A Recyclable, Metal-Free Mechanochemical Approach for the Oxidation of Alcohols to Carboxylic Acids

molecules

Article A Recyclable, Metal-Free Mechanochemical Approach for the Oxidation of Alcohols to Carboxylic Acids

Kendra Leahy Denlinger, Preston Carr, Daniel C. Waddell and James Mack *

Department of Chemistry, University of Cincinnati, 301 Clifton court, Cincinnati, OH 45221-0172, USA; [email protected] (K.L.D.); [email protected] (P.C.); [email protected] (D.C.W.) * Correspondence: [email protected]; Tel./Fax: +1-513-556-9249

Academic Editors: Vjekoslav Štrukil and Matej Baláž Received: 11 November 2019; Accepted: 23 December 2019; Published: 16 January 2020

Abstract: The oxidation of primary alcohols under mechanochemical conditions in a Spex8000M Mixer/Mill was investigated. To facilitate ease of separation and recyclability, a polystyrene-bound version of a TEMPO catalyst was employed. When paired with Oxone® in a stainless-steel vial with a stainless-steel ball, several primary alcohols were successfully oxidized to the corresponding carboxylic acids. The product was isolated using gravity ﬁltration, which also allowed for the polystyrene-bound TEMPO catalyst to be recovered and reused in subsequent oxidation reactions. Furthermore, it was demonstrated that the size and steric hindrance of the primary alcohol does not hinder the rate of the reaction. Finally, the aldehyde was selectively obtained from a primary alcohol under ball milling conditions by using a combination of non-supported TEMPO with a copper vial and copper ball.

Keywords: mechanochemistry; polymer supported; tempo; oxidation; recycle

1. Introduction The emerging field of mechanochemistry has garnered a lot of attention over the last few years [1–8]. This unique solvent-free approach has been applied to various areas of science with exciting results, specifically in the area of oxidation reactions [9–19]. Since mechanochemical reactions are solvent free by nature, these novel conditions would be complementary to reactions that are troublesome in solution. One field that seems to be tailor-made for mechanochemistry is the field of polymer-supported reagents (e.g., Merrifield resins). Merrifield resins have been very valuable to the field of peptide synthesis [20,21]. Conversely, the problems related to the swelling of these resins in solution have limited its potential in other areas of synthetic chemistry [22]. One area where polymer-supported resins have a vast amount of potential is the field of catalysis [23]. Catalysis is a very important area of chemistry that has increased in scope over the last 50 years. However, many catalysts are expensive, sensitive to air and/or moisture, and/or not commercially available. In addition, upon completion of the reaction, the catalyst is often difficult to recover and reuse. On the other hand, many polymer-supported catalysts are commercially available and, in principle, would allow for the complete recovery and reuse of the catalyst at the conclusion of the reaction. Although catalysts can be purchased or synthesized on a solid support, the swelling efficacy is a hindrance, thus preventing these reagents from reaching their full potential. We and others have previously shown that under mechanochemical conditions there are new mechanistic pathways to access the active sites of Merrifield resins [24–28]. Furthermore, since mechanochemical reactions are typically performed in the absence of a solvent, this methodology lends itself readily to the development of environmentally benign reactions. The combination of mechanochemistry and polymer-supported catalysts will allow for the development of catalytic conditions that are new, solvent free and completely recyclable.

