellulose.
Moreover, highly oxygenated solvents can be used to tune CH— aryl interactions in solution and favour formation of one of possible conformers.
In another embodiment of the present invention the compound of formula (I) is a compound of formula (Id)
wherein R4 and R4′ are both a linear or branched C1 to C9 alkyl. The term linear C1 to C10 alkyl stands for an alkyl chain as defined above. Thus, in other words, compounds of formula (Id) stand for compounds of formula (I), wherein R1 and R1′ are a linear or branched C1 to C9 alkoxycarbonyl and each of R2 and R2′ are hydrogen, preferably a linear C1 to C9 alkoxycarbonyl. Preferably R1 and R1′ are selected from the group consisting of methoxycarbonyl and ethoxycarbonyl. Due to the presence of the ester group, compounds of formula (Id) are especially good solvents for positively charged starting compounds and form strong hydrogen bonds.
Most preferably in the compound of formula (Id), each of R4 and R4′ is methyl, and d is 0 which corresponds to compound 14.
Compound (14) shows a high rate constant for Menshutkin reaction and Heck reaction.
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (Ie)
wherein n is a number between 1 and 9 and R5 and R5′ are both a linear or branched C1 to C9 alkyl. Thus, in other words, compounds of formula (Ie) stand for compounds of formula (I), wherein R1 and R1′ are a linear or branched C1 to C9 alkoxyalkyl, and each of R2 and R2′ are hydrogen.
Preferably, in the compound of formula (Ie), n is 1 or 2, and each of R5 and R5′ is selected from the group consisting of methyl, ethyl, propyl, isopropyl or tert-butyl. Compounds of formula (Ie) relatively stable and can withstand harsh reaction conditions.
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (If)
wherein m is a number between 0 and 6 and R6 and R6′ are both a linear or branched C1 to C6 alkyl. R6 and R6′ may be present one or more times at any position of the cycloalkyl residue. Thus, in other words, compounds of formula (If) stand for compounds of formula (I), wherein R1 and R1′ are unsubstituted cycloalkyl or a linear or branched C1 to C6 alkyl substituted cycloalkyl, and each of R2 and R2′ are hydrogen. Most preferably, in the compound of formula (If), m is 1 and the cycloalkyl is unsubstituted, that is, cyclohexyl. It's relatively low polarity can be advantageous for solvating non-polar resins/films, and other non- or middle-polar substrates. Also, similar to cyclohexane, it can be used for recrystallizations (as many organic compounds exhibit good solubility in hot cyclohexane and poor solubility at low temperatures).
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (Ig)
wherein R7 and R7′ are both a linear or branched C1 to C4 alkyl and R7 and R7′ may be optionally present one or more times at any position of the phenyl. Thus, in other words, compounds of formula (Ig) stand for compounds of formula (I) wherein R1 and R1′ are an unsubstituted C6 aryl (i.e., phenyl) or a C1 to C4 alkyl substituted C6 aryl (i.e., phenyl) and each of R2 and R2′ are hydrogen. Most preferably, in the compound of formula (If), the C6 aryl is unsubstituted, that is, phenyl. Due to the presence of aromatic ring, these solvents can be effectively used for dissolution of pigments/dyes, rubber, disinfectants, silicone sealants, substrates with pi-bonds, etc. Like toluene, such solvents could be used for carbon nanomaterials, including nanotubes and fullerenes.
In another embodiment of the present invention, the compound of formula (I) is a compound of formula (Ih)
wherein p is a number between 1 and 6. Thus, in other words, compounds of formula (Ih) stand for compounds of formula (I), wherein R1 and R1′ are C7 to C12 aralkyl, wherein the aryl group of the aralkyl is phenyl, and each of R2 and R2′ are hydrogen.
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (X),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C10 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R21a, R21a′, R22a and R22a′ have the same definitions as R1a, R1a′, R2a and R2a′ in compound of formula Ia, and in particular a compound of formula Xa to Xg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XI),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R21b, R21b′, R22b and R22b′ have the same definitions as R1b, R1b′, R2b and R2b′ in compound of formula Ib, and in particular a compound of formula XIa to XIg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XII),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl and a linear or branched C1 to C9 alkylcarbonyl, and R23 and R23′ have the same definitions as R3, R3′ in compound of formula Ic, and in particular a compound of formula XIIa to XIIg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XIII),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R24 and R24′ have the same definitions as R4 and R4′ in compound of formula Id, and d is 0, 1 or 2, and in particular a compound of formula XIIIa to XIIIg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XIV),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C18 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R25 and R25′ have the same definitions as R5 and R5′ in compound of formula Ie, and n is 1 or 2, and in particular a compound of formula XIVa to XIVg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XV),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R26 and R26′ have the same definitions as R1a and R1a′ in compound of formula If, and m is a number between 1 and 6, and in particular a compound of formula XVa to XVg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XVI),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R27 and R27′ have the same definitions as R7 and R7′ in compound of formula Ig, and in particular a compound of formula XVIa to XVIg:
In another embodiment of the present invention, the compound of formula (III) is a compound of formula (XVII),
wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and and p is a number between 1 and 6, and in particular a compound of formula XVIIa to XVIIg:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XX),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and R31a, R31a′, R32a and R32a′ have the same definitions as R1a, R1a′, R2a and R2a′ in compound of formula Ia, in particular a compound of formula XXa to XXi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXI),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl, and R31b, R31b′, R32b and R32b′ have the same definitions as R1b, R1b′, R2b and R2b′ in compound of formula Ib, in particular a compound of formula XXIa to XXIi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXII),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, C1 to C18 alkenyl, a linear or branched C2 to C18 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and R33 and R33′ have the same definitions as R3 and R3′ in compound of formula Ic, in particular a compound of formula XXIIa to XXIIi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXIII),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50 wherein R50 is hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and and R34 and R34′ have the same definitions as R4 and R4′ in compound of formula Id, and d is 0, 1, or 2, in particular a compound of formula XXIIIa to XXIIIi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXIV),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50 wherein R50 is selected from the group consisting of hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and R35 and R35′ have the same definitions as R5 and R5′ in compound of formula Ie, and n is a number between 1 to 9, in particular a compound of formula XXIVa to XXIVi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXV),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50 wherein R50 is selected from the group consisting of hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and R36 and R36′ have the same definitions as R6 and R6′ in compound of formula If, and a is a number between 0 and 6 in particular a compound of formula XXVa to XXVi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXVI),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50 wherein R50 is selected from the group consisting of hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C alkylcarbonyl, and R37 and R37′ have the same definitions as R7 and R7′ in compound of 5 formula Ig, in particular a compound of formula XXVIa to XXVIi:
In another embodiment of the present invention, the compound of formula (IV) is a compound of formula (XXVII),
wherein Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50 wherein R50 is selected from the group consisting of hydrogen, or a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkylcarbonyl, and p is a number between 1 and 6, in particular a compound of formula XXVIIa to XXVIIi:
In another embodiment of the present invention, in the compound of formula (III) and (IV) R50 is hydrogen or in compound (IV), Y is oxygen which forms together with the adjacent carbon atom carboxy group. Particularly preferred are the following compounds
In another embodiment of the present invention, in the compound of formula (V) R60 is selected from the group consisting of hydrogen, hydroxy and C1 to C18 alkoxy,
wherein and R31a, R31a′, R32a and R32′ have the same definitions as R1a, R1a′, R2a and R2a′ in compound of formula (Ia). Particularly preferred are the following compounds
In one embodiment, the compounds according to the present invention are used as solvent for a chemical reaction, preferably for an organic synthesis, in which at least one starting compound, in particular rearrangement reactions, such as Boulton-Katritzky rearrangement and Beckmann rearrangement, preferably at least two starting compounds are involved, and in particular chemical reactions, in which acid or basic conditions are used.
In another embodiment, the compounds according to the present invention are used as solvents for recrystallizations since they have high boiling points and do not react with the purified product. Preferred are compounds of formula (I) and (II), wherein R1, R1′, R2 and R2′ are all different from hydrogen as these compounds are solvents with a suitable melting point for a recrystallization. In contrast, diformyl xylose has a melting point of 48° C. which is not a suitable recrystallization solvent for many desired products.
In another embodiment, the compounds according to the present invention are used as solvents for extractions since they can solubilize a broad variety of possible target compounds. Furthermore, in case of the polar aprotic solvents they are almost immiscible with water.
The compounds according to the present invention are moderately stable in the presence of acids and bases and can therefore be used under these reaction conditions. In particular, compounds of the formulae (Ia), (Ie), (If), (Ig), (Ih), (Xa-Xg), (XIVa-XIVg), (XVa-XVg), (XVIa-XVIg), (XXa-XXg), (XXIVa-XXIVg), (XXVa-XXVg) and (XXVIa-XXVIg) are relatively stable and thus especially preferred in the presence of strong acids or strong bases. As used herein, the term “strong acid” means an acid that has a pKa less than 4. Strong acids include, for example, H2SO4, HCl and H3PO4. As used herein, the term “strong base” means a base that dissociate into metal ions and hydroxide ions in solution (e.g. NaOH, KOH).
Thus, according to a preferred embodiment, the solvent is used for a chemical reaction in the presence of an acid or a base, preferably a strong acid or strong base. Advantageously the chemical reaction takes place in the presence of an acid that has a pKa less than 4, e.g. H2SO4, HCl and H3PO4, or a base that dissociates into metal ions and hydroxide ions in solution, such as NaOH, KOH.
According to a preferred embodiment of the present invention the solvent is used for a chemical reaction, such as alkylation reaction, hydrogenation reaction, palladium-catalyzed cross-coupling reaction, or aldehyde-assisted biomass fractionation, e.g. biomass fractionation assisted by formaldehyde, propianaldehyde, butyraldehyde, isobutyraldehyde, or other aldehydes, in the presence of an acid or a base, preferably a strong acid.
In one embodiment R1 and R1′ are preferably hydrogen, a linear C1 to C10 alkyl, a linear C2 to C10 alkenyl, a linear C1 to C10 alkoxy, a linear C1 to C9 alkanoyloxy, a linear C1 to C9 alkoxycarbonyl or a linear C1 to C9 alkoxyalkyl, and R2 and R2′ are preferably both hydrogens. Such compounds can be easily obtained by reacting D-xylose with the corresponding aldehyde such as propanal, butanal, pentanal, hexanal, cyclohexanal, benzaldehyd, 4-methylbenzaldehyde.
In one embodiment in the compounds of formula (I) R1 and R1′ are preferably a branched C1 to C10 alkyl, a branched C1 to C9 alkoxyalkyl, and wherein R2 and R2′ are both hydrogen. Preferably the branching occurs in Ω-position, i.e. at the terminal positon of the alkyl chain. Most preferably R1 and R1′ are selected from the group consisting of isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl and isohexyl. Such compounds can be easily obtained by reacting D-xylose with a branched aldehyde such as isobutyraldehyde, isovaleraldehyde, pivaldehyde, isooctanal, isodecanal, 7-tert-butoxyheptanal, preferably the aldehyde is selected from a group consisting of isobutyraldehyde, pivaldehyde and isovaleraldehyde.
