catalysts

Article Studies of the Catalytic Activity of Iron (III) Porphyrins for the Protection of Carbonyl Groups in Homogeneous Media

Gabriel Kaetan Baio Ferreira, Charles Carvalho and Shirley Nakagaki *

Laboratório de Bioinorgânica e Catálise, Departamento de Química—Centro Politécnico, Universidade Federal do Paraná (UFPR), Curitiba PR 81531980, Brazil; [email protected] (G.K.B.F.); [email protected] (C.C.) * Correspondence: [email protected]; Tel.: +55-41-3361-3180



Received: 8 March 2019; Accepted: 31 March 2019; Published: 4 April 2019


Abstract: The protection of carbonyl groups that produce acetal products is a key reaction in fine chemistry due to the high reactivity of aldehydes and ketones in certain media. This process can be catalyzed by protic or Lewis acids. Since metalloporphyrins often possess free axial positions in the central metal, they can be applied as Lewis acid catalysts, allowing the additional coordination of substrates. Therefore, three ferric complexes were selected to be evaluated as catalysts for the acetalization of benzaldehyde with ethanol and triethyl orthoformate (TEOF) in the homogeneous phase: (i) 5,10,15,20-tetrakis(phenylporphyrin) iron (III) chloride (Fe0F); (ii) 5,10,15,20-tetrakis(2,6-difluorphenylporphyrin) iron (III) chloride (Fe2F); and (iii) 5,10,15,20-tetrakis (pentafluorphenylporphyrin) iron (III) chloride (Fe5F). The complex Fe5F showed the highest catalytic activity, and kinetic parameters were evaluated for this reaction, exhibiting an increasing rate of reaction of about 550-fold in comparison with the non-catalyzed reaction. The reaction scope was also investigated, and Fe5F was found to be active for the acetalization of benzaldehyde and acetophenone, with different protective agents such as alcohols, glycols, glycerol, and epoxide being selective for the formation of cyclic acetals. The protection of benzaldehyde with ethylene glycol and propylene glycol were also studied at different temperatures, and turnover frequency (TOF) values of up to 360 h−1 were determined at 40 ◦C in homogenous media without the need for solvent or drying agents.

Keywords: porphyrin; acetalization; homogeneous catalysis; Lewis acid catalysis

1. Introduction Porphyrins are macrocyclic compounds that are naturally found in diverse forms of life, where they perform distinct roles, including oxygen transport in cellular respiration processes, and mainly in catalytic processes, such as the detoxification of xenobiotic compounds and the oxidation of fatty acids [1,2]. Over the last 40 years, these compounds have been intensively studied due to their application as bio-inspired models of heme proteins that present catalytic activity, e.g., the cytochrome P450 enzyme family [3]. The cytochrome P450 enzymes are defined by the presence of a heme (iron protoporphyrin IX) prosthetic group coordinated on the proximal side by a thiolate ion deriving from a protein residue [4–7]. In 1979, Groves et al. demonstrated for the first time the catalytic activity of a cytochrome P450 biomimetic model based on a synthetic iron (III) porphyrin [Fe(TPP)]Cl (Figure1A), which was able to catalyze the hydroxylation and epoxidation of hydrocarbons with iodosylbenzene as an oxygen source under mild conditions [8]. This transformation was indicated as occurring through the formation of a high valent metal–oxygen intermediate complex [3,9].

Catalysts 2019, 9, 334; doi:10.3390/catal9040334 www.mdpi.com/journal/catalysts Catalysts 2018, 8, x FOR PEER REVIEW 2 of 14

Catalystssource 2019under, 9, 334 mild conditions [8]. This transformation was indicated as occurring through2 ofthe 14 formation of a high valent metal–oxygen intermediate complex [3,9].

Figure 1. Iron (III) porphyrins mentioned in this work: (A) [5,10,15,20-tetrakis(phenylporphyrin) Figure 1. Iron (III) porphyrins mentioned in this work: (A) [5,10,15,20-tetrakis(phenylporphyrin) iron iron (III)] chloride, [Fe(TPP)]Cl (Fe0F); (B) [5,10,15,20-tetrakis(mesitylporphyrin) iron (III)] (III)] chloride, [Fe(TPP)]Cl (Fe0F); (B) [5,10,15,20-tetrakis(mesitylporphyrin) iron (III)] chloride, chloride, [Fe(TMP)]Cl; (C) [5,10,15,20-tetrakis (2,6-difluorophenylporphyrin) iron (III)] chloride, [Fe(TMP)]Cl; (C) [5,10,15,20-tetrakis (2,6-difluorophenylporphyrin) iron (III)] chloride, [Fe(TDFPP)Cl] (Fe2F), and (D) [5,10,15,20-tetrakis (pentafluorophenylporphyrin) iron (III)] chloride, [Fe(TDFPP)Cl] (Fe2F), and (D) [5,10,15,20-tetrakis (pentafluorophenylporphyrin) iron (III)] chloride, [Fe(TPFPP)Cl] (Fe5F). [Fe(TPFPP)Cl] (Fe5F). Although the biomimetic catalytic system developed by Groves et al. [8] qualitatively reproduced the P450Although reaction, the thebiomimetic catalytic activitycatalytic wassystem rapidly developed diminished by byGroves extensive et al. destruction [8] qualitatively of the metalloporphyrin.reproduced the P450 However, reaction, in the 1981, catalytic the same activity group was showed rapidly that diminished the iron porphyrinby extensive ([Fe(TMP)]Cl destruction (Figureof the 1metalloporphyrin.B) was able to resist However, oxidative in destruction 1981, the duesame to thegroup steric showed hindrance that imposed the iron by porphyrin the meso substitutes([Fe(TMP)]Cl present (Figure in 1B) the porphyrinwas able to structure resist oxidative [10,11]. destruction due to the steric hindrance imposed by theChang meso andsubstitutes Ebina, in present 1981, demonstrated in the porphyrin that structure fluorinated [10,11]. iron porphyrin [Fe(TPFPP)]Cl (Figure1D) had aChang superior and catalytic Ebina, in activity 1981, demonstrated toward cyclohexane that fluorinated hydroxylation iron porphyrin in contrast [Fe(TPFPP)]Cl with the [Fe(TPP)]Cl (Figure (Figure1D) had1A), a achievingsuperior catalytic a 71% yieldactivity of cyclohexanoltoward cyclohexane versus thehydroxylation 5% yield of in the contrast non-fluorinated with the compound.[Fe(TPP)]Cl (Figure The electronic 1A), achieving effects of a fluorine71% yield atoms of cyclohexanol were attributed versus to causingthe 5% theyield improvement of the non- offluorinated the catalytic compound. activity in The comparison electronic to theeffects results of presentedfluorine atoms by the were [Fe(TPP)]Cl attributed used to by causing Groves (8%the cyclohexanol)improvement [of8, 11the,12 catalytic]. activity in comparison to the results presented by the [Fe(TPP)]Cl used by GrovesBoth the(8% iron cycloh porphyrinsexanol) [8,11,12]. [Fe(TMP)]Cl and [Fe(TPFPP)]Cl (Figure1B,D) were more effective catalystsBoth for the hydrocarbon iron porphyrins oxidation [Fe(TMP)]Cl due to the and structural [Fe(TPFPP)]Cl modification (Figure of 1B the and porphyrin D) were ringmore periphery. effective Thatcatalysts modification for hydrocarbon increased oxidation the robustness due ofto thethe complexstructural during modification the catalytic of the reaction porphyrin against ring the periphery. That modification increased the robustness of the complex during the catalytic reaction electrophilic attack that can occur in a solution (homogeneous catalysis), and it was able to form a against the electrophilic attack that can occur in a solution (homogeneous catalysis), and it was able reasonably stable high-valent iron porphyrin catalytic active species [3,11]. to form a reasonably stable high-valent iron porphyrin catalytic active species [3,11]. All of these distinct structural features of the tetrapyrrolic macrocycles have led to a better All of these distinct structural features of the tetrapyrrolic macrocycles have led to a better understanding and the development of more robust catalysts based on porphyrins, enabling their use understanding and the development of more robust catalysts based on porphyrins, enabling their as a sophisticated bulky, chiral, and surface-linked catalysts [13]. use as a sophisticated bulky, chiral, and surface-linked catalysts [13]. In a multistep reaction, where multifunctional compounds are involved, sometimes it is necessary In a multistep reaction, where multifunctional compounds are involved, sometimes it is to protect a specific functional group to avoid undesired side reactions. Among the functional necessary to protect a specific functional group to avoid undesired side reactions. Among the group protection reactions, the acetalization of aldehydes and ketones is an important step in fine functional group protection reactions, the acetalization of aldehydes and ketones is an important step chemistry and organic synthesis to protect carbonyl groups, leading to pharmaceutical compounds in fine chemistry and organic synthesis to protect carbonyl groups, leading to pharmaceutical and intermediates of carbohydrates and steroids [14,15]. compounds and intermediates of carbohydrates and steroids [14,15]. Wang et al. demonstrated the attainment of a mono and a disubstituted optically active Wang et al. demonstrated the attainment of a mono and a disubstituted optically active α- α-hydroxy acid with high enantiomeric excesses, which are important intermediates for an asymmetric hydroxy acid with high enantiomeric excesses, which are important intermediates for an asymmetric synthesis. By the transacetalization reaction using BF3·Et2O as a catalyst, the asymmetry of synthesis. By the transacetalization reaction using BF3·Et2O as a catalyst, the asymmetry of (1S)-(+)- (1S)-(+)-N,N-diisopropyl-10-camphorsulfonamide was transferred to the α-hydroxy acid, leading N,N-diisopropyl-10-camphorsulfonamide was transferred to the α-hydroxy acid, leading to the to the formation of the desired product [16]. formation of the desired product [16].

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Biasutto et al. synthesized acetal derivatives as prodrugs of resveratrol, a polyphenol compound that exhibits a range of activities of biomedical interest, such as reducing inflammation, (anti-inflammatory), neuroprotection, protection of the cardiovascular system, and the improvement of glucose processing in diabetes, among others. They observed that the use of acetal derivatives may be a convenient strategy to protect polyphenols and possibly other drugs from metabolism while still allowing a sustained absorption [17]. The acetalization reaction is usually carried out by treating aldehydes or ketones with an excess of the corresponding alcohol or glycol in an acid medium, and continuously removing the water formed to shift the equilibrium [18]. Inorganic acids, oxides, zeolites, porous materials, and inorganic complexes are some examples of acid catalysts that can be used for the protection of carbonyl compounds [18–23]. Metalloporphyrins are widely used as efficient and selective catalysts for oxidative processes, both in homogeneous and heterogeneous phases [24]. However, there are few studies that have explored their use as catalysts in functional groups’ protection and reaction and their activity as Lewis acid catalysts. Suda et al. reported the use of a high-valent manganese porphyrin [Mn(TPP)]Cl as a mild acid catalyst for the rearrangement of N-phenyl-spirooxaziridines into lactams [25]. Subsequently, the same group demonstrated the use of a series of metalloporphyrins that are able to effectively catalyze the isomerization reaction of epoxides into carbonyl compounds, where an iron (III) porphyrin [Fe(TPP)]ClO4 was the most efficient catalyst [26]. In 1997, Firouzabadi et al. utilized [Fe(TPP)]Cl as an acid catalyst for the silylation reaction of hydroxyl groups in the presence of hexamethyldisilazane (HMDS) as a silylation agent. They found that diphenylcarbinol, which is resistant to silylation with HMDS, could undergo this transformation very easily and with excellent yields in the presence of [Fe(TPP)]Cl at room temperature [27]. Tangestaninejad et al. used [Fe(TPFPP)]Cl as a new and efficient acid catalyst for the conversion of epoxides into thiiranes, obtaining more than 90% conversion in 15 min of reaction [28]. The reduction of cyclohexanone to cyclohexanol by the Meerwein–Ponndorf–Verley (MPV) reaction catalyzed by an aluminum(III) porphyrin, [Al(TPP)]Cl, was demonstrated by Inoue et al. The aluminum porphyrin was an efficient acid catalyst with good results [29]. There are some examples in the literature where metalloporphyrins were employed as catalysts to open epoxides and generate protected diols through the reaction of acetolysis [30–32]. However, there are no systematic studies on the acetalization reaction with metalloporphyrins acting as acid catalysts. In this work, electron-deficient metalloporphyrins iron (III) porphyrins (Figure1A,C,D) were used as mild Lewis acid catalysts in the acetalization of benzaldehyde with different protective groups. To the best of our knowledge, this is the first systematic study of this type of reaction catalyzed by metalloporphyrins aiming to protect carbonyl groups.