Molecules 2020, 25, 364; doi:10.3390/molecules25020364 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 10 Molecules 2020, 25, 364 2 of 10 catalysts will allow for the development of catalytic conditions that are new, solvent free and completely recyclable. The oxidation of alcohols typically requires the use of an oxidant oxidant and and a a catalyst catalyst to to be be successful, successful, however many of these conditions are not consideredconsidered environmentally benign [[29–31].29–31]. Therefore, Therefore, developing conditions conditions in in an an environmentally environmentally benign benign manner manner has hasbeen been important important in the in area the of area green of chemistrygreen chemistry [32–35]. [32 The–35 ].oxidation The oxidation of alcohols of alcohols is also is important also important in medicinal in medicinal chemistry. chemistry. Pfizer, Pfizer, for example,for example, has published has published a solvent a solvent selection selection guide guide as well as as well an asintroductory an introductory reagent reagent selection selection guide [36].guide One [36]. of One the of four the fourreactions reactions examined examined in this in this article article was was the the oxidation oxidation of of primary primary alcohols alcohols to aldehydes. SeveralSeveral didifferentfferent reaction reaction conditions conditions were were examined examined and placedand placed into the into appropriate the appropriate position positionon a Venn on diagram, a Venn diagram, according according to their abilityto their toability meet to criteria meet criteria in the areas in the of areas scalability, of scalability, wide utility, wide utility,and greenness. and greenness. Reaction Reaction conditions conditions utilizing TEMPO utilizing (i.e., TEMPO 2,2,6,6-tetramethyl-piperidine-1-oxyl) (i.e., 2,2,6,6-tetramethyl-piperidine-1-/NaOCl oxyl)/NaOClfell into the middle fell into of the Vennmiddle diagram, of the Venn meeting diagra the criteriam, meeting of all the three criteria categories. of all Thoughthree categories. there are Thoughmany options there are for themany oxidation options of for alcohols, the oxidation most do of notalcohols, meet the most criteria do not for meet Pfizer’s the greennesscriteria for category, Pfizer’s greennessindicating thatcategory, there isindicating still much that work there to beis donestill much in this work area to of greenbe done organic in this chemistry. area of green Even organic though chemistry.there are several Even though alternatives there toare using several toxic alternatives metals in theto using oxidation toxic ofmetals alcohols in the to oxidation aldehydes, of therealcohols are tofew aldehydes, metal-free there methods are few in themetal-free literature methods for the in conversion the literature of an for alcohol the conversion to a carboxylic of an acid.alcohol Of to the a carboxylicmetal-free variantsacid. Of in thethe literature,metal-free many variants use catalysts in the thatliterature, are not commerciallymany use catalysts available that and typicallyare not commerciallyrequire column available chromatography and typically in the require isolation column step. chromatography in the isolation step. Bolm and co-workers reported on the TEMPO oxidation of primary alcohols to aldehydes in the ® presence of Oxone® (i.e.,(i.e., Potassium Potassium peroxymonosulfate peroxymonosulfate)) [37]. [37]. This This report report demonstrated demonstrated a a clean clean and facile conversion of of alcohols to to aldehydes in in th thee presence of a quaternary ammonium salt using a biphasic medium. It It has has been been shown shown that that under under solvent-free solvent-free mechanochemical mechanochemical conditions, conditions, aldehydes aldehydes ® can be be readily readily converted converted to to the the corresponding corresponding carboxylic carboxylic acids acids in the in thepresence presence of Oxone of Oxone® [38]. [The38]. oxidationThe oxidation of primary of primary alcohols alcohols to the to corresponding the corresponding carboxylic carboxylic acids acidshas also has been also accomplished been accomplished using polymer-supportedusing polymer-supported TEMPO TEMPO in solution; in solution; however, however, under under these these conditions conditions an an organic organic solvent solvent was needed in the reaction and/or and/or at the purificationpurification stage [[39–41].39–41]. We envisionedenvisioned that the combination of a polystyrene bound sulfonic esterester linked 2,2,6,6-tetramethyl-piperidine-1-oxyl species (hereafter ® referred toto as as PS-TEMPO) PS-TEMPO) in thein the presence presence of Oxone of Oxoneunder® under mechanochemical mechanochemical conditions conditions would providewould provideenvironmentally environmentally benign conditions benign thatconditions reduce theth useat ofreduce undesired the solvents,use of chromatography-free,undesired solvents, chromatography-free,metal-free, and recyclable metal-free, for the oxidationand recyclable of alcohols for the to oxidation carboxylic of acids.alcohols to carboxylic acids. 2. Results and Discussion 2. Results and Discussion We started our investigation by milling benzyl alcohol with 1 equivalent of PS-TEMPO in the We started our investigation by milling benzyl alcohol with 1 equivalent of PS-TEMPO in the presence of 1 equivalent of Oxone® for 16 h in a stainless-steel vial with a 3/16” stainless steel ball. presence of 1 equivalent of Oxone® for 16 h in a stainless-steel vial with a 3/16” stainless steel ball. We chose to use a stoichiometric amount of PS-TEMPO because it allows us to increase the reaction rate We chose to use a stoichiometric amount of PS-TEMPO because it allows us to increase the reaction without increasing the cost by using the recovered catalyst in subsequent trials. These initial conditions rate without increasing the cost by using the recovered catalyst in subsequent trials. These initial would give us a broad baseline by which to compare other substrates that may be sensitive to less than conditions would give us a broad baseline by which to compare other substrates that may be sensitive stoichiometric equivalents and shorter reaction times. At the conclusion of the reaction, we washed to less than stoichiometric equivalents and shorter reaction times. At the conclusion of the reaction, the crude reaction mixture with acetone and filtered the pulverized polymer support, which then we washed the crude reaction mixture with acetone and filtered the pulverized polymer support, could be recycled and used in subsequent reactions. After removing the solvent, we observed a near which then could be recycled and used in subsequent reactions. After removing the solvent, we quantitative yield to the pure benzoic acid (Scheme1). observed a near quantitative yield to the pure benzoic acid (Scheme 1).

Scheme 1. Oxidation of benzyl alcohol to benzoic acid with polymer supported TEMPO. Scheme 1. Oxidation of benzyl alcohol to benzoic acid with polymer supported TEMPO.