Due to their excellent combination of solvent properties in terms of polarity, boiling point, melting point, viscosity and their poor miscibility with water the polar, aprotic solvents of the present invention can be used for a broad variety of chemical reaction. Especially good results could be obtained for reactions selected from the group consisting of the Heck reaction, alkylation reaction, hydrogenation reaction, Ullmann reaction or Ullmann coupling, Wurtz reaction, Grignard reaction, Gomberg-Bachmann reaction, Castro-Stephens coupling, Corey-House synthesis, Cassar reaction, Kumada coupling, Sonogashira coupling, Negishi coupling, Stille cross coupling, Suzuki reaction, Hiyama coupling, Buchwald-Hartwig reaction, Fukuyama coupling, Liebeskind-Srogl coupling, Solid-Phase Peptide Synthesis (SPPS), nucleophilic substitution, amidation, esterification, biginelli reaction, carbonyl addition, aza-Michael addition, Krapcho dealkoxycarbonylation, Boulton-Katritzky rearrangement and Beckmann rearrangement. Said name reactions are known to the skilled person.
Especially good results can be obtained when using the compounds according to the present invention as polar, aprotic solvent for an alkylation reaction and in particular for the Menshutkin reaction. Alkylation reactions are among the most prevailing transformations performed in medicinal chemistry and pharmaceutical industry and are known to be quite sensitive to solvent polarity. It could be shown that the compounds according to the present invention facilitate a charge separation at the transition state via favourable solute-solvent interactions, accelerating the whole process.
Thus, the compounds according to the present invention are outstanding alternatives for toxic solvents such as DMSO, DMF and NMP.
Furthermore, the polar aprotic solvents according to the present invention are particularly useful in a Heck/Mizoroki-Heck reaction. The Heck/Mizoroki-Heck reaction is a palladium-catalyzed cross-coupling reaction that is ubiquitous in the pharmaceutical industry and is routinely used for preparation of substituted alkenes from aryl halides. As shown in the examples, the compounds of the present invention have all the excellent properties to promote a Heck reaction.
It could be shown that the compounds according to the present invention are suitable solvents for hydrogenation reaction. As shown in the Examples, the compounds according to the present invention are suitable bio-based solvents for hydrogenation reactions, preferably in the presence of a catalyst, which is most preferably present in a concentration of between 5 to 15% by weight.
Aprotic polar solvents being used by the present invention or being produced by the method according to the present invention are especially preferred selected from group consisting of compounds 1 to 80:
In an especially preferred embodiment, the solvent of the present invention is selected from the group consisting of diformyl xylose (DFX), dipropyl xylose, dibutyl xylose, diisobutyl xylose and dimethylglyoxylate xylose, preferably diformyl xylose. Due to its high melting point, diformyl xylose can replace conventional solvents that are solids at room temperature as well such as ethylene carbonate, N-formylmorpholine, cygnet and sulfolane.
For reactions having a reaction temperature below 50° C. however, compounds of the formula (I), wherein all of R1, R1′, R2, and R2′, are different from hydrogen are preferred.
Preferably, the compounds according to the present invention are used in large-scale processes, preferably in batch reactor tanks or continuous reactor tanks having a filling volume of at least 500 liters, preferably at least 1000 liters and most preferably 10000 liters. The compounds according to the present invention can potentially be manufactured in high quantities for a reasonably price utilizing different biomass sources. Therefore, production of compounds according to the present invention either from lignocellulosic feedstock or D-xylose would not only be sustainable, but also economically feasible.
Preferably, the polar aprotic solvents according to the present invention, most preferably the compounds of formula (I) or (II) are used a replacement of N-methylpyrrolidinone, N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF) allowing to provide a green solvent substitute for said very toxic solvents.
Due to their excellent combination of solvent properties in terms of polarity, boiling point, melting point, and viscosity the polar, protic solvents of the present invention can be used for a broad variety of chemical reaction. Especially good results could be obtained for reactions selected from the group consisting of reduction and in particular the reduction of nitro compounds, hydrogenation, halogenation, synthesis of ionic liquids, nucleophilic substitution with SN1 mechanism, elimination reaction with E1 mechanism and E2, in particular if a very strong base is used, synthesis via SnAr mechanism, and extractions of bioactive compounds or any compounds from biological sources. The polar, protic solvents of the present invention are particularly preferred for extraction of bioactive compounds or any compounds from biological sources because they contain both polar and non polar groups which make them able to extract both polar and non polar compounds.
The term bioactive compounds as used throughout this application refers to compounds that interact with a living organism such as plants, bacteria, viruses, animals and humans. Exemplary bioactive compounds are carbohydrates, carboxylic acids, lignin and alcohols. The majority of bioactive compounds are well dissolved by protic solvents due to hydrogen bonding between solvent and solute.
The compounds according to the present invention can be produced during aldehyde-assisted lignocellulosic biomass processing, at a yield close to 95-99% of initially appearing in biomass xylan (M. Talebi Amiri, G. R. Dick, Y. M. Questell-Santiago and J. S. Luterbacher, Nat. Protoc., 2019, 14, 921-954.). They can also be directly synthesized from D-xylose with an aldehyde, a ketone or a carbonate in the presence of HCl using 1,4-dioxane as a solvent (Y. M. Questell-Santiago, R. Zambrano-Varela, M. Talebi Amiri and J. S. Luterbacher, Nat. Chem., 2018, 10, 1222-1228).