2. Results and Discussion

2.1. Study of the Dependence on the Number of Fluorine Atoms in the Macrocycle Structure and the Catalytic Activity The investigation of the catalytic activity of metalloporphyrins for benzaldehyde acetalization started with studies about the influence of peripheral fluorine atoms in the structure of three different iron (III) porphyrins, since these electronegative atoms can withdraw electron density from the macrocycle structure, modulating the charge density over the complex. For this purpose, a first generation porphyrin with no fluorine atoms was selected, [Fe(TPP)]Cl (named Fe0F), along with two second-generation chromophores: [Fe(TDFPP)]Cl (Fe2F) and [Fe(TPFPP)Cl] (Fe5F) (Figure1A,C,D respectively) [7,11]. These two second-generation macrocycle porphyrins possess two and five fluorine atoms, respectively, for each of the four meso-aryl rings of the macrocycle structure. For a clear comparison of catalytic tests, these three complexes have chloride as counter ions, avoiding misinterpretation of the role of axial ligands. Catalysts 2019, 9, 334 4 of 14 Catalysts 2018,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 14 Catalysts 2018, 8, x FOR PEER REVIEW 4 of 14 The acetalizationThe acetalization of benzaldehyde of benzaldehyde (1) was (1)) waswas selected selectedselected as the asas thethe preliminary preliminarypreliminary reaction reactionreaction using usingusing ethanol ethanolethanol asas as a protectivea Theprotective acetalization group group in of the inbenzaldehyde presencethe presence of ( triethyl1 )of was triethyl selected orthoformate orthoformate thoformateas the preliminary (TEOF) (TEOF)(TEOF) as reaction a asas drying aa dryingdrying using agent, agent,ethanolagent, producing producingproducing as benzaldehydea protectivebenzaldehyde diethylgroup diethyl in acetal the presenceacetal (2a). Since (2a of).). SinceSince watertriethyl waterwater is or athoformate by-product isis aa by-productby-product (TEOF) of this ofof reaction,asthth isisa reaction,dryingreaction, a dryingagent, aa dryingdrying agentproducing agentagent may maymay be bebe benzaldehyde diethyl acetal (2a). Since water is a by-product of this reaction, a drying agent may be neededneeded to avoid toCatalysts productavoid 2018 product, 8 hydrolysis, x FOR PEER hydrolysis REVIEW (Scheme (Scheme1)[19]. 1)) [19].[19]. 4 of 14 needed to avoid product hydrolysis (Scheme 1) [19]. The acetalization of benzaldehyde (1) was selected as the preliminary reaction using ethanol as a protective group in the presence of triethyl orthoformate (TEOF) as a drying agent, producing benzaldehyde diethyl acetal (2a). Since water is a by-product of this reaction, a drying agent may be needed to avoid product hydrolysis (Scheme 1) [19].

SchemeScheme 1. Acetalization 1. AcetalizationAcetalization of benzaldehyde ofof benzaldehydebenzaldehyde (1) with ((1)) ethanolwithwith ethanolethanol in the inin presence thethe presencepresence of triethyl ofof triethyltriethyl orthoformate orthoformateorthoformate Scheme 1. Acetalization of benzaldehyde (1) with ethanol in the presence of triethyl orthoformate (TEOF)(TEOF)(TEOF) and catalyst andand catalystcatalyst producing producingproducing benzaldehyde benzaldehydebenzaldehyde diethyl diethyldiethyl acetal acetalacetal (2a) and ((2a water.)) andand water.water. (TEOF) and catalyst producing benzaldehyde diethyl acetal (2a) and water.

ReactionsReactionsReactions using usingScheme ausing 2%a 2% 1. mol a Acetalizationmol 2% of ofmol catalyst catalyst of of catalyst benzaldehydeFe0F Fe0F,, Fe0F Fe2F ,,( , 1Fe2For) or with Fe5FFe5F,, ororethanol were Fe5Fwere incarried werewere carriedthe presence carriedcarried out out in of homogeneous in out outtriethyl homogeneous inin homogeneoushomogeneous orthoformate media media mediamedia ◦ at 70at 70Cat °C and70 and°C samples andsamples(TEOF) samples were were and catalyst analyzedwere analyzed analyzedproducing afterafter benzaldehyde after 1 h, 3 1 h, h, 6 6 3diethylh, h,h, and and6 acetalh, 24 24and h(2a hof )24 ofand reaction reactionh water. of reaction in inthese these in early these early studies early studies studies (Table(Table1(().Table It1). was It 1 was).). clearItIt waswasclear that clearclear that the thethatthat Lewis Lewis thethe LewisLewis acid acid catalyticcatalytic acidacid catalyticcatalytic activi activity tyactiviactivi of of thetyty the ofinvestigatedof investigatedthethe investigatedinvestigated iron iron (III) irir on(III)porphyrins (III) porphyrins porphyrins is is Reactions using a 2% mol of catalyst Fe0F, Fe2F, or Fe5F were carried out in homogeneous media is strictlystrictly dependent dependent on on the the level level of of fluorine fluorine substitution substitution of of the the aryl aryl groupgroup atat thethe meso positions. No strictlystrictly dependent dependentat 70 °C on and the on samples levelthe level ofwere fluorine ofanalyzed fluorine substitution after substitution 1 h, 3 of h, the6 h, of aryland the 24group aryl h of groupatreaction the mesoat in the these positions. meso early positions. studies No No Noproduct productproduct was was (was Tableobserved observed observed 1). It after was after afterclear 1 h 1of that1 h reactionh of theof reaction reactionLewis with acid with thewith catalytic use thethe of useactiviuse Fe0F of ty and Fe0Fof the Fe2F andandinvestigated, while Fe2FFe2FFe2F, , after, whilewhile whileiron the (III) afterafterafter same porphyrins thethe the time, samesame same is time,time, time,84% 84%84% conversion conversion conversionstrictly was dependent was wasreached reached reached on using the using usinglevel Fe5F Fe5Fof ,Fe5F fluorinewhich, which,, whichwhich issubstitution the is istheismost thethe most of fluorinatedmostmost the fluorinated aryl fluorinatedfluorinated group catalyst. at catalyst. the catalyst.catalyst. mesoAfter Afterpositions. 2 After Afterh, 2full h, 22No full h,h, fullfull conversionconversionconversion was wasproduct observed wasobserved wasobserved forobserved forFe5F Fe5F for ,after ,Fe5F and and 1 after ,,afterh andand of reaction 24 24afterafter h, there there2424 with h,h, wastherethere wasthe usean an waswas increased of increased Fe0F anan increasedincreased and conversion Fe2F conversion, conversionconversionwhile for after for the the the formationforfor same formationthethe time,formationformation of 2aof with2aof with 2a rising withwith rising84% catalystrisingrising conversioncatalyst catalystcatalyst fluorination fluorination was fluorinationfluorination reachedlevels. levels. using levels.levels. These Fe5F ,TheseThese ca catalyticwhichtalytic caca istalytictalytic resultsthe results most resultsresults indicate indicatefluorinated indicateindicate that that catalyst.the that thethat inductive inductive the theAfter inductiveinductive 2effect h, effectfull effecteffect conversion was observed for Fe5F, and after 24 h, there was an increased conversion for the formation playsplays aplays key a key rolea keyrole in rolein the the in regulation regulationthe regulation of of the the of LewisLewis the Lewis acidityacidit yacidit of of Fe(III), Fe(III),y of Fe(III), since since this since this is isconsideredthis considered is consideredconsidered thethe catalytic catalyticthethe catalyticcatalytic of 2a with rising catalyst fluorination levels. These catalytic results indicate that the inductive effect activeactive species species responsible responsible for thefor activationthe activation of th eof carbonyl the carbonyl group groupfor acet foralization acetalization reactions, reactions, as as active speciesplays responsible a key role for in the the regulation activation of the of Lewis the carbonyl acidity of Fe(III), group since for this acetalization is considered reactions, the catalytic as previously observed by Tangestaninejad and Mirkhani in the conversion of epoxides to thiiranes, previouslypreviously observedactive observed species by Tangestaninejad responsibleby Tangestani for thenejad and activation Mirkhaniand Mirkhani of th ine carbonyl the in conversion the group conver forsion ofacet epoxides alizationof epoxides reactions, to thiiranes, to thiiranes, as which is a Lewis acid-dependent reaction [28]. which iswhich a Lewis is previouslya Lewis acid-dependent acid-dependent observed by reaction Tangestani reaction [28nejad]. [28]. and Mirkhani in the conversion of epoxides to thiiranes, which is a Lewis acid-dependent reaction [28]. 1 Table 1. Conversion (%) in the synthesis of 2a catalyzed by Fe0F, Fe2F, and Fe5F at different times. 11 Table 1.TableConversion 1. Conversion (%) in the(%) synthesisin the synthesis of 2a catalyzed of 2a catalyzedcatalyzed by Fe0F byby, Fe0FFe0FFe2F,,, Fe2F and ,Fe5F, and Fe5Fat different atat differentdifferent times. times.times.1 Table 1. Conversion (%) in the synthesis of 2a catalyzed by Fe0F, Fe2F, and Fe5F at different times.1

Catalyst

Catalyst CatalystCatalyst Reaction Time

(h)

Reaction TimeReaction Time Reaction Time (h) (h) Fe0F Fe0FFe0F Fe2F Fe2FFe2F Fe5FFe5FFe5F (h)(h) 1 Fe0F 0 Fe2F 0 84 Fe5F 1 10 0 0 0 84 84 1 2 0 0 0 4 98 84 2 21 0 0 4 4 0 98 98 84 3 0 8 >99 3 32 0 0 8 8 4 >99 >99 98 24 3 23 >99 2424 3 3 30 23 23 8 >99 >99 >99 1 Reaction conditions: 2% mol catalyst in relation to aldehyde, 0.2 mmol of benzaldehyde, 0.6 mmol 1 Reaction1 Reaction conditions:24 conditions: 2% mol 2% catalystmol catalyst in3 relation in relation to aldehyde, to aldehyde, 0.2 mmol 230.2 of mmol benzaldehyde, of benzaldehyde, 0.6 mmol 0.6 of >99TEOF,mmol and of TEOF,◦ and 12 mmol of ethanol at 70 °C, under magnetic stirring. All of the reactions were 12 mmolof TEOF,11 ofReactionReaction ethanol and conditions:12conditions: at 70mmolC, underof 2% 2%ethanol mol magneticmol catalyst catalystat 70 stirring. °C, inin relationunderrelation Allof magnetic thetoto aldehyde,aldehyde, reactions stirring. were 0.20.2 mmolmmolAll performed of ofofthe benzaldehyde,benzaldehyde, reactions at least in were triplicate. 0.60.6 mmolmmol The estimated errorperformed in conversion at least rate in triplicate. values equals The estimated 0.1 to 1. error in conversion rate values equals 0.1 to 1. performedof TEOF, at least and in 12 triplicate. mmol ofThe ethanol estimated at erro70 °C,r in underconversion magnetic rate values stirring. equals All 0.1 of to the 1. reactions were Benzoic acid was not detected in the product composition, showing that the catalyst was not performed at least in triplicate. The estimated errorr inin conversionconversion raterate valuesvalues equalsequals 0.10.1 toto 1.1. BenzoicBenzoic acidactive acid was forwas notaldehyde not detected detected oxidation inin the thein these productproduct conditions. composition, Since Fe5F showingshowing was the thatmost that theactive the catalyst metalloporphyrin catalyst was was not not in this first screening, it was selected as the catalyst to be investigated in the following experiments. activeactive for for aldehydeBenzoic aldehyde oxidationacid oxidation was not in in these detected these conditions. conditions. in the product Since SinceFe5F Fe5F composition, waswas thethe mostmost showing active thatmetalloporphyrin metalloporphyrin the catalyst was in not in this first screening,To optimize it was selected the catalyst as the catalystload, reactions to be investigated were conducted in the following with variations experiments. of the this firstactive screening, for aldehyde it was selectedoxidation as in the these catalyst conditions. to be investigated Since Fe5F waswas in the thethe following mostmost activeactive experiments. metalloporphyrinmetalloporphyrin To optimizeFe5F/benzaldehyde the catalyst ratio. Reactionsload, reactions with 0.5%, were1.0%, 2.0%,conducted and 4.0% molwith of Fe5Fvariations in relation of to 1the were Toinin optimize thisthis firstfirst the screening,screening, catalyst itit load, waswasreactions selectedselected asas were thethe conducted catalystcatalyst toto withbebe investigatedinvestigated variations ofinin thethethe Fe5Ffollowingfollowing/benzaldehyde experiments.experiments. Fe5F/benzaldehyde ratio. Reactions with 0.5%, 1.0%, 2.0%, and 4.0% mol of Fe5F in relation to 1 were ratio. ReactionsTo optimize with 0.5%, the 1.0%, catalyst 2.0%, andload, 4.0% reactions mol of Fe5Fwerein relationconducted to 1 werewith carriedvariations out, andof the Fe5F/benzaldehyde/benzaldehyde ratio.ratio. ReactionsReactions withwith 0.5%,0.5%, 1.0%,1.0%, 2.0%,2.0%, andand 4.0%4.0% molmol ofof Fe5F inin relationrelation toto 1 werewere

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Catalysts 2018, 8, x FOR PEER REVIEW 5 of 14 all of these compositions led to the formation of 2a (Figure2 and Table S1; Supplementary Materials carried(SM)). Inout, order and to makeall of betterthese comparisons,compositions turnover led to the frequencies formation (TOF) of 2a were (Figure determined 2 and afterTable 1 hS1; of Supplementaryreaction at 70 ◦C[ Materials33]. (SM)). In order to make better comparisons, turnover frequencies (TOF) were determined after 1 h of reaction at 70 °C [33].