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From observed From ball. of previous the previousDemonstrating alcohola 52% work workyield to thatconditions,of the the alcohol metal we to from conducted the carboxylicthe stainless the sameacid steel by reaction isconducting not needed in a Teflonth efor reaction oxidation vial with in Teflon toa 1/4”occur, for Teflon 16we h. observed Fromball. Demonstrating previous a 52% workyield theinofin thatthe carboxylic the Mack the alcoholMack metal group group acid to from the [42], by [42], carboxylic conductingthe this thisstainless lower lower acid thepercent steel percentby reaction conducting is notconversion conversion needed in Teflon the was forreaction was for oxidation anticipated 16anticipated h.in FromTeflon to becauseoccur, previous becausefor 16 we h.Teflon TeflonobservedFrom work is previous in isnot the nota as52% Mackas hard work hardyield ofthatin thethe the alcoholMack metal group to from the [42],carboxylicthe stainlessthis lower acid steel percentby isconducting not conversion needed th efor reaction was oxidation anticipated in Teflon to occur, becausefor 16we h. observed TeflonFrom previous is anot 52% as work yieldhard groupinof the the [42 Mack alcohol], this group lower to the percent[42], carboxylic this conversion lower acid percent by was conducting anticipatedconversion the becausereactionwas anticipated Teflonin Teflon is notbecause for as 16 hard h. Teflon From as stainless previousis not® ® as steel. hardwork asofas stainless thestainless alcohol steel. steel. to Whenthe When carboxylic benzyl benzyl alcoholacid alcohol by isconducting ismi milledlled with with the PS-TEMPO reaction PS-TEMPO in Teflonin in the the forabsence absence 16 h. 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PS-TEMPO, Likewise, benzyl of benzoicwe wealcohol whenalso also acid.did benzyldidis notmi Likewise, notlled observe alcohol observe with when isanyPS-TEMPO milledany benzoicbenzyl benzoic in the inalcoholacid. acid. presencethe Thisabsence Thisis milledshows of shows Oxoneof inOxonethat thatthe bothwithout ® presenceboth, we the thedid notasof stainlessOxone observe® without steel.any formation When PS-TEMPO, benzyl of benzoic alcoholwe also acid. is did mi Likewise, llednot observewith whenPS-TEMPO any benzyl benzoic in alcohol the acid. absence Thisis milled shows of Oxone in thatthe presence,both we didthe PS-TEMPO,PS-TEMPOofPS-TEMPOnot Oxone observe® and wewithout and any alsoOxone Oxone formation didPS-TEMPO,® not®are are needed observeof needed benzoic we foralso any for acid.the did benzoicthe oxidation notLikewise,oxidation observe acid. to when Thisto occur,any occur, shows benzylbenzoic which which thatalcohol acid.was was both Thisexpected is expected themilled shows PS-TEMPO basedin basedthat the bothonpresence on and the the ofnotPS-TEMPO Oxone observe® without andany formationOxone PS-TEMPO,® are of neededbenzoic we also for acid. did the Likewise, notoxidation observe when to any occur, benzyl benzoic which alcohol acid. was Thisis expectedmilled shows in basedthatthe presenceboth on thethe ® ® ® OxonePS-TEMPOof Oxoneare® needed withoutand Oxone for PS-TEMPO, the oxidationare needed we to also occur,for didthe which oxidationnot observe wasexpected to anyoccur, benzoic based which onacid. was the This proposedexpected shows mechanismbased that both on the the proposedofPS-TEMPOproposed Oxone mechanism mechanism without and Oxone PS-TEMPO, of of the® theare reaction reaction needed we [43]. also [43].for To did theTo study notstudyoxidation observe the the scope scope to any occur, of of benzoicour our whichreaction reaction acid. was conditions, This conditions, expected shows we based thatwe extended extended both on the PS-TEMPOproposed mechanism and Oxone of ® theare reaction needed [43].for theTo studyoxidation the scope to occur, of our which reaction was conditions, expected based we extended on the ofourproposedour thePS-TEMPO method reactionmethod mechanism to to [andvarious43 various]. ToOxone study ot of other® theher are thealcohols reaction alcohols needed scope (Table of[43]. (Tablefor our Tothe 1), reaction 1),study includingoxidation including the conditions, scope bothto both occur, ofsolid wesolidour which extendedand reaction and liquid liquidwas conditions, our alcohols.expected alcohols. method webased to variousextended on the proposedPS-TEMPOour method mechanism andto various Oxone of ot theherare reaction alcoholsneeded [43]. for(Table theTo 1),studyoxidation including the scope to bothoccur, of solidour which reaction and wasliquid conditions, expected alcohols. basedwe extended on the otherourproposed alcoholsmethod mechanism to (Table various1), including ofot herthe alcoholsreaction both solid [43].(Table andTo 1), study liquid including the alcohols. scope both of solid our reactionand liquid conditions, alcohols. we extended proposedour method mechanism to various of ot theher reaction alcohols [43]. (Table To 1),study including the scope both of solidour reaction and liquid conditions, alcohols. we extended our methodTableTable to various 1. 1.Oxidation Oxidation other of alcohols ofalcohols alcohols to(Table tocarboxylic carboxylic 1), including acids acids with with both polymer-supported polymer-supported solid and liquid TEMPO. alcohols.TEMPO. our method toTable various 1. Oxidation other alcohols of alcohols (Table to carboxylic 1), including acids withboth polymer-supported solid and liquid alcohols. TEMPO. TableTable 1. Oxidation1. Oxidation of of alcohols alcohols to to carboxylic carboxylic acids acids with with polymer-supported polymer-supported TEMPO. TEMPO. Table 1. Oxidation of alcohols to carboxylic acids with polymer-supported TEMPO. Table 1. Oxidation of alcohols to carboxylic acids with polymer-supported TEMPO. Table 1. Oxidation of alcohols to carboxylic acids with polymer-supported TEMPO.

EntryEntryEntry AlcoholAlcohol Alcohol %% %Yield Yield Entry Alcohol % Yield Entry Alcohol % Yield Entry Alcohol % Yield 1Entry1 1 Alcohol >98%>>98 Yield98 Entry1 Alcohol % >98Yield 1 >98 1 >98 1 >98 1 >98 2 2 >98>98 22 >>9898 2 >98 2 >98 2 >98 2 >98 3 3 >98>98 3 >98 33 >>9898 3 >98 3 >98 3 >98