According to a further aspect of the invention, the compounds according to the present invention can be produced by reacting D-xylose or D-glucose with an aldehyde, a ketone or a carbonate in the presence of H2SO4 using 2-Me-THE as a solvent preferably at about 80° C. These modifications allow to use the green solvent 2-MeTHF in the reaction instead of 1,4-dioxane, a carcinogen linked to organ toxicity and environmental contaminant. Moreover, significantly less amount of solvent can now be used (3-times less by volume) to achieve the same yield (75-80%).
One embodiment of the present invention relates a method for producing a compound of the general formula (I), (II), (III) (VI), (V) or (VI)
wherein R1 and R1′, R21 and R21′, R31 and R31′ are the same and are hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C2 to C18 alkenyl, a linear or branched C1 to C10 alkoxy, a linear or branched C1 to C9 alkanoyloxy, a linear or branched C1 to C9 alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C9 alkoxyalkyl, an unsubstituted cycloalkyl, a linear or branched C1 to C6 alkyl substituted cycloalkyl, preferably an unsubstituted cyclohexyl, an unsubstituted C6 to C12 aryl, a linear or branched C1 to C4 alkyl substituted C6 to C12 aryl, or C7 to C12 aralkyl,
R2 and R2′, R22 and R22′, R32 and R32′ are the same and are hydrogen, a linear or branched C1 to C18 alkyl, a linear or branched C1 to C9 alkoxyalkyl, or R2 and R2′ form together with R1 and R1′ respectively, R22 and R22′ form together with R21 and R21′ respectively, R32 and R32′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated or saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms,
X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C9 alkanoyloxy, alkoxycarbonyl, aminocarbonyl, hydroxycarbonyl, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl,
Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, a linear or branched C1 to C18 alkyl, a C1 to C18 alkenyl, a linear or branched C2 to C10 alkenyl, a sulfonate and OR50, wherein R50 is selected from the group consisting of hydrogen, a linear or branched C1 to C18 alkyl, and a linear or branched C1 to C9 alkylcarbonyl,
R60 is selected from the group consisting of hydrogen, hydroxy and C1 to C18 alkoxy, and
R61 is selected from the group consisting of hydrogen, hydroxy, C1 to C10 alkylsulfonyl-C1 to C5 (preferably methylsulfonylmethyl) and C1 to C18 alkyl
The following reactions and their products are preferred:
The present invention also relates to the following new compounds of formula (I):
wherein R1 and R1′ are the same and are a linear or branched C1 to C10 alkyl, R2 and R2′ are the same and are a linear or branched C1 to C10 alkyl or
R2 and R2′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated carbocyclic ring or a 5 or 6 membered saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms, as for example shown in compound 13.
Especially preferred are compounds of formula I wherein R2 and R2′ form together with R1 and R1′ respectively, a 5 or 6 membered unsaturated or saturated carbocyclic ring optionally comprising 1 or 2 oxygen atoms. Examples of this type of compound are compound 12 and compound 13.
The method of the present invention involves the reaction step of
This allows direct production of the compounds defined in claim 16 from D-xylose or D-glucose, in particular direct production of DFX form D-xylose using safer, more environmental friendly chemicals compared to the prior art (solid paraformaldehyde powder instead of aqueous formaldehyde solution, sulfuric acid instead of aqueous solution of HCl, 2-MeTHE instead of 1,4-dioxane).
According to a preferred embodiment of the method of the present invention, the aldehyde is paraformaldehyde.
Using concentrated (98-99 wt %) H2SO4 instead of 37 wt % aqueous solution of HCl and paraformaldehyde instead of formaldehyde (37 wt % aqueous solution formalin) allows to eliminate water from the synthesis and to use green solvent 2-Me-THE, which is not miscible with water, in the synthesis instead of 1,4 dioxane, a carcinogen linked to organ toxicity and an environmental contaminant. Moreover, significantly less amount of solvent can now be used (3-times less by volume) to achieve the same yield (75-80%). The new method enables much easier and less time- and labour-consuming workup at the end of the synthesis by excluding distillation and extraction steps as the residue is rapidly crystallizing directly from the final oil.
The method advantageously comprises the steps of
According to an embodiment of the present invention the method may not comprise an extraction or distillation step. This embodiment is specifically preferred for the production of DFX.
According to an alternative embodiment the method may further comprise the steps of
According to a preferred embodiment of the present invention, ethyl acetate and/or cyclopentyl methyl ether (CPME) are used as extraction solvents. These extraction solvents are safer than n-hexane, a known neurotoxin which is used in prior art as extraction solvent.
D-xylose (15 g, 0.1 mol, 1.0 equiv.) and paraformaldehyde (7.5 g, equivalent to 0.25 mol formaldehyde, 2.5 equiv.) were added to 2-Me-THF (75 mL) in a round bottom flask. Then, H2SO4 (98 wt %, 2.46 mL, 0.045 mol, 0.45 equiv.) was added drop-wise with stirring to avoid the localized concentration of acid, which can degrade the sugar. The mixture was then heated to 80° C. for 3 h with stirring. The resulting solution was cooled to room temperature (˜23-25° C.), neutralized with sodium hydroxide saturated aqueous solution, filtered, and concentrated in vacuo using a rotary evaporator with a bath temperature of 45° C. The residue was crystallized directly and washed with ethanol while filtering to remove impurities and by-products. The resulting DFX product is white crystalline solid (298% pure by 1H-NMR and GC-FID).
Alternatively, if the residue is not crystallizing from the final oil, the following workup can be done. Extract the residue three times with 100 ml of ethyl acetate (or 50 ml of cyclopentyl methyl ether) and 25 ml of water in a separatory funnel. The resulting solution can be distilled at 80° C., under reduced pressure (0.02 mbar) to obtain a light yellow solid. The solid can then be recrystallized in ethanol and dried in a vacuum desiccator, yielding the DFX as a white crystalline solid (298% pure by 1H-NMR and GC-FID).