Figure 2. Dependence of turnover frequencies (TOF) values (h−1) in function of catalyst load (% Figure 2. Dependence of turnover frequencies (TOF) values (h−1) in function of catalyst load (% mol). mol). Reaction conditions: 0.5%, 1.0%, 2.0%, and 4.0% mol catalyst (Fe5F), 0.2 mmol of benzaldehyde, Reaction conditions: 0.5%, 1.0%, 2.0%, and 4.0% mol catalyst (Fe5F), 0.2 mmol of benzaldehyde, 0.6 0.6 mmol of TEOF, and 12 mmol of ethanol at 70 ◦C, under magnetic stirring. mmol of TEOF, and 12 mmol of ethanol at 70 °C, under magnetic stirring. Figure2 shows that the lowest amount of catalyst (0.5% mol) led to the highest TOF value, while the oppositeFigure 2 wasshows observed that the for lowest the highest amount catalyst of catalyst load, (0.5% 4.0% molmol) of ledFe5F to the, yielded highest TOF TOF equal value, to 33 while h−1 . theThe opposite more diluted was observed the reaction for the media, highest the catalyst less aggregated load, 4.0% the mol metalloporphyrins of Fe5F, yielded were,TOF equal which to can 33 −1 hexplain. The more this pattern diluted if the one reaction considers media, that the the less catalytic aggregated species the is anmetalloporphyrins isolated and soluble were, molecule which can of explainiron (III) this porphyrin pattern inif one the solution.considers The that lowest the catalytic TOF value species for theis an use isolated of 4.0% and mol soluble of Fe5F moleculecan also beof ironattributed (III) porphyrin to the total in non-solubilizationthe solution. The lo ofwest this TOF amount value of for catalyst the use in of the 4.0% reaction mol of medium. Fe5F can also be attributedIntermediate to the total values non-solubilization of TOF are appropriate of this amount to study of the catalyst kinetic in profiles the reaction and other medium. features, since the reactionIntermediate is not values too fast of or TOF too sloware appropriate to determine to physicochemicalstudy the kinetic parameters.profiles and Reactionsother features, conducted since thewith reaction 1.0% and is not 2.0% too molfast or of too catalyst slow to yielded determine TOF physicochemical values equal to parameters. 86 h−1 and Reactions 91 h−1, respectively, conducted −1 −1 withinducing 1.0% the and choice 2.0% ofmol 1.0% of molcatalyst catalyst yielded for further TOF values studies, equal since to this 86 amounth and resulted91 h , respectively, in the same inducingTOF of 2.0% the molchoice and of used 1.0% a mol lesser catalyst amount for of further iron (III) studies, porphyrin. since this amount resulted in the same TOF of 2.0% mol and used a lesser amount of iron (III) porphyrin. 2.2. Kinetic Studies for 2a Synthesis at Different Temperatures 2.2. Kinetic Studies for 2a Synthesis at Different Temperatures To evaluate the influence of temperature and time on benzaldehyde acetalization, studies were conductedTo evaluate for the the same influence reaction of usingtemperature 1.0% mol and of timeFe5F onas benzaldehyde catalyst at 70 ◦ acetalization,C, 65 ◦C, 60 ◦ C,studies 55 ◦C, were and conducted50 ◦C, and thefor samplesthe same were reaction analyzed using at 1.0% different mol of times Fe5F up as to catalyst 6 h (Table at 270 and °C, Figure 65 °C, S1, 60 SM).°C, 55 A °C, control and 50reaction, °C, and in the the samples absence ofwere catalyst, analyzed was at also different performed times at up 70 ◦toC. 6 h (Table 2 and Figure S1, SM). A control reaction, in the absence of catalyst, was also performed at 70 °C. a Table 2. Values of kobs and TOF for 2a synthesis catalyzed by Fe5F at different temperatures . Table 2. Values of kobs and TOF for 2a synthesis catalyzed by Fe5F at different temperatures a. ◦ −2 −1 −1 Temperature/ C kobs/10 min TOF/h −2 −1 −1 Temperature/°C50 k 0.391obs / 10± 0.062 min 14.7 TOF± 1.5 / h 50 55 1.430 0.391± ±0.055 0.062 36.8 14.7± 1.0 ± 1.5 55 60 2.130 1.430± ±0.092 0.055 46.4 36.8± 1.1 ± 1.0 60 65 2.770 2.130± ±0.073 0.092 59.2 46.4± 1.6 ± 1.1 70 7.73 ± 0.20 90.6 ± 1.3 65 2.770 ± 0.073 59.2 ± 1.6 70, control 0.0134 ± 0.0012 - 70 7.73 ± 0.20 90.6 ± 1.3 a Reactions conditions: 1.0% mol Fe5F, 0.2 mmol of benzaldehyde, 0.6 mmol of TEOF, and 12 mmol of ethanol at 50 ◦C, 55 ◦C, 60 ◦C, 65 ◦70,C, andcontrol 70 ◦C, under magnetic 0.0134stirring. ± Control 0.0012 reaction performed - as described but in the aabsence Reactions of catalyst. conditions: 1.0% mol Fe5F, 0.2 mmol of benzaldehyde, 0.6 mmol of TEOF, and 12 mmol of ethanol at 50 °C, 55 °C, 60 °C, 65 °C, and 70 °C, under magnetic stirring. Control reaction performed as described but in the absence of catalyst.

Catalysts 2019, 9, 334 6 of 14

Catalysts 2018, 8, x FOR PEER REVIEW 6 of 14 The catalyst Fe5F was active for 2a synthesis at all of the evaluated temperatures, with an increasingThe catalyst rate of acetalFe5F was formation active with for 2a rising synthesis temperature, at all of and the the eval bestuated result temperatures, was observed with at 70 ◦anC. increasingIn contrast, rate at the of acetal same temperatureformation with inthe rising control temp reaction,erature, onlyand the 1.8% best benzaldehyde result was observed was converted at 70 °C. to Inthe contrast, desired productat the same after temperature 4 h, indicating in the that controFe5Flis reaction, the active only species 1.8% forbenzaldehyde this reaction. was converted to theAll desired of the product data could afte ber 4 fitted h, indicating in a first-order that Fe5F exponential is the active equation. species After for this data reaction. linearization from zeroAll to 45 of min,the data it was could possible be fitted to estimate in a first-order values ex forponential pseudo-first equation. order After rate constants data linearization (kobs), because from zeroethanol to 45 was min, in largeit was excess possible in the to reactionestimate mediavalues (Table for pseudo-first2). The ratio order between rate theconstants rate constants (kobs), because for the ◦ ethanolcatalyzed was and in non-catalyzedlarge excess in reactions the reaction performed media ( atTable 70 C( 2).k Thecat/k rationon-cat between) gives an the idea rate of constants how fast thefor thecatalyst catalyzed promotes and thenon-catalyzed reaction in comparisonreactions performed to the stoichiometric at 70 °C (kcat process./knon-cat) Ingives this an case, idea benzaldehyde of how fast theacetalization catalyst promotes in the presence the reaction of 1.0% molin comparison of Fe5F accelerated to the stoichiometric 576 times in the process. homogeneous In this phasecase, benzaldehydecompared to the acetalization non-catalyzed in reaction.the presence of 1.0% mol of Fe5F accelerated 576 times in the homogeneousThe activation phase parameterscompared to for the this non-catalyzed reaction could reaction. be determined from kinetic data. From the linearizedThe activation form of the parameters Arrhenius for equation this reaction (Equation could (1)), be activation determined energy from ( Ekinetica) was data. estimated From to the be −1 linearized126 ± 17.2 form kJ·mol of the. Using Arrhenius the Eyring equation equation (Equation in its (1)), linearized activation form energy (Equation (Ea) was (2)) estimated [34,35], it to was be 126possible ± 17.2 to kJ·mol estimate−1. theUsing activation the Eyring enthalpy equation and entropy,in its linearized∆H‡ and form∆S‡, respectively.(Equation (2)) In both[34,35], equations, it was possibleA is the pre-exponential to estimate the activation factor, k is theenthalpy rate constant, and entropy,R is the ∆H universal‡ and ΔS‡ gas, respectively. constant, T Inis theboth temperature, equations, AkB isis thethe Boltzmannpre-exponential constant, factor, and kh is thethe Planckrate constant, constant. R is the universal gas constant, T is the temperature, kB is the Boltzmann constant, and h is the Planck constant. E ln(k) = ln(A) − a (1) 𝐸 𝑙𝑛𝑘 =𝑙𝑛𝐴 − R.T (1) 𝑅. 𝑇   ‡   ‡ k −∆H kB ∆S ln = ‡ + ln + ‡ (2) T 𝑘 −∆𝐻R.T 𝑘h ∆𝑆R 𝑙𝑛 = +𝑙𝑛 + (2) 𝑇 𝑅.𝑇 ℎ 𝑅 Activation enthalpy was estimated to be 119 ± 18.3 kJ·mol−1 and activation entropy was equal to Activation enthalpy−1 −1 was estimated to be 119 ± 18.3 kJ·mol−1 and activation‡ entropy was equal to 80.4 ± 15.9 J·mol ·K . Considering experimental errors, Ea and ∆H values are close, indicating a −1 −1 ‡ 80.4convergence ± 15.9 J·mol between·K . theConsidering activation experimental parameters. Aerrors, positive Ea and value ∆H of ∆valuesS‡ for are this close, reaction indicating indicates a ‡ convergencethat the formation between of the transitionactivation stateparameters. is a dissociative A positive process value of with ∆S an for increase this reaction of the indicates system’s thatdisorder the formation [36]. of the transition state is a dissociative process with an increase of the system’s disorderBased [36]. on the accepted mechanism of acetal formation from carbonyl compounds and alcohols catalyzedBased byon acidsthe accepted [37], the mechanism first steps areof acetal all associative, formation evolving from carbonyl carbonyl compounds activation and by alcohols the acid catalyzedcatalyst, nucleophilic by acids [37], attack, the first hemiacetal steps are formation, all associ andative, a consecutive evolving carbonyl nucleophilic activation attack by (Scheme the acid2). catalyst, nucleophilic attack, hemiacetal formation, and a consecutive nucleophilic attack (Scheme 2).

Scheme 2. General mechanism for the acetalization of carbonyl compounds catalyzed by a Lewis or Scheme 2. General+ mechanism for the acetalization of carbonyl compounds catalyzed by a Lewis or Bronsted acid (M ). R1 and R2 = alkyl, aryl, –H; R3 and R4 = alkyl groups. Adapted from Reference 37. Bronsted acid (M+). R1 and R2 = alkyl, aryl, –H; R3 and R4 = alkyl groups. Adapted from Reference 37. Considering Fe5F as the active catalytic species, and based on the catalytic results observed Considering Fe5F as the active catalytic species, and based on the catalytic results observed (Table2 and Figure S1-SM), the coordination of the oxygen atom of carbonyl to Fe(III) center (M+) can (Table 2 and Figure S1 - SM), the coordination of the oxygen atom of carbonyl to Fe(III) center (M+) enhance carbonyl’s electrophilicity. As ∆S‡ has a positive value, the product release from catalyst can can enhance carbonyl’s electrophilicity. As ∆S‡ has a positive value, the product release from catalyst be considered the determining step in this case, as it is a dissociative step. can be considered the determining step in this case, as it is a dissociative step.