4 4 >98>98 4 >98 44 >>9898 4 >98 4 >98 4 >98

5 5 >98>98 5 >98 55 >>9898 5 >98 5 >98 5 >98 6 6 6464 6 64 6 64 66 64 6 64 6 64 7 7 7575 7 75 7 75 7 75 7 7 7575 7 75 8 8 <5<5 8 <5 8 <5 8 <5 8 <5 88 <<55 TheThe success success of of the the solid solid alcohol alcohol oxidations oxidations indica indicatestes the the true true solid-phase solid-phase nature nature of of the the system. system. The success of the solid alcohol oxidations indicates the true solid-phase nature of the system. TheThe melting meltingThe success points points offor forthe the the solid solid solid alcohol alcohols alcohols oxidations are: are: 4- 4-methylbenzylmethylbenzyl indicates the alcohol alcoholtrue solid-phase m.p.: m.p.: 59–61 59–61 nature °C; °C; 4-bromobenzyl 4-bromobenzyl of the system. The meltingThe success points of forthe the solid solid alcohol alcohols oxidations are: 4-methylbenzyl indicates the alcoholtrue solid-phase m.p.: 59–61 nature °C; 4-bromobenzyl of the system. alcoholThealcohol melting Them.p.: m.p.: success 75–77 points 75–77 °C;of for°C; the 4-chlorobenzyl the4-chlorobenzyl solid solid alcohol alcohols alcohol oxidations alcohol are: m.p.4- m.p.methylbenzyl indica: 68–71: 68–71tes °C; °C;the and alcohol andtrue 4-nitrobenzyl 4-nitrobenzylsolid-phase m.p.: 59–61 alcoholnature alcohol°C; 4-bromobenzyl ofm.p.: m.p.: the 92–94system. 92–94 Thealcohol meltingThe m.p.: success points 75–77 of for°C;the the4-chlorobenzylsolid solid alcohol alcohols oxidations alcohol are: 4- m.p.methylbenzyl indica: 68–71tes the °C; alcoholtrue and solid-phase4-nitrobenzyl m.p.: 59–61 nature alcohol°C; 4-bromobenzyl of them.p.: system. 92–94 °C.alcohol°C.The The The melting temperature m.p.:temperature 75–77points of °C; forof the the4-chlorobenzylthe system system solid wasalcohols was monitored monitoredalcohol are: 4- m.p. methylbenzylas as the: 68–71the reaction reaction °C; alcoholand progressed progressed 4-nitrobenzyl m.p.: using 59–61 using analcohol °C;an iButton, iButton,4-bromobenzyl m.p.: which which92–94 alcoholThe°C.The The melting success m.p.:temperature points 75–77 of the for°C; of solid thethe4-chlorobenzyl solidsystem alcohol alcohols was oxidations alcoholmonitored are: 4- indicatesm.p.methylbenzyl as: 68–71the thereaction °C; true alcohol and solid-phaseprogressed 4-nitrobenzyl m.p.: 59–61 using nature alcohol°C; an of4-bromobenzyl iButton, the m.p.: system. which92–94 is °C.isshownalcohol shown The temperature inm.p.: in Figure Figure 75–77 1. 1. °C;ofThe The the 4-chlorobenzyl maximum systemmaximum was temperature temperature monitored alcohol m.p. reachedas reached :the 68–71 reaction during °C;during and progressed the 4-nitrobenzylthe reaction reaction using was was alcohol an 43 iButton,43 °C, ° C,m.p.: and and which the92–94 the The°C.alcoholis meltingshown The m.p.:temperature in points Figure 75–77 for °C;1. theof The the4-chlorobenzyl solid systemmaximum alcohols was temperature are:monitoredalcohol 4-methylbenzyl m.p. as :reached 68–71the reaction °C;alcohol during and progressed 4-nitrobenzyl m.p.:the reaction 59–61 using◦ C; wasalcohol an 4-bromobenzyl iButton,43 °m.p.:C, and which92–94 the systemissystem°C. shown The stayed stayed temperature in Figurebetween between 1. of 41The 41the °C °maximum systemCand and 43 43 was°C ° temperatureCfor monitored for the the duration duration asreached the of reactionof the theduring 16-h 16-h progressed reaction the reaction reaction (Figure using(Figure was an1). 1).43 iButton,Because Because°C, and whichthe the alcoholis°C.system shown The m.p.: stayedtemperature in 75–77 Figure between◦C; 1. 4-chlorobenzylof The the 41 system°maximumC and was43 alcohol ° temperatureC monitored for m.p.: the duration 68–71 as reached the◦ C;reaction of and theduring 4-nitrobenzyl 16-h progressed the reaction reaction alcoholusing (Figure was an m.p.: 1).43iButton, Because° 92–94C, and which◦ C. the meltingsystemmeltingis shown temperatures stayed temperatures in Figure between of1. of theThe41 the °substrates Cmaximum substrates and 43 °areC temperatureare for well wellthe ab durationaboveove reached the the temperatureof temperature the during 16-h reactionthe of of reactionthe the system (Figure system was (Figure 1). (Figure43 Because °C, 1), and 1), we the wethe Thesystemismelting temperatureshown stayed temperatures in Figure between of the 1.system ofThe 41 the °maximumC substrates was and monitored43 ° temperatureC are for wellthe as theduration ab ove reactionreached the of temperature the progressedduring 16-h the reaction usingreactionof the (Figure ansystem was iButton, 1).43 (Figure Because°C, which and 1), is thewe canmeltingcansystem conclude conclude temperaturesstayed that that between the the reaction reaction of 41the ° mixtureCsubstrates mixtureand 43 in °in Ctheare thefor vialwell vialthe is ab duration isnot ovenot a meltathe melt of temperature but the but rather 16-h rather reaction solids ofsolids the interacting (Figuresysteminteracting (Figure1). with Because with other 1), other we the meltingsystemcan conclude stayed temperatures that between the reactionof 41 the °C substrates andmixture 43 ° Cin are for the wellthe vial durationab is ovenot thea meltof temperature the but 16-h rather reaction ofsolids the (Figure systeminteracting 1). (Figure Because with 1), other thewe canmelting conclude temperatures that the reaction of the substratesmixture in are the wellvial isab notove a the melt temperature but rather solids of the interacting system (Figure with other1), we canmelting conclude temperatures that the reaction of the substrates mixture in are the well vial ab is ovenot athe melt temperature but rather ofsolids the systeminteracting (Figure with 1), other we can conclude that the reaction mixture in the vial is not a melt but rather solids interacting with other can conclude that the reaction mixture in the vial is not a melt but rather solids interacting with other

Molecules 2020, 25, 364 4 of 10

Molecules 2019, 24, x FOR PEER REVIEW 4 of 10 shown in Figure1. The maximum temperature reached during the reaction was 43 ◦C, and the systemsolids. Regarding stayed between the reactivity, 41 ◦C and when 43 ◦stronglyC for the electr durationon donating of the groups 16-h reaction are placed (Figure on 1the). Becausearyl ring thesystem, melting the temperaturesmajor product of is the the substrates corresponding are well phenol, above thenot temperaturethe desired ofcarboxylic the system acid. (Figure This1 ),is weconsistent can conclude with the that results the reaction of a Dakin mixture oxidation in the that vial have is not been a melt observed but rather in the solids literature interacting with similar with othersystems solids. [39,44–47]. Regarding the reactivity, when strongly electron donating groups are placed on the aryl ring system,The temperature the major of product the system is the was corresponding monitored as phenol, the reaction not the progressed desired carboxylic using an acid. iButton. This A is consistentgraph is shown with thein Figure results 1. of The a Dakin maximum oxidation temperat that haveure reached been observed during inthe the reaction literature was with 43 °C, similar and systemsthe system [39 stayed,44–47]. between 41 °C and 43 °C for the duration of the 16-h reaction (Figure 1).