NMR spectra for the synthesized DFX are depicted in
The new synthesis to of DFX allows to use the green solvent 2-MeTHE instead of 1,4-dioxane. Moreover, significantly less amount of solvent can now be used (3-times less by volume) to achieve the same yield (75-80%). The new method enables much easier and less time- and labour-consuming workup at the end of the synthesis by excluding distillation and extraction steps. In alternative procedure, ethyl acetate or CPME can be used as extraction solvents instead of n-hexane (a known neurotoxin). Optimization studies reveal that the overall yield of DFX around 75-80% can be achieved after 50 min of the reaction. Also, the yield of furfural is almost negligible in the synthesis according to the present invention, meaning much less degradation of xylose occurred during the reaction.
D-xylose (35 g, 1.0 equiv.) and corresponding aldehyde, ketone, or diketoester (3.0 equiv.) were added to 1,4-dioxane (550 mL) in a 1 L round bottom flask. Then, HCl (37 wt %, 1.3 equiv.) was added. The mixture was then heated to 60° C. for 60 min with stirring. The resulting solution was cooled to room temperature (˜23-25° C.), neutralized with potassium bicarbonate, filtered, and concentrated in vacuo using a rotary evaporator with a bath temperature of 45° C. The residue was extracted three times with 100 ml of ethyl acetate (or 50 ml of cyclopentyl methyl ether) and 100 ml of water in a separatory funnel. The resulting solution was distilled at 80-95° C., under reduced pressure (0.02 mbar) to obtain a light yellow solid. The yield in all cases was >75%. The solid was then recrystallized in ethanol and dried in a vacuum desiccator, yielding the product as a white crystalline solid (298% pure by 1H-NMR and GC-FID).
Corresponding aldehydes are for example: benzaldehyde; cyclohexanal; acetaldehyde; propionaldehyde; butyraldehyde; valeraldehyde, isobutyraldehyde, pivaldehyde, 2-methoxyethanal, 2-ethoxyethanal, 2-propoxyethanal, 2-butoxyethanal, 2-pentoxyethanal, 2-hexoxyethanal, 2-heptoxyethanal, 2-phenoxyethanal and 2-benzyloxyethanal.
Corresponding ketones are for example: acetone, benzophenone, acetophenone, methyl ethyl ketone, methyl isobutyl ketone, methyl-sec-butylketone, cyclopentanone and cyclohexanone.
Corresponding diketoesters are α-diketoesters such as methyl pyruvate or ethylpyruvate or β-diketoesters such as ethyl acetoacetate or methyl acetoacetate.
GC-MS spectra showing fragmentation of molecules and molecular ion of some of the synthesized compounds are depicted in
1,2-O-methylene-α-D-xylofuranose (35 g, 1.0 equiv.) and corresponding carbonate (3.0 equiv.) were added to DMF (550 mL) in a 1 L round bottom flask. Then, NaOH (12 g, 1.3 equiv.) and catalyst TBD (1 mol %) was added. The mixture was then stirred for 4 h at 60° C. The resulting solution was quenched with acetic acid, filtered, and concentrated in vacuo using a rotary evaporator with a bath temperature of 45° C. The obtained mixture was directly purified by flash column chromatography on silica gel (hexane/ethyl acetate 1:6) to produce the product—O3,O5-carbonyl-O1,O2-methylene-α-D-xylofuranose.
The product (1 mol eq.) was then oxidized with KMnO4 (3 mol eq.) in the presence of phosphoric acid (2 mol eq.) and water. The reaction mixture was heated to 70° C. for 15 min to ensure solubilization of all components and then cooled down to 0° C. and stirred for 3 h. The mixtures was extracted 3 times with ethyl acetate and the organic phase was concentrated under vacuum to obtain the product in oil which then can be separated by flash chromatography or distilled.
Alternatively, D-xylose (35 g, 1.0 equiv.) and corresponding carbonate (3.0 equiv.) were added to DMF (550 mL) in a 1 L round bottom flask. Then, NaOH (12 g, 1.3 equiv.) and catalyst TBD (1 mol %) was added. The mixture was then stirred for 4 h at room temperature. The resulting solution was quenched with acetic acid, filtered, and concentrated in vacuo using a rotary evaporator with a bath temperature of 45° C. The obtained mixture was directly purified by flash column chromatography on silica gel (hexane/ethyl acetate 1:6)
Corresponding carbonates are for example 1, 3-dioxolan-2-on, diphenyl carbonate, dimethyl carbonate. Additionally, the following catalysts can be used: TBD, DMAP, Zn(OAc)2, NaOCH3, CS2CO3, K2CO3.
For preparation of compounds of formula (III) and (IV), in particular of diformylglucose isomers, specifically compounds 25 and 53, pure glucose (35 g) was reacted with 73 ml of 37 wt % HCl and 173 ml of 37 wt % FA in 1550 ml of 1,4-dioxane at 80° C. for 30 min. Before separation, the solution was neutralized with sodium bicarbonate and dried under reduced pressure with a rotary evaporator at 60° C. The residue was extracted five times with 500 ml of ethyl acetate. All organic phases were combined and dried under reduced pressure with a rotary evaporator set a 40° C. The resultant residue was distilled at 125° C. and ˜0.06 mbar to obtain a yellowish paste. To obtain pure diformylglucose isomers, the solution was separated by HPLC and targeted peaks were collected using an automated fraction collector.