2.3. Studies of Solvent Composition and the Role of TEOF To clarify the real role of TEOF in the acetalization reaction and its influence on the final product, some experiments were performed with different solvent composition media. Reactions were carried

Catalysts 2019, 9, 334 7 of 14

2.3. Studies of Solvent Composition and the Role of TEOF To clarify the real role of TEOF in the acetalization reaction and its influence on the final product, some experiments were performed with different solvent composition media. Reactions were carried out at 60 ◦C, in the presence or absence of the catalyst Fe5F, with and without TEOF and in different solvents: ethanol, methanol, acetonitrile (CH3CN), carbon tetrachloride (CCl4), and excess of TEOF. The reaction conditions are summarized in Table3.

Table 3. Reaction conditions and TOF values for product formation in different tests to evaluate the role of TEOF in benzaldehyde acetalization at 60 ◦C.

Test Catalyst a n (TEOF)/mmol Solvent b Product (TOF/h−1) c I Fe5F 0.6 Ethanol 2a (68) II Fe5F - Ethanol 2a (54) III Fe5F 12 - - IV Fe5F 0.6 CH3CN - V Fe5F 0.6 CCl4 - VI Fe5F - Methanol 2b (23) d VII Fe5F 0.6 Methanol 2b(21) + 2c (1.7) e VIII - 0.6 Ethanol - IX - - Ethanol - X - 12 - - XI - - Methanol - a 1% mol of catalyst Fe5F in relation to 0.2 mmol of benzaldehyde in all of the reactions. b Solvent volume was 1.0 mL in all of the reactions. c TOF was determined during the initial minutes of reaction. d 2b: benzaldehyde dimethyl acetal. e 2c: benzaldehyde ethyl methyl acetal.

Analysis of the three tests shows that the synthesis of 2a is dependent on ethanol in the reaction medium. The presence of TEOF with ethanol and Fe5F (Test I) yielded higher conversion than the same reaction without the drying agent (TOF = 68 h−1 for Test I and 54 h−1 for Test II), while the absence of alcohol and a large excess of TEOF (Test III, molar ratio TEOF/benzaldehyde = 60) didn’t yield results. A no-product reaction was observed when TEOF was mixed with 1 in the presence of catalyst and with acetonitrile (Test IV) and carbon tetrachloride (Test V) as solvents—polar and non-polar respectively—indicating the metalloporphyrin catalytic activity. The reaction of 1 with methanol in the presence of Fe5F and absence of TEOF (Test VI) rendered benzaldehyde dimethyl acetal (2b) as the single product, with a TOF value equal to 23 h−1, showing that alcohol is the protecting group. When triethyl orthoformate was added to the reaction medium (Test VII), 2b was produced at TOF = 21 h−1 and benzaldehyde ethyl methyl acetal (2c) was detected in lower concentration (TOF = 1.7 h−1). The presence of 2c, a mixed acetal, in the product composition indicates that ethanol produced from TEOF hydrolysis can serve as a protective group. It is important to state that 2c started to be detected after 20 min of reaction. In previous reactions, TEOF was not able to act as an acetalizing group (see tests III to V in Table3), so we assumed that the ethyl group was derived from TEOF hydrolysis. The formation of 2c can be explained by the acid catalysis mechanism [37], where the formation of hemiacetal is an intermediate step, corroborating the evidence that Fe5F acts as a Lewis acid catalyst. Diethyl acetal 2a was not observed as a product from these reactions. Control reactions in the absence of Fe5F (tests VIII to XI) didn’t result in any product, confirming the catalytic action of the compound Fe5F as a Lewis acid catalyst.

2.4. Study of the Scope of Acetalization Reactions Catalyzed by Fe5F The investigation of the scope of carbonyl compounds acetalization catalyzed by Fe5F took place using 1 and acetophenone (3)—an aldehyde and a ketone, respectively—and as protective groups, we used ethanol, methanol, TEOF, ethylene glycol, propylene glycol, glycerol, and cyclooctene oxide. All of the reactions were carried out with 1% mol of Fe5F related to aldehyde or ketone at 70 ◦C (except for methanol, where the temperature was 60 ◦C due to its boiling point) and the molar ratio Catalysts 2019, 9, 334 8 of 14 between protective agent and carbonyl compound was of 60—the reactions were performed without solvent (Table4). CatalystsCatalysts 2018 2018, 8, x, 8FOR, x FOR PEER PEER REVIEW REVIEW 8 of8 14 of 14 CatalystsCatalystsCatalystsCatalystsCatalysts 2018 2018 2018, ,8 8 2018,2018, , x 8x ,FOR FORx,,, 8FOR8,,, xxPEER xPEER FORFORFOR PEER REVIEW PEERPEERREVIEWPEER REVIEW REVIEWREVIEWREVIEW 88 of of8 14of 14 8 148 ofof 1414 CatalystsCatalystsCatalystsCatalystsCatalysts 2018 2018,, 8 20182018,,, 2018 xx8 ,FORFOR x,, 8,FOR8 ,8, x ,xPEERPEER x FORFOR PEERFOR REVIEW PEERREVIEWPEER PEER REVIEW REVIEWREVIEW REVIEW 8 of8 14of8 814 8 ofof of 1414 14 CatalystsCatalystsCatalystsTableCatalystsCatalysts 2018 20182018 4. 2018 ,,2018 , 8Products 88,, , x xx, ,FOR 8FOR FOR8, ,x x FOR FORPEER PEERPEER from PEER PEER REVIEW REVIEWREVIEW acetalization REVIEW REVIEW reactions of benzaldehyde (1) and acetophenone (2) catalyzed888 of ofof 148 14814 of of by 14 14 TableTable 4. Products 4. Products from from acetalization acetalization reactions reactions of benzaldehyde of benzaldehyde (1) and(1) and acetophenone acetophenone (2) catalyzed(2) catalyzed by by Table 4. Products from acetalizationa reactions of benzaldehyde (1) and acetophenone (2) catalyzed by TableFe5FTableTableTable with4. 4. Products 4.Products Products different4. Products from from from protective acetalizationfromacetalization acetalization acetalization agents reactions reactions reactions areactionsanda of of their ofbenzaldehyde benzaldehyde benzaldehyde ofTOF benzaldehyde values. ( (11 )() 1and and) and(1 acetophenone )acetophenone and acetophenone acetophenone ( (22 )() 2catalyzed catalyzed) catalyzed(2) catalyzed by by by by TableTableFe5FTable Table4.TableFe5F Products4. with Products 4.4. with4. Products Products differentProducts fromdifferent from acetalization fromfromprotective from acetalization protective acetalizationacetalization acetalization agents reactionsreactions agents reactions reactionsreactions andreactions ofofand their ofbenzaldehydebenzaldehyde benzaldehydetheir ofof ofTOF benzaldehydebenzaldehyde benzaldehyde TOF values. values. ((1) )( 1andand) and ((1 1( acetophenone)1acetophenone) and)and acetophenoneand acetophenoneacetophenone acetophenone ((2 ))( 2catalyzedcatalyzed) catalyzed ((2 2()2) catalyzed)catalyzed catalyzed byby by byby by TableTableTableTableTable 4. 4.4. Products ProductsProducts 4. 4. Products Products from fromfrom from from acetalization acetalizationacetalization acetalization acetalizationa a reactions reactionsreactions reactions reactionsaa of ofof benzaldehyde benzaldehydebenzaldehyde of of benzaldehyde benzaldehyde ( (1(11)) ) and andand( (11)) and acetophenoneand acetophenoneacetophenone acetophenone acetophenone ( (2(22)) ) catalyzed catalyzedcatalyzed( (22)) catalyzed catalyzed by byby by by Fe5FFe5F with Fe5FwithFe5F different differentwithwith differentdifferent protective protective protectiveprotective agents agents agentsagents a and anda a theiratheir a andand TOF theirTOFtheir values. values. TOFTOF values.values. Fe5FFe5F withFe5FFe5FFe5F with differentwithwith with different differentdifferent different protective protective protectiveprotective protective agents agents agentsagents agentsa and a and atheir andandand theirand TOFtheirtheirtheir their TOF values. TOFTOFTOF TOFvalues. values.values.values. values. Fe5FFe5FFe5FFe5F withFe5FFe5F with withwith different withwith different differentdifferent differentdifferent protective protective protectiveprotective protectiveprotective agents agents agentsagents agentsagents and a a a and andandand their a and theirand theirtheirtheir TOF theirtheir TOF TOFTOFTOF values. TOF TOF values. values.values.values. values.values.

CarbonylCarbonylCarbonyl Compound Compound Compound CarbonylCarbonyl CompoundCompound CarbonylCarbonylCarbonylCarbonylCarbonyl Compound Compound Compound CompoundCompound CarbonylCarbonylCarbonylCarbonyl Compound Compound Compound Compound CarbonylCarbonylCarbonyl Compound Compound Compound BenzaldehydeBenzaldehydeBenzaldehyde (1) (1) (1) AcetophenoneAcetophenone (3) (3) BenzaldehydeBenzaldehydeBenzaldehydeBenzaldehyde (1) (1) (1) (1) AcetophenoneAcetophenoneAcetophenone (3) (3) (3) BenzaldehydeBenzaldehydeBenzaldehydeBenzaldehyde (1) (1) (1)(1) b −b1 −1 AcetophenoneAcetophenoneAcetophenoneAcetophenone (3) (3) (3)(3) b −b1 −1 ProtectiveProtectiveProtective agent agent agent ProductBenzaldehydeBenzaldehyde ProductBenzaldehyde ProductBenzaldehyde (1) (1) TOF (1) (1) TOF b TOF/h −/h1 / h AcetophenoneAcetophenoneProductProductAcetophenoneProductAcetophenone (3) (3) (3) (3) TOFTOFTOF b/h/h −/ h1 BenzaldehydeBenzaldehydeBenzaldehyde (1) (1) (1)bb −−11 bb −−11 AcetophenoneAcetophenoneAcetophenoneAcetophenone (3) (3)(3) (3) bb −−11 bb −−11 ProtectiveProtectiveProtectiveProtective agent agent agentagent Product Product Product Product TOF TOF b TOF/ TOF/hhb−1 − b 1b/b/hh−−11− 1 ProductProductProductProduct TOFTOF bTOF/TOF/hhb−1 − b 1b/b/hh−−11− 1 ProtectiveProtectiveProtectiveProtectiveProtective agent agent agent agent agent Product Product Product Product Product TOF TOF b TOF TOF/ TOFhb−/1h − b1/ /hh/h−1 ProductProductProductProductProductProduct TOFTOF bTOFTOFTOF/TOFh b−/1h − b1 / /hh/h−1 ProtectiveProtectiveProtectiveProtectiveProtectiveProtective agent agent agentagent agentagent Product Product Product Product Product Product TOF TOF TOF TOF TOF/ TOFh b bb//h/hh −− 1− 1 1b / /hh−1 ProductProductProductProductProductProductProduct TOFTOFTOFTOFTOF TOF/TOF h b bb//h/hh −− 1− 1 1b / /hh−1 EthanolEthanol EthanolEthanolEthanolEthanolEthanol 51 ±51 1.8 ± 1.8 - - EthanolEthanolEthanolEthanolEthanol 515151 ± ± 1.8 ±1.851511.8 ±± 1.81.8 -- -- EthanolEthanolEthanol EthanolEthanol 51 51 ± 1.8±5151 1.851 ±± ± 1.81.8 1.8 - - -- - 515151 51± 1.8± ±±51 511.8 1.81.8 ±± 1.81.8 ------2 2 4a 4a 22 22 4a 4a4a 2 2 22 2 4a 4a 4a4a4a 2 222 22 4a4a4a 4a 4a4a MethanolMethanol c c cc cc 31 ± 1.2 - MethanolMethanolMethanolMethanol c c c c 31 ± 1.2 - MethanolMethanolMethanolMethanol c c c MethanolMethanolMethanol ccc c c 313131 ± ± 1.2 ±1.231311.2 ±± 1.21.2 -- -- MethanolMethanolMethanolMethanolMethanol 3131 ± 1.2±3131 1.231 ±± ± 1.21.2 1.2 - - -- - 2b 2b 313131 31± 1.2± ±±31 311.2 1.21.2 ±± 1.21.2 4b ------2b 2b2b 4b 2b2b2b 2b2b 4b4b 4b4b 2b2b 2b2b 4b4b 4b4b4b 2b2b 2b 4b4b4b 4b 4b4b 1.8 1.8± 0.5 ± 0.5 - - ±1.81.8 ±± 0.50.5 -- 1.81.8 1.81.8 ± ± 0.5 1.80.5±1.8 0.50.5 ±± 0.50.5 ------1.81.8 ± 0.5±1.8 1.80.5 ± ±0.5 0.5 - -- - - TEOFTEOF 2a 1.81.8 ± ±1.8 0.5 0.5 ± 0.5 4a - - - TEOFTEOFTEOFTEOF TEOF 2a 4a TEOFTEOFTEOFTEOF TEOF 2a2a 2a2a 4a4a 4a4a TEOFTEOFTEOFTEOF 2a2a 2a2a2a 4a4a 4a4a4a TEOFTEOF 2a2a2a 2a 2a2a 4a4a4a 4a 4a4a 99 ±99 1.0 ± 1.0 18 ±18 1.1 ± 1.1 9999 ±± 1.01.0 1818 ±± 1.11.1 EthyleneEthylene glycol glycol 999999 99± ± 1.0 ±±1.09999 1.01.0 ±± 1.01.0 1818 18± ± 1.1 ±1.11818 1.1 ±± 1.11.11.1 EthyleneEthylene glycol glycol 2d 2d 9999 ± 1.0±99 1.099 ± ±1.0 1.0 4d 1818 ± 1.1±18 1.118 ± ±1.1 1.1 EthyleneEthyleneEthyleneEthyleneEthylene glycol glycol glycol glycolglycol 9999 ± ± 991.0 1.0 ± 1.0 4d 1818 ± ± 181.1 1.1 ± 1.1 EthyleneEthyleneEthyleneEthyleneEthylene glycol glycol glycol glycol 2d2d2d 2d2d2d 4d4d 4d4d EthyleneEthyleneEthylene glycol glycol glycol 2d2d 2d2d 4d4d 4d4d4d 2d2d2d 2d 4d4d4d 4d 4d4d 99 ±99 1.0 ± 1.0 12 ±12 1.6 ± 1.6