Figure 1. TemperatureTemperature inside the ball mill during oxidation of benzyl alcohol. The temperature of the system was monitored as the reaction progressed using an iButton. A graph We have previously shown that the combination of mechanochemistry and polymer supports is shown in Figure1. The maximum temperature reached during the reaction was 43 C, and the can significantly increase the greenness of a reaction. Using the Ecoscale [48], we compared◦ a solution system stayed between 41 C and 43 C for the duration of the 16-h reaction (Figure1). Wittig reaction with unsupported◦ triphenylphosphine◦ to a ball-milled Wittig reaction with polymer- We have previously shown that the combination of mechanochemistry and polymer supports can supported triphenylphosphine; the reaction conditions went from inadequate on the EcoScale to significantly increase the greenness of a reaction. Using the Ecoscale [48], we compared a solution Wittig excellent [49]. In this case, using mechanochemistry and the polymer-supported TEMPO as a reaction with unsupported triphenylphosphine to a ball-milled Wittig reaction with polymer-supported substitute for the non-supported TEMPO in solution, the EcoScale improved from adequate to triphenylphosphine; the reaction conditions went from inadequate on the EcoScale to excellent [49]. excellent. In this case, using mechanochemistry and the polymer-supported TEMPO as a substitute for the After testing the initial reaction conditions, we wanted to determine the recyclability of the non-supported TEMPO in solution, the EcoScale improved from adequate to excellent. polymer-supported TEMPO catalyst. Starting with benzyl alcohol, we conducted four subsequent After testing the initial reaction conditions, we wanted to determine the recyclability of the oxidation reactions, each time using the polymer-supported TEMPO from the previous run and polymer-supported TEMPO catalyst. Starting with benzyl alcohol, we conducted four subsequent charging the reaction with fresh Oxone®. We observed greater than 90% conversion of the benzyl oxidation reactions, each time using the polymer-supported TEMPO from the previous run and alcohol to benzoic acid in each run (Figure 2). charging the reaction with fresh Oxone®. We observed greater than 90% conversion of the benzyl We also wanted to test whether we needed to charge the reaction with Oxone® after each run. alcohol to benzoic acid in each run (Figure2). After conducting the recyclability study without the addition of Oxone®, we observed limited We also wanted to test whether we needed to charge the reaction with Oxone® after each conversion of the alcohol to the carboxylic acid. It is clear that although the polymer-supported run. After conducting the recyclability study without the addition of Oxone®, we observed limited catalyst can be reused, a fresh load of Oxone® is needed for every run. conversion of the alcohol to the carboxylic acid. It is clear that although the polymer-supported catalyst When Merrifield resins are swollen by a solvent, it allows the substrate greater accessibility to can be reused, a fresh load of Oxone® is needed for every run. the active sites inside the polymer support. However, this mode of reactivity can be dependent on When Merrifield resins are swollen by a solvent, it allows the substrate greater accessibility the size of the substrate, often requiring longer reaction times for larger substrates [50–54]. Under to the active sites inside the polymer support. However, this mode of reactivity can be dependent mechanochemical conditions, the polymer resin is pulverized; thus, the active sites of the polymer on the size of the substrate, often requiring longer reaction times for larger substrates [50–54]. should be completely exposed to the substrate. Therefore, the reaction rate should be completely Under mechanochemical conditions, the polymer resin is pulverized; thus, the active sites of the independent of the size of the substrate. To test this attribute, we compared the reaction rates of 1- polymer should be completely exposed to the substrate. Therefore, the reaction rate should be octanol, 1-dodecanol, and 1-adamantanemethanol in order to study the effect the size of substrate has completely independent of the size of the substrate. To test this attribute, we compared the reaction on the rate of reactivity. One equivalent of a base, K2CO3, was added to the linear aliphatic alcohol rates of 1-octanol, 1-dodecanol, and 1-adamantanemethanol in order to study the effect the size of oxidations in order to suppress ester side product formation. Oxone® itself creates an acidic substrate has on the rate of reactivity. One equivalent of a base, K CO , was added to the linear environment, so without the addition of the base, the carboxylic acid product2 3 reacted with the alcohol aliphatic alcohol oxidations in order to suppress ester side product formation. Oxone® itself creates starting material to form an ester. It is important to note that when aryl alcohols were oxidized additional base was not needed. We believe this is because the rate of aryl alcohols is faster than aliphatic alcohols, limiting the opportunity of the free alcohol to participate in an esterification. After