The reaction was performed between 1,2-dimethylimidazole (0.320 g, 3.33 mmol) and 1-bromodecane (0.65 ml, 3.13 mmol) in the chosen solvent (3 ml) with stirring at 70° C. The rate of the reaction was studied in DFX and 9 other solvents in order to cover a range of polarities and obtain strong correlations (
As shown in
The same reaction was tested in other compounds—Dipropylxylose (DPX, compound I wherein each of R1 and R1′ is ethyl and each of R2 and R2′ is hydrogen), Dibutylxylose (DBX, compound I wherein each of R1 and R1′ is propyl and each of R2 and R2′ is hydrogen), Diisobutylxylose (DIBX, compound I wherein each of R1 and R1′ is isopropyl and each of R2 and R2′ is hydrogen), Dimethylglyoxylate xylose (DMGX, VII).
As depicted in
For DMGX compounds, the procedure was the same as about but at 90° C. instead of 70° C. because melting point of DMGX derivative is about 82° C. For the comparison, the same protocol has been performed on DFX and DPX as well. The observed product was studied in all solvents and corresponding rate constants were calculated (
The hydrogenation of cinnamaldehyde (CAL) was examined in a series of organic solvents at 70° C. over Pd/C catalyst in a 25 mL stainless steel Parr reactor. The reactor was loaded with cinnamaldehyde (CAL, 0.665 g, 5 mmol, 1.00 equiv.), Pd/C (1 wt %, 30 mg), and solvent (10 mL) and then sealed and pressurized with H2 (40 bar). The reactor was heated up to 70° C. with stirring (600 rpm) and held at that temperature for the specified reaction time.
It is important to note that, DFX was stable under hydrogenation conditions (40 bar of H2, 70° C., 24 h), thus it can be used in reactions requiring high pressure of H2, elevated temperature, and/or long reaction time, which is a very desirable property for biomass-derived solvents.
Iodobenzene (0.69 mL, 6.00 mmol, 1.00 equiv.), methyl acrylate (0.54 mL, 6.00 mmol, 1.00 equiv.), triethylamine (0.84 mL, 6.00 mmol, 1.00 equiv.), and Pd(OAc)2 (0.1 mol %) were reacted at 90° C. in 5 ml of DFX and other solvents to compare their relative performance.
The kinetics of Mizoroki-Heck reaction demonstrated strong dependence on the polarity of the solvent used (
For DPX and DMGX in model Heck reaction, the following trend was observed: with increasing polarity, the rate of the reaction increases, and all molecules possessed the right properties to promote the reaction (
A test of the same reaction protocol in DBX, DIBX (variations of compound (I)) showed accumulation of product with 15% conversion after 10 min of the reaction. For comparison, in 1,4-dioxane at the same reaction time no conversion has been observed.
The most relevant solvent properties were measured for DFX and listed in Table 1a in comparison with other solvents. The boiling point of DFX was measured to be 237° C., which is close to the value of ethylene carbonate. Therefore, DFX can be separated from the reaction mixture by distillation, making its recycling more energy-consuming than for low-boiling solvents. However, high-boiling solvents are considered greener because human exposure risks and environmental impact (specifically aquatic toxicity) are reduced due to low volatility. DFX has a high melting point as well (48° C.). The density of DFX as determined experimentally is 1.35 g/mL at 50° C., which is close to the density of Sulfolane, Cyrene, and some chlorinated solvents. DFX has poor solubility in water, very similar to 2-Me-THE, which allows to easily recover DFX from water and use it in certain applications that require water-immiscible solvent and in water-organic extractions.
Flash point of 1 (DFX) was measured to be 137.5° C. In terms of safety, the greatest risk of injury is coming from solvents with a lower flash point, e.g. 2-Me-THF (−10° C.), CPME (−1° C.), NMP (86° C.), MTBE (−28° C.), Cyrene (108° C.), GVL (96.1° C.). In this regard, DFX is much more advantageous alternative.
The solvatochromism of DFX (Table 1a) demonstrates that DEX is very polar since its value of measured Kamlet-Abboud-Taft solvatochromic parameter π* (0.92) is in a range of conventional highly polar aprotic solvents (e.g. DMSO, NMP). Hydrogen bond accepting ability (B) is also very high for DFX, which is due to the presence of 5 oxygen atoms in the structure, which can donate an electron pair. The parameter a was assigned to 0.00 as well as for other PAS because they cannot be hydrogen bond donors. Determination of the Kamlet-Abboud-Taft parameters was based on the absorption spectrum of two dyes (N,N-diethyl-4-nitroaniline and 4-nitroaniline) in different solvents, that allow calculating corresponding values using known procedures (P. G. Jessop, D. A. Jessop, D. Fu and L. Phan, Green Chem., 2012, 14, 1245-1259).
Table 1b depicts Physical and Solvation properties of selected compounds from claim 13.
Depending on the protection agent used to synthesize the compounds from claim 13, molecules with diverse physical properties that can be suitable for different applications can be produced. For example, compound 24 has the lowest melting point (24.5° C.) and can be used in reactions not requiring or avoiding high temperatures. Compounds 1, 3, 4, and 11 have a medium-range melting point, while 2, 5, and 14 are considered as high-melting compounds.
As for boiling points, the experimental values so far indicate little dependency on the type of aldehyde, resulting in boiling points remaining similar and high (234-238° C.). Although, ketone-protected compound 11 has the boiling point significantly lower (120° C.), which opens extra separation opportunities for this molecule. The advantage of having a low volatile solvent is a much lower risk of human exposure and reduced environmental impact, making the solvent more “green” compared to low-boiling analogs. The boiling points of the molecules are similar to some other “green” polar aprotic solvents such as Cygnet, N-butylpyrrolidinone, Ethylene carbonate, GVL, N-formylmorpholine. DMF.