9999 99± ± 1.0 ±1.09999 1.0 ±± 1.01.0 1212 12± ± 1.6 ±1.61212 1.6 ±± 1.61.6 Propylene glycol 99 99 99± 1.0 ±±9999 991.01.0 ±± ± 1.01.0 1.0 12 12± 1.6 ±1212 121.6 ±± ± 1.61.6 1.61.6 Propylene glycol 999999 ± ±±99 991.0 1.01.0 ±± 1.01.0 121212 ± ±±12 121.6 1.61.6 ±± 1.61.6 PropylenePropylenePropylenePropylene glycol glycol glycol glycol 2e 2e 4e 4e PropylenePropylenePropylenePropylenePropylene glycol glycol glycolglycol glycol 2e2e 2e2e 4e4e 4e4e PropylenePropylenePropylenePropylenePropylenePropylene glycol glycol glycolglycol glycol glycol 2e2e2e 2e2e2e 4e4e 4e4e4e 2e2e2e 2e 2e2e 4e4e4e 4e 4e4e

36 ±36 1.2 ± 1.2d d 2.1 2.1± 0.5 ± 0.5e e dd dd ee ee 3636 ± ± 1.2 1.23636 d ± ± d1.21.2 d d d 2.12.1 ± ± 0.5 0.52.12.1 e± ± e0.50.5 e e e GlycerolGlycerol 3636 ± 1.2±3636 1.236 d ±± ± 1.2d1.2 1.2 d 2.12.1 ± 0.52.1±2.1 2.10.5 e ±± ± 0.5e0.5 0.5 e e GlycerolGlycerol 363636 ± 1.2±±36 1.21.2 ± dd1.2d d 2.12.1 ± 0.5±2.1 0.5 ± ee0.5e 0.5 e GlycerolGlycerolGlycerolGlycerolGlycerol 3636 ± ± 361.2 1.2 ± 1.2 2.12.1 ± ±2.1 0.5 0.5 ± 0.5 GlycerolGlycerolGlycerolGlycerol GlycerolGlycerolGlycerolGlycerol 2f and 2g 2f and 2g 4f and4f and 4g 4g 2f2f and and2f2f 2g 2g andand 2g2g 4f4f and and4f4f 4g 4g andand 4g4g 2f2f 2fandand and2f2f 2f2g2g andandand 2gand 2g2g 2g 4f 4fand and4f4f 4f4g andand 4gand 4g4g4g 4g 2f2f 2fand2f and andand2f2f 2g and 2gand 2g 2g 2g2g 4f4f 4fand4f and andand4f4f 4g and 4gand 4g4g 4g 4g4g 18 ±18 1.9 ± 1.9 - - 18 ± 1.91818 ±± 1.91.9 - -- 18 18± 1.9 ±1818 1.918 ±± ± 1.91.9 1.9 ------f f 18 18 ± 1.9±18 1.9 ± 1.9 - - - CycloocteneCyclooctene oxide oxide 2h 2h 1818 ± ± 181.9 1.9 ± 1.9 - - - ff ff 4h 4h CycloocteneCycloocteneCycloocteneCyclooctene oxide oxide oxide oxidef f f ff f 2h2h 2h2h CycloocteneCycloocteneCycloocteneCycloocteneCyclooctene oxide oxide oxide oxidef oxide f f 2h2h 2h2h 4h 4h4h CycloocteneCycloocteneCyclooctenea a oxide oxide oxide fff f 2h2h 2h 4h4h 4h4h CycloocteneCycloocteneCycloocteneCyclooctene Reaction Reaction oxide oxideoxide conditions: oxide conditions: 1.0% 1.0% mol2h mol2h2h 2hof Fe5F 2hof2h Fe5F , 0.2, 0.2mmol mmol of carbonyl of carbonyl compound, compound,4h 124h mmol 12 4h 4hmmol of protective of protective agent agent a aa 4h4h4h 4h4h a a aa ReactionReaction conditions:conditions: 1.0%1.0% molmol ofof Fe5FFe5F,, 0.20.2 mmolmmol ofof carbonylcarbonyl compound,compound, 1212 mmolmmol ofof protectiveprotective agentagent a Reaction Reactiona Reaction aReactionReaction conditions: conditions: conditions: conditions:conditions: 1.0% 1.0% 1.0% mol mol1.0%1.0% mol of of molmol ofFe5F Fe5F Fe5F ofof, , 0.2Fe5F 0.2, 0.2 mmol mmol,, mmol0.20.2 mmolmmolof of ofcarbonyl carbonyl carbonyl ofof carbonylcarbonyl compound, compound, compound, compound,compound, 12 12 12mmol mmol mmol 1212 mmolmmolof of ofprotective protective protective ofof protectiveprotective agent agent agent agentagent a ReactionReactiona Reactionata Reaction70 atReaction conditions:°Cconditions:70 conditions: °Cand conditions: andconditions: under under1.0%1.0% 1.0% magnetic molmol1.0% magnetic1.0% mol ofof mol ofFe5Fmol stirring Fe5F of ofstirring,, Fe5F0.20.2 Fe5F, 0.2 mmolmmoland, 0.2mmol, 0.2and openmmol of ofmmol openofcarbonylcarbonyl atmosphere.carbonyl of of atmosphere.carbonyl carbonyl compound,compound, compound, compound,Control compound, Control 1212 12 mmolreactionsmmol mmol 12reactions 12 mmol of ofmmol ofprotectiveprotective were protective of ofwere protective protectiveperformed performed agentagent agent agent agent as as a aReaction a Reaction ReactionReactionata Reaction Reaction 70 conditions: °C conditions: conditions:conditions: and conditions: conditions: under 1.0% 1.0% 1.0%1.0% magnetic mol1.0% 1.0% mol molmol of mol ofmol ofFe5Fof Fe5F Fe5FFe5F stirringof of, 0.2Fe5F Fe5F,, , 0.2 0.20.2 mmol , mmol, mmoland0.2 mmol0.2 mmol ofmmolopen of carbonylofof carbonyl carbonylcarbonyl of ofatmosphere. carbonyl carbonyl compound, compound, compound,compound, compound, compound, Control 12 mmol 12 1212 mmolreactions mmol mmol12 12 of mmol mmol protective of ofof protective protectiveprotective wereof of protective protective performed agent agent agentagent at agent agent 70 ◦asC and atat at 7070 70 at°C°C °C 70 andand and°C under underand under under magneticmagnetic magnetic magnetic stirringstirring stirring stirring andand and open openand bopen b openatmosphere.atmosphere. atmosphere. atmosphere. ControlControl Control Control reactionsreactions reactions reactions werewere were wereperformedperformed performed performed asas as as at at70 described, 70at°Catat described, °C70 70and70 °Cand °C°C under and andbutandunder but inunder underundermagnetic the inmagnetic theabsence magnetic magneticmagnetic absence stirring stirringof a stirringof stirringcatalyst.stirring aand catalyst.and open and and andopen TOF openatmosphere.open TOFopen atmosphere.was atmosphere.was atmosphere. determinedatmosphere. determined Control Control Controlduring ControlControl reactionsduring reactions the reactions reactionsreactions theinitial were initial were minutes wereperformed werewere minutesperformed performed performed performedof reaction. of as reaction. as as as as underatatat 707070atat magnetic °C°C °C7070 and and°Cand°C and and under stirringunderunder underunder magneticmagneticmagnetic and magneticmagnetic open stirringstirring atmosphere.stirring stirringstirring andandbandb and and openControlopenopenbb openopen atmosphere.atmosphere.atmosphere. reactions atmosphere.atmosphere. were ControlControlControl performed ControlControl reactionsreactionsreactions reactionsreactions as described, werewerewere werewere performedperformedperformed but performedperformed in the asas absenceas asas of described,described,described,described, but but in in but butthe the in absence inabsence the the absence absence of of a a catalyst. catalyst. of of a a catalyst. catalyst. b TOF TOFb b bwas wasTOF TOF determined determined was was determined determined during during during during the the initial initial the the initial initialminutes minutes minutes minutes of of reaction. reaction. of of reaction. reaction. described,described,c described,described,c butb but in butbut inthe the ininabsence theabsencethe absenceabsence of ofa catalyst. a of ofcatalyst. aa catalyst.catalyst. b TOFTOF b TOF waswas TOF bTOFTOF was determineddetermined was waswas determined d determined determineddeterminedd duringduring during during duringduringc thethe the initialinitial the initialthethe initial initial initialminutesminutes minutes minutes minutesminutes ofof ofreaction.reaction. reaction. of ofof reaction. reaction.reaction. e e described,a catalyst.described, Reactiondescribed, Reaction butTOF but in with inthe wasbut with the absencemethanol in determined absence themethanol absence of wasofa catalyst. duringawas catalyst.ofcarried a carried catalyst. the TOF b boutbinitial TOF out bwasbat TOF was 60 minutesat determined °C.60 determinedwas °C. determinedIsomers of reaction.Isomers during during 2f and during 2ftheReaction theand initial2g initial werethe2g minuteswith wereinitial minutesquantifiedmethanol quantified minutes of ofreaction. reaction.together.was of together. reaction. carried out cc described,described,described,described,ccdescribed, but butbut inbut inbutin the thethe in in absencethe absenceabsencethe absence absence of ofof a aa of catalyst. catalyst.ofcatalyst. a a catalyst. catalyst. TOF TOFTOF TOF TOF was waswasd was d determinedwas determineddetermined determined determineddd during duringduring during during the thethe initial theinitial initialthe initial initial minutes minutesminutes minutes minutes of ofof reaction. reaction.reaction. of of reaction. reaction.ee ee c ReactionReactionc cc ReactionReaction withwith methanol withmethanolwith methanolmethanol waswas carried carried waswas carriedcarried outout atat out out 6060 °C.atat°C. 60 60 d Isomers°C.Isomersd°C. dd IsomersIsomers 2f2f andand 2f2f 2g 2g andand werewere 2g2g quantifiedwerewerequantified quantifiedquantified together.together. together.together. e e ee c ReactionReactionc Reaction◦ cReactionReactionReactiond withwith with methanolmethanolwithwithwith methanol methanolmethanolmethanol waswas was carried carried waswaswas carried carriedcarriedcarried outout out atat out out out at6060 60 f at°C.°C.atat °C.60f6060 d Isomers°C.Isomers°C.°C.de Isomers dIsomersIsomersIsomers 2f 2fandand and 2f2f 2g andandand 2g werewere were2g2g werequantifiedquantifiedwerewere quantified quantifiedquantifiedquantified together.together. together. together.together.together. e f e e at Reactioncc 60ReactionIsomersc C. IsomersReaction withIsomers 4fwith and methanol4f with methanoland 2f4g and were4gmethanol werewas2g quantifiedwaswere carriedquantified wascarried quantified carried together.out out together. at at60 together.out 60 °C.Reaction at °C. Reaction60 Isomersdd °C. IsomersIsomers condition:d Isomers condition: 2f 2f4fand and 1.0% 2f2g 1.0%4gand2g were mol werewere 2gmol Fe5Fquantified were quantified quantifiedFe5F, 0.2 quantified, 0.2mmol together. mmoltogether. together. of carbonyl together.of carbonyl eeReaction e c Reactionc Reaction with with methanol methanol was was carried carried out f outat 60 atff °C.60 °C.d Isomers d Isomers 2f and2f and 2g were2g were quantified quantified together. together. e e Reaction ReactionIsomersIsomers Reaction with with 4f4f andandwith methanol methanol 4g4g methanol werewere was was quantifiedquantified wascarried carried carried together.together.out outf at outatf 60 60 f atff Reaction°C. Reaction °C.60 °C. Isomers Isomers condition: condition:Isomers 2f 2f and and 2f 1.0%1.0% and2g 2g were molmol were2g Fe5FwereFe5F quantified quantified, , quantified 0.20.2 mmolmmol together. together. ofof together. carbonylcarbonyl IsomersIsomersIsomersIsomers 4f 4f 4fand and and 4f 4g 4g and 4g were were wereFe5F 4g quantified werequantified quantified quantified together. together. together. together. f Reaction Reaction f Reaction Reactionf condition: condition: condition: condition: 1.0% 1.0% 1.0% mol mol1.0% mol Fe5F Fe5F mol Fe5F, ,0.2Fe5F 0.2, 0.2 mmol mmol, mmol0.2 mmolof of ofcarbonyl carbonyl carbonyl of carbonyl Isomerscondition:Isomerscompound,IsomersIsomersIsomerscompound, 4f 4f 1.0%and and 4f4f 4f4g mol andand0.6 4gand were 0.6 weremmol 4g4g 4g werequantifiedmmolwere were, quantified 0.2 of quantified quantifiedmmol quantifiedcycloocteneof cyclooctene together. of together. carbonyl together.together. together. oxide, f Reaction foxide, Reaction compound, f and ReactionReaction Reaction and condition:1.0 condition: 1.0mL 0.6 condition:condition: condition: mL mmolof 1.0% CHof 1.0% ofCH3 CNmol 1.0%1.0% cyclooctene1.0% mol3CN asFe5F molmol Fe5F molsolventas, Fe5FFe5F0.2solvent Fe5F, 0.2 oxide,mmol ,, at 0.2mmol,0.2 0.2 70 at mmolmmol andofmmol °C70 ofcarbonyl 1.0 carbonyl°Cand ofof of mL carbonylandcarbonyl carbonylunder of under CH 3 CN IsomersIsomersIsomersIsomersIsomersIsomers 4f 4f 4fand4f and andand 4f 4f 4g◦ and 4gand 4g 4gwere were were were4g 4g quantifiedwere were quantified quantifiedquantified quantified quantified together. together. together.together. together. together. Reaction f f Reaction ReactionReaction fReaction Reaction condition: condition: condition:condition: condition: condition: 1.0% 1.0% 1.0%1.0% mol 1.0% 1.0% mol molmol Fe5F mol Fe5Fmol Fe5FFe5F, Fe5F0.2 Fe5F,, , 0.2 0.20.2 mmol , mmol, mmol0.2 