Molecules 2020, 25, 364 5 of 10 an acidic environment, so without the addition of the base, the carboxylic acid product reacted with theMolecules alcohol 2019, starting24, x FOR materialPEER REVIEW to form an ester. It is important to note that when aryl alcohols5 wereof 10 oxidizedMolecules 2019 additional, 24, x FOR basePEER wasREVIEW not needed. We believe this is because the rate of aryl alcohols is5 faster of 10 thanadding aliphatic the base, alcohols, the ester limiting side product the opportunity was successfully of the free suppressed, alcohol to participate and we observed in an esterification. very little MoleculesMolecules 2019 2019, 24, 24, x, FORx FOR PEER PEER REVIEW REVIEW 5 of5 of10 10 AfterdifferenceaddingMolecules adding the 2019 between base,, the24, x base,FORthe the PEER ester the rates REVIEW ester side of reaction side product product of was the was varisuccessfully successfullyous-sized suppressed, substrates suppressed, compared and and we we observed to observed the 5reaction of very10 very withlittle non-supporteddifferenceadding the between base, TEMPO the the ester rates (Table side of reaction2)product [55]. This wasof the successfullysuggests various-sized the suppressed, size substrates of the and substrate comparedwe observed has tovery verythe little reaction little effect with on diffaddingerenceadding the betweenthe base, base, the thethe ester ratesester side ofside reactionproduct product was of was the successfully successfully various-sized suppressed, suppressed, substrates and and comparedwe we observed observed to thevery very reaction little little with thenon-supporteddifference rate of reaction. between TEMPO the rates (Table of reaction 2) [55]. of This the varisuggestsous-sized the substrates size of the compared substrate to thehas reaction very little with effect on non-supporteddifferencedifference between between TEMPO the the rates (Table rates of of2 reaction)[ reaction55]. Thisof of the the suggests vari various-sizedous-sized the size substrates substrates of the substratecompared compared hasto to the verythe reaction reaction little with e ffwithect on the non-supported TEMPO (Table 2) [55]. This suggests the size of the substrate has very little effect on ratethenon-supported non-supportedrate of reaction. of reaction. TEMPO TEMPO (Table (Table 2) 2) [55]. [55]. This This suggests suggests the the size size of of the the substrate substrate has has very very little little effect effect on on the rate of reaction. thethe rate rate of of reaction. reaction. Recyclabilty of PS-TEMPO 99% Recyclabilty98% 95% of PS-TEMPO 98% 100% Recyclabilty of 92%PS-TEMPO91% 99%Recyclabilty98%Recyclabilty of of PS-TEMPO PS-TEMPO 98% 90% 99%99%98% 95% 98% 100% 99% 98% 95%95% 92% 91% 98% 100%100% 98% 95% 92%92% 91%91% 98% 100%80%90% 92% 91% 90%90% 90%70% 80%80%80% 80%60% 70%70%70% 70% 60%50%60%60% 60% 50%40%50% 50%50% 30% 40%30%40%40% 30%30% 40% 30%30% 30%20%30%30% 30% 6% 20%10%20% 20%20% 6%6% 1% 0% 10%10% 6% 6% 1%1% 0%0% 10%10%0% 1% 1% 0% 0%0% 0% 0%0% Run 1 Run 2 Run 3 Run 4 Run 5 RunRun 1 1 Run Run 2 2 Run Run 3 3 Run Run 4 4 Run Run 5 5 RunRun 1 1 Run Run 2 2 Run Run3 3 Run 4 Run 4 Run 5 Run 5 adding Oxone after each run addingadding Oxone Oxone after after each each run run adding Oxone after each run adding Oxone after each run OxoneOxone added added added only only only in inthe inthe firstthe first runfirst run run Oxone added only in the first run Oxone added only in the first run

FigureFigureFigure 2. 2.Recyclability Recyclability study study study of of PS-TEMPO. ofPS-TEMPO. PS-TEMPO. Figure 2. Recyclability study of PS-TEMPO. Figure 2. Recyclability study of PS-TEMPO. TableTable 2. 2.Comparison Comparison of of PS-TEMPO PS-TEMPO with with non-supported non-supported TEMPO. TEMPO. Table 2.2. Comparison Comparison of ofPS-TEMPO PS-TEMPO with with non-supported non-supported TEMPO. TEMPO. Table 2. Comparison of PS-TEMPO with non-supported TEMPO. Table 2. Comparison of PS-TEMPO with non-supported TEMPO.

%% %% EntryEntry AlcoholAlcohol CatalystCatalyst % CatalystCatalyst % EntryEntry Alcohol Alcohol Catalyst Catalyst ConversionConversion % Conversion% Catalyst Catalyst ConversionConversion % Conversion % Entry Alcohol CatalystConversion Catalyst Conversion ConversionPS- PS- Conversion 11 1 TEMPOTEMPOTEMPO 8181 81 % PS- PS-TEMPO9595 % 95 Entry1 Alcohol TEMPOCatalyst 81 TEMPOCatalyst 95 ConversionTEMPOTEMPO PS- Conversion 1 TEMPO 81 PS-PS- 95 22 2 TEMPOTEMPOTEMPO 7676 76 PS- PS-TEMPOTEMPOPS- 9595 95 1 2 TEMPOTEMPO 76 81 TEMPOTEMPO 95 95 TEMPOTEMPO PS- 2 TEMPO 76 95 TEMPOPS- 2 TEMPO 76 PS-PS- 95 3 3 TEMPO TEMPO 8080 * * PS- 8989 * * 33 TEMPOTEMPO 80 * 80 *TEMPO PS-TEMPOTEMPO 89 * 89 * TEMPOTEMPO PS-