The molecules are very close to being insoluble in water. This low solubility allows for these compounds to be easily separated from water mixtures and opens some applications for them when water-immiscible solvents are required.
The densities measured for the compounds are comparable to other solvents such as DMSO (1.1 g/cm3) and DCM (1.3 g/cm3).
Table 1c depicts Kamlet-Taft parameters measured for selected compounds from claim 13.
According to measured Kamlet-Taft parameters, compounds 3, 4, and 24 are very close by solvation properties to medium-polarity solvents such as THE, 1,4-dioxane, 2-Me-THF. This means that the compounds can successfully complement the list of conventional ethers bringing new properties and, possibly, a safer profile. Moreover, the possibility of these compounds being produced sustainably from renewable sources makes them successful replacement candidates. Compound 1 is significantly more polar and can be a promising renewable alternative to toxic common polar aprotic solvents such as DMF, NMP, sulfolane, etc.
Based on the measured Kamlet-Abboud-Taft parameters, we established a two-dimensional solvent map to compare some of these compounds with other existing solvents in a parametric space (
The absorbance spectra of 4-nitroaniline dye (cf.
For the compounds 1 (Diformylxylose) and 24, miscibility with different organic solvents was tested to explore how this compound can be separated.
Table 1d shows Miscibility for Diformylxylose (compound 1) and compound 24 with “*” indicating—not miscible:
The toxicological assessment of DFX was performed using the Ames test to quickly determine if it has a mutagenic and carcinogenic potential.
An AMES-384 ISO test kit by EBPI Inc. (Canada) with two Salmonella typhimurium bacterial strains (TA100 with base-pair mutation hisG46 and TA98 with frameshift mutation hisD3052) was used. S9 liver homogenate from Aroclor 1254 Sprague-Dawley rats was used in a number of experiments as a source of mammal metabolic enzymes to expand the detection capabilities of the assay. For the test, DFX was dissolved in sterile water (100 mg/mL) and filtered through a 0.22 μm membrane filter. The maximum concentration of DFX in the exposure well was 80 mg/exposure well. Serial dilution of the sample was performed with a dilution factor of 2 (the minimum tested concentration was 2.5 mg/exposure well). 4-Nitroquinoline-N-oxide (4-NQO) was used as a positive control for the TA100 strain. 2-Nitrofluorene (2-NF) was used as a positive control for the TA98 strain. 2-Aminoanthracene (2-AA) was used as a positive control when a rat liver fraction S9 was added to the TA100 or TA98 strains. For the negative controls, the same quantity of sterile water was added to the wells as was added in the case of the DFX assay. Statistical analysis of the results included calculation of the baseline (the average response of negative control data and standard deviation), positive criteria for considering the testing compound as a mutagen (must be ≥2× baseline), and standard error of the mean. All calculations were conducted using an Excel spreadsheet provided by EBPI Inc.
The following procedure was applied in accordance with manufacturer's guidelines. Briefly, TA100 and TA98 bacterial strains were grown overnight and diluted until OD600 was 0.1 (for TA98) or 0.05 (for TA100). In a 24-well plate, samples containing grown bacteria and negative controls (water), positive controls, sterility controls, 5-serial dilutions of the DFX water (80, 40, 20, 10, 5, 2.5 mg/ml) were prepared and incubated at 37° C. for 100 min in a medium including sufficient histidine to initiate cell division. After the exposure, these samples were diluted in Reversion Media absent histidine in a second 24-well plate, then aliquoted into three 384-well plates and incubated at 37° C. for 48 h. After this, plats were scored visually: yellow wells indicated bacterial growth as they had undergone reverse mutation and could produce the histidine needed for their growth; purple wells indicated no reverse mutation of His+ biopathway in bacteria as they couldn't grow without histidine. The number of yellow wells was calculated and averaged to obtain the mean number of revertants. Baseline and positive criteria were then calculated in accordance with the manufacturer's guide.
DFX is able to act as a solvent in formaldehyde-assisted biomass fractionation at several pre-treatment conditions (Table 2). The original procedure employs 1,4-dioxane as the main processing solvent, so it was used as a control. For pre-treatment in DFX, the yields of lignin and cellulose are slightly higher than in dioxane, possibly, due to the presence of solid degradation products (humins), formed because of interaction between acid and sugar derived DFX. The high boiling point of DFX (237° C.) allows to recovering pure DFX at the end of the procedure after evaporating other washing/precipitating solvents such as dioxane, methanol, water.
The quality of the isolated lignin after pretreatment of Birch wood in DFX was assessed by determining the yield of aromatic monomers that could be produced after hydrogenolysis of the isolated lignin. The yield of monomers obtained after direct hydrogenolysis can be considered as an estimate of the theoretical monomer yield for a given biomass source. Lignin monomer identification and quantification were performed using GC-FID and GC-MS.
For pre-treatment in DFX, yields of aromatic monomers produced after hydrogenolysis of the isolated formaldehyde-stabilized lignin were in a range 70-80% (wt/wt) as compared with the direct hydrogenolysis of the biomass feedstock (2017 birch wood) (
Solubility tests confirmed that DFX is a powerful solvent for the solubilization of lignin. The solubility of propionaldehyde-protected lignin in DFX is 0.633 g/g, which is higher than the corresponding value for 1,4-dioxane (0.450 g/g) and 2-Me-THF (0.330 g/g) after stirring the mixture for 1 h at 85° C.
Cellulose fibers were depolymerized after pretreatment in DFX in the same manner as for 1,4-dioxane and 2-Me-THF used as pretreatment solvents.
The stability of the compound (Ia) where R1a=R2a=R1′a=R2′a=H (DFX) was tested in acid and basic conditions.