mmol0.2 mmol mmolof of ofcarbonylof carbonyl carbonylcarbonyl of of carbonyl carbonyl compound,ascompound, solventcompound,compound, at 0.60.6 70 mmolmmolC 0.60.6 and mmol mmol of underof cyclooctenecyclooctene ofof magnetic cyclooctenecyclooctene oxide,oxide, stirring oxide, oxide, andand and 1.0 1.0 and openand mLmL 1.01.0 atmosphere. ofof mLmL CHCH ofof33CNCN CHCH asas33CNCN solventsolvent asas solventsolvent atat 7070 at°Cat°C 7070 andand °C°C under under andand under under compound,compound,compound,compound,compound,magnetic 0.6 0.6 mmol stirring0.60.6 mmol0.6 mmolmmol mmolof ofandcyclooctene cycloocteneofof ofopen cyclooctenecyclooctene cyclooctene atmosphere. oxide, oxide, oxide,oxide, oxide,and and 1.0 andand and1.0 mL 1.01.0 mL1.0 of mL mL ofmLCH CHofof 3ofCN CH3CH CNCH as33CN CN3as CNsolvent solventasas as solventsolvent solvent at at70 70atat °Cat °C70 70and70 °Cand°C °C under andand andunder underunder under compound,compound,magneticcompound, 0.6 stirring0.6 mmol 0.6mmol mmol andof ofcyclooctene open cycloocteneof cyclooctene atmosphere. oxide, oxide, oxide, and and 1.0 and 1.0 mL 1.0mL of mL ofCH CHof3CN 3CHCN as3 CN assolvent solventas solvent at at70 70at°C °C 70and and°C under and under under magneticmagneticcompound,compound,magneticmagneticcompound, stirring stirring 0.60.6 stirringstirring and mmoland0.6mmol open mmolopen and and ofof cycloocteneatmosphere. open atmosphere.cycloocteneopenof cyclooctene atmosphere.atmosphere. oxide, oxide, oxide, andand and 1.01.0 mL1.0mL ofmLof CH CHof3 CN3CHCN 3 asCNas solvent solventas solvent atat 7070 at °C °C70 and and°C and underunder under magneticmagneticmagneticmagneticmagnetic stirring stirring stirringstirring stirring and and open andand openand openatmosphere.open open atmosphere. atmosphere.atmosphere. atmosphere. magneticmagneticmagneticmagneticAllmagneticmagneticAll of stirring stirringthe stirringofstirring the stirringreactionsstirring and reactions and andand open and openand openopen with atmosphere. openopen atmosphere. atmosphere.withatmosphere. 1 atmosphere. atmosphere.yielded 1 yielded the the expected expected acetal acetal products, products, with with no noby-products by-products detected detected AllAllAll ofof All AllAll of thethe the the ofofof reactions reactions thereactions thethereactions reactionsreactionsreactions withwith with with1withwith1 yielded1yielded1 yielded yielded 111 yieldedyieldedyieldedyielded thethe the theexpected expected the thethetheexpected expected expectedexpectedexpectedexpected acetalacetal acetal acetalacetalacetal products,products, products, products,products,products,products, withwith with with withnowithwithno withno by-productsby-products nonoby-productsnono no by-productsby-productsby-productsby-products by-products detecteddetected detected detecteddetecteddetecteddetected detected afterAllAllafter of 3 All of Allh.the 3 the Controlofh. ofreactions Controlthe reactionsthe reactions reactionsreactions reactionswith with with1 with were yielded1yielded yieldedyieldedwere 1 1 performedyielded yielded performedthethe thethe expectedexpected the expectedexpectedthe in expected expected thein acetaltheacetal sa acetalacetalme sa acetal me acetalproducts,products,conditions products,products, conditions products, products, withwith in withwith thein withnono withthe noabsenceno by-productsby-products absencenoby-productsby-products no by-products by-products of catalyst,of catalyst,detecteddetected detecteddetected detected anddetected and no no after afterafter3All Allh. Control of3All3of h. h.the the of ControlControl reactions thereactions reactions reactions reactionsreactions with with were with 1 were1were performedyielded yielded 1 yielded performedperformed the the in expected theexpected the inexpectedin sa thetheme acetal saacetalsa conditionsmeme acetal conditionsproducts, conditionsproducts, products, in the with inwithin absence the thewith no no absenceabsence by-products by-productsno of by-productscatalyst, ofof catalyst,catalyst, detected anddetected detected no andand nono afterafterafter after3after 3after h.conversion3 h. h.Control 3 Control3 3Control h.h. h. ControlControl Control reactions was reactionsreactions reactions reactions detectedreactions were were were werewereafterperformed were performed performed performedtheperformed performed same in inthe time, in the inin insa the the the samethe reinforcingme samesa sa conditionssame meconditionsme conditionsconditions conditions the in inconceptthe the inin inabsence in the the absencethe the that absenceabsence absence absence ofFe5F ofcatalyst, catalyst, of of isof catalyst, catalyst, ofthecatalyst, catalyst,and true and no andand catalytic andno and nono no no afterafterafterafterconversion 3afterafter 3h. 33 h. h.h.Control 3 3Control Control Control h.h. ControlControl was reactions reactions reactions reactionsdetected reactionsreactions were were werewereafter wereperformedwere performed performedtheperformed performed performedsame in time, in ininthe the the the inin sareinforcing thesa thesamesamememe sasaconditions meconditions conditionsmeconditions conditions conditionsthe concept in in ininthe the the the inin absence that theabsence theabsenceabsence absenceabsenceFe5F of of ofof catalyst,is catalyst, catalyst, catalyst, oftheof catalyst,catalyst, true and andand andcatalytic no and and no nono nono conversionconversionconversionconversionconversionconversion waswas waswas detected wasdetectedwaswas detecteddetected detecteddetecteddetected afterafter after after after aftertheafterthe the the same same the thethesame same same samesame time,time, time, time, time, time, time,reinforcingreinforcing reinforcing reinforcing reinforcingreinforcingreinforcing thethe the concept concept the thethe concept conceptconceptconcept concept thatthat that Fe5F thatFe5Fthatthat Fe5F that Fe5FFe5F isFe5Fis Fe5Fis thethe the isisis is true true the thetheisthetrue the catalytic truetruecatalytictruetrue catalytic true catalyticcatalyticcatalyticcatalytic catalytic conversionconversionactiveconversionconversionactive species. was wasspecies. detectedwas wasdetected Higher detected Higherdetected after conversionafter conversion afterthe after the same the samethe valuessame time,same valuestime, time, reinforcingweretime, reinforcing were reinforcing obreinforcing servedob servedthe the conceptwhen the conceptthe when concept conceptglycols that glycols that Fe5Fthat thatwereFe5F were Fe5F isisFe5F appliedisisthethe the theappliedis istruetrue the truetruethe as catalyticcatalytictrue true catalyticcatalyticasprotective catalyticprotective catalytic activeconversionconversionactiveactiveconversion species. species.species. waswas Higher was detecteddetected HigherHigher detected conversion after after conversionconversion after thethe values samethesame valuessamevalues time,weretime, time, were werereinforcingreinforcingobserved reinforcing obobservedserved when thethe when conceptwhentheconcept glycols concept glycolsglycols thatthatwere that Fe5F Fe5Fwere wereapplied Fe5F is is applied applied thethe is as truethetrue protective astrue as catalyticcatalytic protectiveprotective catalytic activeactiveactiveactiveactive activespecies.agents; species. species. species. species.species. productsHigher Higher Higher HigherHigher conversion 2-phenyl-1,3-dioxolane conversion conversion conversion conversionconversion values values values values valuesvalues were were were were were(obwere2d observed) and served observedob obobservedserved served4-methyl-2-phenyl-1,3-dioxolane when when when when whenwhenglycols glycols glycols glycolsglycols glycols were were were wereappliedwere wereapplied applied appliedapplied appliedas as protective(2e protectiveasas as), protective protectivewhichasprotective protective were activeactiveactiveactiveagents;activeactive species. species.species.species. productsspecies.species. Higher HigherHigherHigher Higher Higher2-phenyl-1,3-dioxolane conversion conversionconversionconversion conversionconversion values valuesvaluesvalues valuesvalues were were werewere(2d werewereob) and obobobservedserved served servedob ob4-methyl-2-phenyl-1,3-dioxolaneservedserved when whenwhenwhen when whenglycols glycolsglycolsglycols glycolsglycols were werewerewere werewereapplied appliedappliedapplied appliedapplied as( 2e asas asprotective), protective protectiveasprotectivewhichas protectiveprotective were agents;agents;agents;agents;agents; productsproducts products productsproducts 2-phenyl-1,3-dioxolane2-phenyl-1,3-dioxolane 2-phenyl-1,3-dioxolane 2-phenyl-1,3-dioxolane2-phenyl-1,3-dioxolane ((2d2d (2d)) and and()(2d 2dand )) 4-methyl-2-phenyl-1,3-dioxolane 4-methyl-2-phenyl-1,3-dioxolane andand 4-methyl-2-phenyl-1,3-dioxolane 4-methyl-2-phenyl-1,3-dioxolane4-methyl-2-phenyl-1,3-dioxolane ((2e2e (2e),), which),(which(2e2e which),), whichwhich werewere were were were agents;agents;agents;obtainedagents;agents;agents;obtained products products products products products fromproducts from 2-phenyl-1,3-dioxolane 2-phenyl-1,3-dioxolanethe2-phenyl-1,3-dioxolane the2-phenyl-1,3-dioxolane 2-phenyl-1,3-dioxolane reaction2-phenyl-1,3-dioxolane reaction of 1of with 1 with (ethylene2d ( 2d))ethylene( andand 2d()( 2d (2dand2d)) ) and4-methyl-2-phenyl-1,3-dioxolane 4-methyl-2-phenyl-1,3-dioxolane) andand and4-methyl-2-phenyl-1,3-dioxolane and 4-methyl-2-phenyl-1,3-dioxolane4-methyl-2-phenyl-1,3-dioxolanepropylene4-methyl-2-phenyl-1,3-dioxolane 4-methyl-2-phenyl-1,3-dioxolane propylene glyc glycol, ol,respectively, respectively, ((2e ( 2e),),were which(),which( 2e2e(were 2ewhich), (),synthesized2e), whichwhich which ),weresynthesizedwere whichwere were were were were agents;agents;agents;obtainedobtainedagents; products productsproducts products fromfrom 2-phenyl-1,3-dioxolane 2-phenyl-1,3-dioxolane2-phenyl-1,3-dioxolane thethe 2-phenyl-1,3-dioxolane reactionreaction ofof 11 withwith (ethylene (ethylene(2d2d2d) )) ( and 2dandand) and 4-methyl-2-phenyl-1,3-dioxolane and4-methyl-2-phenyl-1,3-dioxolaneand4-methyl-2-phenyl-1,3-dioxolane 4-methyl-2-phenyl-1,3-dioxolane propylenepropylene glycglycol,ol, respectively,respectively, ( ((2e2e2e were),were), ),( 2ewhich whichwhich), synthesizedsynthesizedwhich were werewere were obtainedobtainedobtainedobtainedobtainedobtained fromfrom from fromfrom thethefrom the reactionreaction the the reactionthe reactionreaction reaction ofof of 11 withwith 1withofof ofwith 11 1 with ethylenewithethylene ethylenewith ethylene ethyleneethylene ethylene andandand and propylene propyleneandpropyleneand andpropylene propylenepropylene propylene glycglycglyc glycol, ol,glycglyc glycol, respectively,respectively, ol,respectively,ol,ol, respectively,respectively, respectively, werewere were werewere synthesizedsynthesizedwere synthesized synthesizedsynthesized synthesized obtainedobtainedobtainedobtainedobtainedobtained from from fromfrom fromthefrom the thethe reaction thereaction thereactionreaction reactionreaction of of ofof1 1 with1 1of of with withwith 11 withethylenewith ethylene ethyleneethylene ethyleneethylene and and andand propylene and and propylene propylenepropylene propylenepropylene glyc glyc glycglycol, glycglycol,ol,ol, respectively, respectively, respectively,ol,respectively,ol, respectively,respectively, were were werewere weresynthesizedwere synthesized synthesizedsynthesized synthesizedsynthesized