3 TEMPO 80 * 89 * * *Recorded Recorded percent percent conversion conversion includes includes both both 1-adamantanecarboxylic 1-adamantanecarboxylic acid acid and and TEMPO1-adamantanol 1-adamantanolPS- 3 * Recorded percent conversion includes both 1-adamantanecarboxylicTEMPO 80 acid* and 1-adamantanol 89 * (produced(produced analogously analogously to to the the Dakin Dakin reaction reaction as as de describedscribed above above in in the the aryl aryl system system with with a astrong strong * Recorded(produced percent analogously conversion to includesthe Dakin both reaction 1-adamantanecarboxylic as described above acid in and the 1-adamantanol aryl systemTEMPO with (produced a strong analogously toelectron theelectron Dakin donating donating reaction group) as group) described [16,20–23]. [16,20–23]. above in the aryl system with a strong electron donating group) [16,20–23]. * electronRecorded donating percent group) conversion [16,20–23]. includes both 1-adamantanecarboxylic acid and 1-adamantanol (producedWe are also analogously investigating to theselectively Dakin reactionoxidizing as th dee 4-methylbenzylscribed above in alcohol the aryl to thesystem corresponding with a strong * WeRecordedWe are are also also percent investigating investigating conversion selectively selectively includes oxidizing oxidizing both th1-adamantanecarboxylic the 4-methylbenzyle 4-methylbenzyl alcohol alcohol acid to to the andthe corresponding corresponding 1-adamantanol aldehyde.We are Based also investigating work by Stahl selectively and co-workers, oxidizing we hypothesized the 4-methylbenzyl that copper, alcohol in the to thepresence corresponding of aldehyde.aldehyde.electron(produced Based donating Based analogously work work group) by by Stahlto [16,20–23].Stahl the and Dakinand co-workers, co-workers, reaction aswe we de hypothesized scribedhypothesized above that thatin thecopper, copper, aryl insystem in the the presence withpresence a strong of of oxygen, could catalyze the oxidation instead of Oxone® [56].® We tested this theory using a copper vial aldehyde.oxygen,oxygen,electron could could Based donating catalyze catalyze work group) the bythe oxidation Stahloxidation[16,20–23]. and instead instead co-workers, of of Oxone Oxone® we [56]. [56]. hypothesized We We tested tested this this thattheory theory copper, using using a in coppera copper the presencevial vial of as Wethe arecopper also investigatingsource. No conversion selectively was oxidizing obtained th ®ewith 4-methylbenzyl PS-TEMPO, alcoholhowever, to quantitativethe corresponding oxygen,asas the the couldcopper copper catalyze source. source. the No No oxidation conversion conversion instead was was ofobtained obtained Oxone with [with56]. PS-TEMPO, WePS-TEMPO, tested thishowever, however, theory quantitative using quantitative a copper vial aldehyde.conversionWe are Based alsoto the investigatingwork corresponding by Stahl selectively andaldehyde co-workers, oxidizingwas obtained we th ehypothesized when4-methylbenzyl non-supported that alcohol copper, TEMPO to inthe was the corresponding usedpresence of asconversion theconversion copper to source.to the the corresponding corresponding No conversion aldehyde aldehyde was obtained was was obtained obtained with PS-TEMPO,when when non-supported non-supported however, TEMPO quantitativeTEMPO was was used conversionused oxygen,aldehyde.under thesecould Based conditions catalyze work the(Schemeby oxidationStahl 2). and instead co-workers, of Oxone we ®hypothesized [56]. We tested that this copper, theory usingin the a presencecopper vial of underunder these these conditions conditions (Scheme (Scheme 2). 2). asoxygen, the coppercould catalyze source. the No oxidation conversion instead was of Oxoneobtained® [56]. with We testedPS-TEMPO, this theory however, using aquantitative copper vial conversion to the corresponding aldehyde was obtained when non-supported TEMPO was used as the copper source. No conversion was obtained with PS-TEMPO, however, quantitative underconversion these toconditions the corresponding (Scheme 2). aldehyde was obtained when non-supported TEMPO was used under these conditions (Scheme 2).

Molecules 2020, 25, 364 6 of 10

toMolecules the corresponding 2019, 24, x FOR PEER aldehyde REVIEW was obtained when non-supported TEMPO was used under6 theseof 10 conditions (Scheme2).