The stability of pure DFX under typical acidic conditions (0.8M HCl) was evaluated to determine if this sugar-derived molecule could be used without extensive degradation. The results demonstrated that at a temperature range between 70 to 95° C., more than 80% of DFX could be recovered (
In particular
Some variations of compound (I), specifically DPX, DBX, DIBX, Dineopentylxylose (DNPX, compound I wherein each of R1 and R1′ is tert-butyl and each of R2 and R2′ is hydrogen) also showed sensitivity to strong acids, which is visually observed as orange-colored solution compared to pure yellowish compound without acid.
To assess DFX stability under basic conditions, we tested a series of organic and inorganic bases at 80° C. and 110° C. for maximum 48 h (Table 6). Visual color change compared to a blank solution of pure DFX indicated some reactions were occurring. After 0.5 h, 24 h, 48 h of exposure, the samples were injected in GC-FID and GC-MS and the area of DFX was compared with the one in blank sample using decane as the internal standard. As a result of this experiment, we identified some potential limitations of this emerging solvent. Specifically, inorganic bases such as K2CO3, NaOH, CsCO3 led to the highest extent of degradation (maximum 21% after 48 h). Triethylamine (NEt3) caused less than 5% of degradation, but led to the formation of dark solution as well as K2CO3, NaOH, CsCO3. Probably, impurities existing in DFX (95% pure) also contribute to a color change as they could interact with bases. Pyridine and KOAc as relatively weak bases didn't show any significant effect on stability of DEX.
DEX remained stable up to 210° C., according to TGA and DSC measurements. After 210° C. degradation with evaporation occurs.
Some variations of compound (I), specifically DPX, DBX, DIBX, Dineopentylxylose (DNPX, compound I wherein each of R1 and R1′ is tert-butyl and each of R2 and R2′ is hydrogen) as well as DMGX showed similar behaviour and were stable up to 200° C.
DFX remained stable under the following hydrogenation conditions:
Deep eutectic solvents (DESs) are mixtures composed of a hydrogen bond donor and a hydrogen bond acceptor, resulting in a significantly suppressed melting point compared to those of the individual components. They are similar to ionic liquids but have some advantages to due their tunability, biodegradability and low cost.
DFX has a melting point of 48° C. and contains 5 oxygens in its structure and, therefore, is a strong hydrogen bond acceptor. Several hydrogen bond donors have been tested to check if they will form eutectic with DFX.
The following compounds mixed with DFX in 1:1 molar ratio were found to be stable liquids at room temperature and some of them are still liquids even at less than −18° C. (Table 3)
These findings expand possible opportunities for DFX and its derivatives not only as simple solvents but also constituents for deep eutectic solvents. DESs composed of these molecules can be used in many applications. The physical properties of the liquids are dependent upon the hydrogen bond donor and can be easily tailored for specific applications. The two major application areas of DESs are metal processing (including metal electrodeposition, metal electropolishing, metal extraction and the processing of metal oxides) and synthesis media (e.g. alkylation, ionothermal synthesis, gas adsorption, biotransformations using microorganisms and reactions of sugars, cellulose, and starch, purifying and manufacturing biodiesel, etc).
We performed the alkylation reaction (the same as in the Example 3) in deep eutectic solvents (DES) composed of DFX and propyl guaiacol (DFX:PG) and DES composed of DFX and Phenol (DFX:PhOH) mixed in 1:1 molar ratio. We observed formation and accumulation of the reaction product with time and the reaction rate constant was quite similar to the one in CPME.
Since DESs contain hydrogen bond donors, they exhibit properties of protic solvents as well. Therefore applications for protic solvents are applicable to this class of solvents.
In order to explore DES composed of DFX better, the physical and solvation properties of the mixture of DFX and propyl guaiacol (DFX:PG) mixed in 1:1 molar ratio were measured.
Table 4 shows physical and solvation properties of DFX:PG (1:1 molar ratio).
Based on the results, one can see that DFX:PG is a polar solvent with protic activity. Kamlet-Taft parameters suggest that DFX:PG is similar to acetonitrile, acetone, ethyl lactate. Hansen Parameters show that DFX:PG has some similarity to 1,3-dioxalane, NMP, Cyrene.
The Nile red value for DEX:PG is 553 nm, indicating similar chemical behavior to Methanol (550 nm) and Ethanolamine (557 nm).
In terms of thermal stability, no degradation of components was observed up to 250° C. (followed by refluxing and boiling).
Table 5 shows miscibility of DES-DEX:PG (1:1 molar ratio) with “*” indicating—not miscible.
Each solvent can be characterized by three Hansen parameters, each generally measured in MPa 0.5. They are used to determine solubility of targets, estimate rate of reactions, etc.
All three parameters were calculated for the molecules of Table 7 using HSPiP 5.3.02 Software (Table 7).
Based on determined HSP, solvents 1-24 were placed in a 3D space, called Hansen space with three coordinates D, P, H (values from Table 4). This allows for the calculation of a distance between new molecules and already known compounds from the database to determine their chemically similar counterparts. Solvents that are the closest match by properties to the compounds 1-24 are likely to have similar applications and performance. However, in the case of 1-24 they could be produced sustainably from a renewable source and they probably could have a safer profile as they are derived from natural carbohydrates (D-xylose).
Table 8 depicts Hansen Solubility Parameters for variations of compound (III) of claim 1.
Table 9 depicts Hansen Solubility Parameters for variations of compounds (IV) (V) and (VI) of claim 1
| Number | Date | Country | Kind |
|---|---|---|---|
| 21169040.9 | Apr 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/060153 | 4/14/2022 | WO |