Catalysts 2019, 9, 334 9 of 14

obtained from the reaction of 1 with ethylene and propylene glycol, respectively, were synthesized withCatalysts >99% 2018 conversion, 8, x FOR PEER in 1 REVIEW h (TOF = 99 h−1). In contrast, acetals 2a and 2b, from ethanol and methanol,9 of 14 were produced with TOF values of 51 h−1 and 31 h−1, respectively. with >99% conversion in 1 h (TOF = 99 h−1). In contrast, acetals 2a and 2b, from ethanol and methanol, Both isomers from reaction between 1 and glycerol, one from 1,3-addition (2f) and the other were produced with TOF values of 51 h−1 and 31 h−1, respectively. from 1,2-addition (2g), were detected but not separately quantified: the conversion for the mixture Both isomers from reaction between 1 and glycerol, one from 1,3-addition (2f) and the other from was 36% after 1 h of reaction. In addition, an epoxide, cyclooctene oxide, was a good protective 1,2-addition (2g), were detected but not separately quantified: the conversion for the mixture was −1 agent36% forafter1, 1giving h of reaction. acetal 2hIn addition,with a TOF an epoxide, value of cyclooctene 18 h . This oxide, product was a cangood be protective obtained agent from for the hydrolysis1, giving ofacetal epoxide 2h with ina a first TOF step, value generating of 18 h−1. This 1,2-diol, product which can can be thenobtained serve from as the thenucleophile hydrolysis of for acetalizationepoxide in a [30 first–32 step,]. generating 1,2-diol, which can then serve as the nucleophile for acetalization [30–32].No conversion was observed, even after 3 h of reaction, when ketone 3 was used as a substrate in the presenceNo conversion of ethanol, was observed, methanol, even TEOF, after 3 and h of cyclooctene reaction, when oxide. ketone Cyclic 3 was acetals used as derived a substrate from acetophenone,in the presence 2-methyl-2-phenyl-1,3-dioxolane of ethanol, methanol, TEOF, and (4d cyclooctene) and 2,4-dimethyl-2-phenyl-1,3-dioxolane oxide. Cyclic acetals derived from (4e ) − − wereacetophenone, obtained at 2-methyl-2-phenyl-1,3-dioxolane TOF values of 18 h 1 and 12 h 1(,4d respectively.) and 2,4-dimethyl-2-phenyl-1,3-dioxolane Only a small amount of the mixture (4e) − ofwere isomers obtained4f and at4g TOFwas values detected of 18 afterh−1 and 1 h12 of h reaction−1, respectively. (TOF =Only 2.1 ha small1). The amount higher of activitythe mixture of Fe5F of towardisomers benzaldehyde 4f and 4g was acetalization detected after in 1 h comparison of reaction (TOF to acetophenone = 2.1 h−1). The canhigher be activity related of to Fe5F the carbonyltoward electronicbenzaldehyde features. acetalization From the acceptedin comparison mechanism to acetop forhenone acetal can formation be related [37 ]to and the by carbonyl the perspective electronic of anfeatures. iron (III) From porphyrin the accepted acting asmechanism a Lewisacid for acetal (Fe5F formationbeing represented [37] and by the M+ perspectivein Scheme2 ),of carbonylan iron activation(III) porphyrin would acting come as from a Lewis the coordinationacid (Fe5F being of itsrepresented oxygen atoms by M+ toin theScheme metalloporphyrin, 2), carbonyl activation making thewould carbon come atoms from more the electrophilic.coordination of The its presenceoxygen atoms of a methylto the metalloporphyrin, group adjacent to making C=O in the the carbon ketone reducesatoms themore positive electrophilic. charge The of carbon presence due of to a themethyl inductive group effectadjacent and to hyperconjugation C=O in the ketone effect. reduces This the set ofpositive effects may charge lead of to carbon lower due reactivity to the inductive when compared effect and to aldehydehyperconjugation [37]. effect. This set of effects may lead to lower reactivity when compared to aldehyde [37]. 2.5. Study of the Selectivity of Benzaldehyde Acetalization in Competitive Reactions 2.5. Study of the Selectivity of Benzaldehyde Acetalization in Competitive Reactions To evaluate the selectivity for benzaldehyde acetalization using glycols instead of alcohols, competitiveTo evaluate reactions the were selectivity performed for benzaldehyde where 1 was reacted acetalization simultaneously using glycols with instead ethanol of and alcohols, ethylene glycolcompetitive in different reactions molar fractions,were performed using 1% where mol of1 Fe5Fwas atreacted 70 ◦C simultaneously during 30 min (Figurewith ethanol3). and ethylene glycol in different molar fractions, using 1% mol of Fe5F at 70 °C during 30 min (Figure 3). Catalysts 2018, 8, x FOR PEER REVIEW 5 of 14 carried out, and all of these compositions led to the formation of 2a (Figure 2 and Table S1; Supplementary Materials (SM)). In order to make better comparisons, turnover frequencies (TOF) were determined after 1 h of reaction at 70 °C [33].

Figure 3. TOF values (h−1) for 2a ( black) and 2d (•, red) conversion in the function of ethylene Figure 3. TOF values (h−1) for 2a (▪, black) and 2d (•, red) conversion in the function of ethylene glycol glycol molar fraction (χ) from the reaction between 1, ethanol, and ethylene glycol catalyzed by Fe5F. molar fraction (χ) from the reaction between 1, ethanol, and ethylene glycol catalyzed by Fe5F. Reaction conditions: 1% mol of Fe5F, 0.2 mmol of 1, 12 mmol of acetalizing agent (sum of ethanol and Reaction conditions: 1% mol of Fe5F, 0.2 mmol of 1, 12 mmol of acetalizing agent (sum of ethanol and ethylene glycol amounts in different molar fractions of glycol: 0, 0.25, 0.50, 0.75, and 1.00) at 70 ◦C ethylene glycol amounts in different molar fractions of glycol: 0, 0.25, 0.50, 0.75, and 1.00) at 70 °C during 30 min under magnetic stirring and open atmosphere. Figure 2. Dependence of turnover frequenciesduring (TOF) 30 min values under (h− magnetic1) in function stirring of catalyst and open load atmosphere. (% mol). Reaction conditions: 0.5%, 1.0%, 2.0%, andFrom 4.0% the mol results catalyst of the (Fe5F TOF), 0.2 variation mmol of in benzaldehyde, the function of 0.6 molar fraction of ethylene glycol in ethanol From the results of the TOF variation in the function of molar fraction of ethylene glycol in mmol of TEOF, and 12 mmol of ethanol(Figure at 370), °C, it was under possible magnetic to stirring. verify that competitive reactions are selective to the formation of cyclic ethanol (Figure 3), it was possible to verify that competitive reactions are selective to the formation acetal 2d when compared to the aliphatic 2a. In the presence of equimolar amounts of alcohol and Figure 2 shows that the lowest amountof cyclic of catalystacetal 2d (0.5% when mol) compared led to to the the highest aliphatic TOF 2a .value, In the whilepresence of equimolar amounts of alcohol the opposite was observed for the highestand glycolcatalyst (molar load, ratio 4.0% of mol benzaldehyde/ethylene of Fe5F, yielded TOF glycol/ethanol equal to 33 = 1:30:60, because two molecules of −1 h−1. The more diluted the reaction media,ethanol the less are aggregatednecessary to the produce metalloporphyrins one acetal while were, just whichone of glycolcan is needed), the TOF of 34 h was explain this pattern if one considers that the catalytic species is an isolated and soluble molecule of iron (III) porphyrin in the solution. The lowest TOF value for the use of 4.0% mol of Fe5F can also be attributed to the total non-solubilization of this amount of catalyst in the reaction medium. Intermediate values of TOF are appropriate to study the kinetic profiles and other features, since the reaction is not too fast or too slow to determine physicochemical parameters. Reactions conducted with 1.0% and 2.0% mol of catalyst yielded TOF values equal to 86 h−1 and 91 h−1, respectively, inducing the choice of 1.0% mol catalyst for further studies, since this amount resulted in the same TOF of 2.0% mol and used a lesser amount of iron (III) porphyrin.

2.2. Kinetic Studies for 2a Synthesis at Different Temperatures To evaluate the influence of temperature and time on benzaldehyde acetalization, studies were conducted for the same reaction using 1.0% mol of Fe5F as catalyst at 70 °C, 65 °C, 60 °C, 55 °C, and 50 °C, and the samples were analyzed at different times up to 6 h (Table 2 and Figure S1, SM). A control reaction, in the absence of catalyst, was also performed at 70 °C.

Table 2. Values of kobs and TOF for 2a synthesis catalyzed by Fe5F at different temperatures a.

Temperature/°C kobs / 10−2 min−1 TOF / h−1 50 0.391 ± 0.062 14.7 ± 1.5 55 1.430 ± 0.055 36.8 ± 1.0 60 2.130 ± 0.092 46.4 ± 1.1 65 2.770 ± 0.073 59.2 ± 1.6 70 7.73 ± 0.20 90.6 ± 1.3 70, control 0.0134 ± 0.0012 - a Reactions conditions: 1.0% mol Fe5F, 0.2 mmol of benzaldehyde, 0.6 mmol of TEOF, and 12 mmol of ethanol at 50 °C, 55 °C, 60 °C, 65 °C, and 70 °C, under magnetic stirring. Control reaction performed as described but in the absence of catalyst.