Scheme 2. Conversion of primary alcohol to aldehyde using TEMPO in a copper vial. Scheme 2. Conversion of primary alcohol to aldehyde using TEMPO in a copper vial. We hypothesize that there may be structural differences regarding non-supported TEMPO versusWe PS-TEMPO hypothesize which that dothere not may allow be the structural PS-TEMPO differences to interact regarding with the non-supported copper vial e ffTEMPOectively. Thisversus investigation PS-TEMPO is which ongoing. do not allow the PS-TEMPO to interact with the copper vial effectively. This investigation is ongoing. 3. Materials and Methods 3. Materials and Methods Deuterated chloroform was obtained from Cambridge Isotope Laboratories Inc. (Andover, MA. USA),Deuterated and used withoutchloroform further was obtained purification. from TEMPO Cambridge functionalized Isotope Laboratori polystyrene,es Inc. 2%(Andover, cross-linked MA. withUSA), divinylbenzene, and used without (PS-TEMPO) further purification. was obtained TEMP fromO Biotage functionalized® (Uppsala, polystyrene, Sweden) and2% usedcross-linked without furtherwith divinylbenzene, purification. 1-Dodecanol (PS-TEMPO) waswas obtained from from Biotage Aldrich® (Uppsala, (St. Louis, Sweden) Missouri, and MO, used USA) without and usedfurther without purification. further 1-Dodecanol purification. was Phenethyl obtained alcoholfrom Aldrich was obtained (St. Louis, from Missouri, Matheson MO, ColemanUSA) and & Bellused (MCB) without (Washington, further purification. DC, USA) Phenethyl and used alco withouthol was furtherobtained purification. from Matheson Other Coleman alcohols & Bell and oxidants(MCB) (Washington, were obtained DC, from USA) Fisher and used Scientific without (Hampton, further purification. New Hampshire, Other alcohols NH, USA) and andoxidants used withoutwere obtained further from purification. Fisher Scientific1H NMR (Hampton, spectroscopy New was Hampshire, performed NH, using USA) a Brukerand used Avance without 400 1 spectrometerfurther purification. (Billerica, H Massachusetts, NMR spectroscopy MA, USA).was performed The temperature using a ofBruker the vial Avance was determined400 spectrometer by use of(Billerica, a temperature Massachusetts, logging “iButton” MA, USA). (DS1922E-F5#, The temperat Maximure Integratedof the vial Circuits, was determined San Jose, California, by use of CA, a USAtemperature http://www.ibutton.com logging “iButton”) clamped (DS1922E-F5#, against Maxim the vial. Integrated This temperature Circuits, rises San forJose, approximately California, CA, the firstUSA hour http://www.ibutton.com) and then maintains for clamped the remainder against the of the vial. experiment. This temperature rises for approximately the first hour and then maintains for the remainder of the experiment. 3.1. PS-TEMPO/Oxone®/Stainless Steel 3.1. PS-TEMPO/Oxone®/Stainless Steel To a customized 3.0 mL stainless steel vial was added 250 mg (0.99 mmol/g) of PS-TEMPO, 0.314 g OxoneTo® a(0.5 customized mmol), and3.0 mL 0.25 stainless mmol steel of alcohol. vial was A added 3/16” 250 stainless mg (0.99 steel mmol/g) ball was of PS-TEMPO, added to the 0.314 vial. g Oxone® (0.5 mmol), and 0.25 mmol of alcohol. A 3/16” stainless steel ball was added to the vial. The The vial was shaken at 18Hz for 16 h in a Spex8000M Mixer/Mill (Metuchen, NJ, USA). The resulting vial was shaken at 18Hz for 16 h in a Spex8000M Mixer/Mill (Metuchen, NJ, USA). The resulting mixture was gravity filtered with one of three polar solvents (acetone, ethyl acetate, and ethanol), mixture was gravity filtered with one of three polar solvents (acetone, ethyl acetate, and ethanol), depending on the solubility of the desired product. The solvent was removed under reduced pressure, depending on the solubility of the desired product. The solvent was removed under reduced affording the carboxylic acid product. The PS-TEMPO was recovered, dried and used in the subsequent pressure, affording the carboxylic acid product. The PS-TEMPO was recovered, dried and used in reactions. 1H NMR spectroscopy using a Bruker Avance 400 spectrometer was performed to assess the the subsequent reactions. 1H NMR spectroscopy using a Bruker Avance 400 spectrometer was extent and purity of the reaction products. performed to assess the extent and purity of the reaction products. 3.2. Substrate Size Study 3.2. Substrate Size Study To a customized 3.0 mL stainless steel vial was added 250 mg (0.99 mmol/g) of PS-TEMPO, 0.314 g To® a customized 3.0 mL stainless steel vial was added 250 mg (0.99 mmol/g) of PS-TEMPO, 0.314 Oxone (0.5 mmol), and 0.25 mmol of alcohol. For 1-octanol and 1-dodecanol, 0.25 mmol K2CO3 g Oxone® (0.5 mmol), and 0.25 mmol of alcohol. For 1-octanol and 1-dodecanol, 0.25 mmol K2CO3 was also added to the vial. A 3/16” stainless steel ball was added to the vial. The vial was shaken was also added to the vial. A 3/16” stainless steel ball was added to the vial. The vial was shaken at at 18 Hz for 16 h in a Spex8000M Mixer/Mill. The resulting mixture was gravity filtered with one of 18 Hz for 16 h in a Spex8000M Mixer/Mill. The resulting mixture was gravity filtered with one of three polar solvents (acetone, ethyl acetate, and ethanol), depending on the solubility of the desired three polar solvents (acetone, ethyl acetate, and ethanol), depending on the solubility of the desired product. The solvent was removed under reduced pressure, affording the product. The PS-TEMPO product. The solvent was removed under reduced pressure, affording the product. The PS-TEMPO was recovered, dried and used in the subsequent reactions. 1H NMR spectroscopy using a Bruker was recovered, dried and used in the subsequent reactions. 1H NMR spectroscopy using a Bruker Avance 400 spectrometer was performed to assess the extent and purity of the reaction products. Avance 400 spectrometer was performed to assess the extent and purity of the reaction products.

Molecules 2020, 25, 364 7 of 10

3.3. TEMPO/Copper To a customized copper vial was added 0.25 mmol TEMPO and 0.25 mmol of alcohol. A 1/8” copper ball was added to the vial. The vial was shaken at 18 Hz for 16 h in a Spex8000M Mixer/Mill. The resulting mixture was gravity filtered with one of three polar solvents (acetone, ethyl acetate, and ethanol), depending on the solubility of the desired product. The solvent was removed under reduced pressure, affording a mixture of the aldehyde product and TEMPO. 1H NMR spectroscopy using a Bruker Avance 400 spectrometer was performed to assess the extent and purity of the reaction products. Please find 1H NMR Spectra of selected products in the Supplementary Materials.

4. Conclusions In conclusion, we further demonstrated the powerful combination of mechanochemistry with polymer supported resins. These reaction conditions are a novel way to activate polymer supported reagents that are faster and more general than the traditional swelling mechanism. Additionally, due to the pulverization of the polymer, the rate of the reaction is not dictated by the size of the substrate but rather mostly by the milling process, which is much improved over the traditional solution based conditions. Furthermore, the nature of the reactions allowed us to develop a metal-free, recyclable, environmentally benign method for the conversion of alcohols to their corresponding carboxylic acids. We are currently applying these oxidation conditions to secondary alcohols for the oxidation of ketones and to determine the potential selectivity of primary over secondary alcohols. Mechanochemistry is a rapidly growing ﬁeld and as we learn more about these unique reaction conditions, the more prominent they will become in the chemical literature.

Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/2/364/s1, Figure S1: 1H NMR of substrates and calculation of EcoScale. Author Contributions: Conceptualization and design, J.M., K.L.D. and D.C.W.; experimentation and data analysis, K.L.D., P.C.; funding acquisition J.M.; all authors finally reviewed and approved the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research is supported by the National Science Foundation grant number CHE-1900097, National Science Foundation—grant number CHE-1465110 and the University of Cincinnati Research Council (URC). Conflicts of Interest: The authors declare no conflict of interest.

References and Note

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Sample Availability: Samples of the compounds benzoic acid, 4-nitrobenzoic acid, 4- chlorobenzoic acid, 4-bromobenzoic acid, toluic acid, phenyl acetic acid are available from the authors.

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