Catalysts 2019, 9, 334 10 of 14

CatalystsCatalysts 2018 2018, 8,, 8x, FORx FOR PEER PEER REVIEW REVIEW 1010 of of14 14 glycol (molar ratio of benzaldehyde/ethylene glycol/ethanol = 1:30:60, because two molecules of obtainedobtainedethanol from are from necessary 2d 2d synthesis synthesis to produce against against one 3.5 3.5 acetalh −h1 −from1 from while 2a 2a. justIn. In comparison one comparison of glycol to isto theneeded), the aliphatic aliphatic the acetal, TOF acetal, of the 34 the hcyclic− cyclic1 was oneoneobtained was was produced produced from 2d in synthesisin a aratio ratio of againstof 13:1. 13:1. No No 3.5 diethyl hdiethyl−1 from ac acetal2aetal .was Inwas comparison produced produced when towhen the the aliphaticthe mixture mixture acetal, of of protective protective the cyclic agentsagentsone waswas was produced75% 75% ethylene ethylene in a glycol ratio glycol of and 13:1.and 25% 25% No ethanol. diethylethanol. acetal was produced when the mixture of protective agentsThisThis wasbehavior behavior 75% ethylenecan can be be related glycolrelated to and to both both 25% kinetic ethanol.kinetic an and dthermodynamic thermodynamic effects. effects. From From the the acetalization acetalization mechanism,mechanism,This behaviorafter after the the formation can formation be related of of hemiacetal hemiacetal to both kinetic intermed intermed andiate, thermodynamiciate, there there is isa seconda second effects. nucleophilic nucleophilic From the attack acetalization attack from from thethemechanism, acetalizing acetalizing afteragent agent the (Scheme (Scheme formation 2) 2) [37]. of[37]. hemiacetal In In the the case case intermediate, of of ethanol, ethanol, anotherthere another is molecule a molecule second nucleophilicof of alcohol alcohol is is attackrequired required from toto thepromote promote acetalizing the the addition, agentaddition, (Scheme while while 2the)[ the 37second second]. In the attack attack case for of for ethanol,a aglycol glycol anotheris isan an intramolec intramolec moleculeular ofular alcohol process, process, is since required since the the to freefreepromote hydroxyl hydroxyl the addition,group group acts acts while as as the thethe nucleophile, second nucleophile, attack maki formaki ang glycolng the the process is process an intramolecular faster faster and and yielding process,yielding the since the kinetic thekinetic free product.product.hydroxyl group acts as the nucleophile, making the process faster and yielding the kinetic product. FromFromFrom the the the thermodynamic thermodynamic thermodynamic perspective, perspective, perspective, to to toobtain obtain obtain acetals acetals acetals 2a 2a2a and andand 2d 2d2d, it,, itis it is isnecessary necessary necessary to to tobreak break break a aC=O a C=O C=O bondbondbond and and and form form form two two two new new new C–O C–O C–O bonds, bonds, bonds, so so sothere there there will will will be bebe no no no difference difference difference in in inenthalpy enthalpy enthalpy variation variation variation (∆ ( (H∆∆H)H for)) for for both both both systems.systems.systems. For For For 2a 2a 2asynthesis, synthesis,synthesis, two two two molecules molecules molecules of of ofethano ethano ethanoll arel are are needed needed needed to to react to react react with with with one one one of of of1, 1, while1, whilewhile for for for 2d 2d,2d , , onlyonlyonly one one one molecule molecule molecule of of ofglycol glycol glycol is isnecessary. is necessary. necessary. In In Inboth both both reactions, reactions, reactions, the the the products products products are are are one one one acetal acetal acetal and and and one one one water water water molecule.molecule.molecule. Therefore, Therefore, Therefore, the the thevariation variation variation of of the of the thenumber number number of of molecules ofmolecules molecules for for 2a for2a synthesis 2asynthesissynthesis is isnegative negative is negative and and for and for 2d 2d for is is2dnil, nil,is which nil,which which gives gives gives a anegative negative a negative entropy entropy entropy variation variation variation (∆ (S∆)S ( ∆in) Sin )the inthe thefirst first first case. case. case. From From From the the the Gibbs Gibbs Gibbs free free free energy energy energy equation,equation,equation, a a negative negative value valuevalue of ofof ∆∆ S∆S Sincreasesincreases increases the the freefree free energyenergy energy ( ∆(∆ G(G∆),),G making ),making making the the the process process process less less less favorable favorable favorable than thanthananother another another at theat at the same the same same temperature temperature temperature and and withand with with the the same the same same∆H ∆values. H∆H values. values.

2.6.2.6.2.6. Kinetic Kinetic Kinetic Studies Studies Studies for for forthe the the Synthesis Synthesis Synthesis of ofCyclic of Cyclic Cyclic Benzaldehyde Benzaldehyde Benzaldehyde Acetals Acetals Acetals SinceSinceSince cyclic cyclic cyclic acetals acetals acetals from from from benzaldehyde—1,3-s benzaldehyde—1,3-s benzaldehyde—1,3-substitutedubstitutedubstituted dioxolane dioxolane dioxolane rings—were rings—were rings—were selectively selectively selectively synthesizedsynthesizedsynthesized with with with the the the use use use of of ofFe5F Fe5FFe5F as as ascatalyst, catalyst, catalyst, kinetic kinetic kinetic studies studies studies of of ofthe the the reactions reactions reactions between between between 1 1and1 andand ethylene ethylene ethylene glycolglycolglycol or or orpropylene propylene propylene glycol glycol glycol were were were done done done at at atdifferent different different temperatures temperatures temperatures (30 (30 (30 °C, °C,◦C, 35 3535 °C, °C,◦C, and and and 40 4040 °C). °C).◦C). Reactions Reactions Reactions werewerewere carried carried carried out out out in in inpseudo-first pseudo-first pseudo-first order order order conditions, conditions, conditions, using using using a a100-fold a 100-fold 100-fold excess excess excess of of ofglycol glycol glycol in in inrelation relation relation to to to1 11 (Table((TableTable 55 5and and and Figure Figure Figure S2; S2; S2; SM SM). SM). ).Glycols Glycols Glycols were were were applied applied applied as as as solvents solvents solvents as as as well. well. well.

a aa TableTableTable 5. 5.Values 5. ValuesValues of of k ofobs kkobs andobs andand TOF TOF TOF for for forsynthesis synthesis synthesis of of 2d of 2d 2dand andand 2e 2e 2ecatalyzed catalyzedcatalyzed by by by Fe5F Fe5F in in different different temperatures. temperatures.temperatures.

Product ProductProduct 2d Temperature/◦C 2d2d 2e −2 −1 −1 −2 2e−2e1 −1 kobs/10 min TOF/h kobs/10 min TOF/h Temperature/°CTemperature/°C kobskobs/10/10−2 −min2 min−1 −1 TOF/hTOF/h−1 −1 kobskobs/10/10−2 −min2 min−1 −1 TOF/hTOF/h−1 −1 30 4.79 ± 0.0325 231 0.840 ± 0.0145 37.7 3030 4.79 4.79 ± ±0.0325 0.0325 231 231 0.840 0.840 ± ±0.0145 0.0145 37.7 37.7 35 8.71 ± 0.0210 295 1.57 ± 0.0577 65.0 354035 13.9 8.71 8.71± 0.152± ±0.0210 0.0210 362 295 295 1.57 2.05 1.57 ±± ±0.0577 0.07200.0577 65.0 82.4 65.0 a Reaction4040 conditions: 1.0% mol 13.9 of 13.9Fe5F ± ±0.152, 0.152 0.2 mmol of 1, 20 362 mmol 362 of protective 2.05 2.05 agent ± ±0.0720 0.0720 (ethylene glycol for 82.4 82.42d and a Reactionapropylene Reaction conditions: glycolconditions: for 2e 1.0%) 1.0% at 30mol mol◦C, of 35 of Fe5F◦ Fe5FC, and, 0.2, 0.2 40 mmol ◦mmolC and of of under1, 120, 20 mmol magnetic mmol of of protective stirring protective and agent open agent atmosphere.(ethylene (ethylene glycol Controlglycol reactions were performed as described but in the absence of catalyst. TOF was determined during the initial minutes forfor 2d 2d and and propylene propylene glycol glycol for for 2e 2e) at) at 30 30 °C, °C, 35 35 °C, °C, and and 40 40 °C °C and and un underder magnetic magnetic stirring stirring and and open open of reaction. atmosphere.atmosphere. Control Control reactions reactions were were performed performed as as described described but but in in the the absence absence of of catalyst. catalyst. TOF TOF was was determineddetermined during during the the initial initial minutes minutes of of reaction. reaction. The kinetic profiles for both substrates converged to first-order exponential growth and values of kobsTheThecould kinetic kinetic be determined,profiles profiles for for both such both substrates as substrates in the caseconverge converge of 2adsynthesis dto to first-order first-order (Table exponential 2exponential) due to the growth growth pseudo-first and and values values order ofof experimentalkobs kobs could could be be determined, conditions. determined, Thesuch such formation as as in in the the case of case cyclic of of 2a 2a acetalssynthesis synthesis was (Table faster(Table 2 than )2 due) due the to to formationthe the pseudo-first pseudo-first of 2a atorder order lower experimentalexperimentaltemperatures. conditions. conditions. When the The The synthesis formation formation of 2dof of cycland cyclic2e icacetals wasacetals performed was was faster faster at than 45than ◦theC, the moreformation formation than 90%of of 2a 2aconversion at at lower lower temperatures.temperatures.was reached When inWhen the the firstthe synthesis synthesis five minutes, of of 2d 2d and and and 2e it 2e waswas was notperformed performed possible at toat 45 45 determine °C, °C, more more than the than kinetic 90% 90% conversion conversion parameters waswasat reached higher reached temperatures. in in the the first first five five Control minutes, minutes, reactions and and it itwas in was the not not absence possible possible of to ato determine catalyst determine were the the alsokinetic kinetic carried parameters parameters out at all at at of higherhigherthe temperatures, temperatures. temperatures. but Control Control no product reactions reactions was in detectedin the the absence absence even of afterof a acatalyst catalyst 3 h of were reaction, were also also suchcarried carried as thoseout out at observedat all all of of the the in temperatures,temperatures,previous tests but but (Table no no product4 ).product was was detected detected even even af afterter 3 3h hof of reaction, reaction, such such as as those those observed observed in in previouspreviousEthylene tests tests (Table ( glycolTable 4 ).provided4 ). dioxolane moiety faster than propylene glycol did, with kobs values for 2dEthylenesynthesisEthylene glycol 6.7glycol times provided provided higher dioxolane thandioxolane those moiety moiety for 2e faster. faster Due than to than the propylene propylene elevated glycol reaction glycol did, did, rates, with with TOF kobs kobs values values for were for 2d2destimated synthesis synthesis at6.7 6.7 15 times mintimes andhigher higher were than than higher those those for for 2dfor 2ethan 2e. Due. Due for to2e to the. Thesethe elevated elevated differences reacti reaction inon reactionrates, rates, TOF TOF rates values values for different were were estimatedestimated at at 15 15 min min and and were were higher higher for for 2d 2d than than for for 2e 2e. These. These differences differences in in reaction reaction rates rates for for different different protectiveprotective groups groups at at all all of of the the investigated investigated temper temperaturesatures can can be be related related to to the the medium’s medium’s viscosity. viscosity. EthyleneEthylene glycol glycol is isless less viscous viscous (16.1 (16.1 mPa mPa s ats at 25 25 °C) °C) than than propylene propylene glycol glycol (40.4 (40.4 mPa mPa s ats at 25 25 °C) °C) [38], [38],

Catalysts 2019, 9, 334 11 of 14 protective groups at all of the investigated temperatures can be related to the medium’s viscosity. Ethylene glycol is less viscous (16.1 mPa s at 25 ◦C) than propylene glycol (40.4 mPa s at 25 ◦C) [38], which leads to more efficient stirring and a better diffusion of aldehyde and metalloporphyrin molecules dissolved in the medium, causing more frequent collisions than in propylene glycol. It is also known that the rate constants are inversely proportional to medium viscosity [39], and this was confirmed by the comparison between the two glycols when applied as protective agents. These factors can lead to a higher product conversion in a shorter time, enhancing kobs and TOF values, as can be seen (Table5 and Figure S2; SM). When TOF values for 2a synthesis in ethanol and triethyl orthoformate medium (Table2) are compared to TOF values for 2d or 2e (Table5), it is possible to note that even in more viscous systems (for comparison, ethanol viscosity is 1.07 mPa s at 25 ◦C[38]) and at lower temperatures, Fe5F showed greater catalytic activity toward benzaldehyde acetalization. In addition, for the synthesis of cyclic acetals, it was not necessary to use a drying agent such as TEOF, indicating that with a large excess of glycol, the medium stabilizes acetal without requiring the use of an apparatus for water removal, such as a Dean–Stark system [18].

3. Materials and Methods All of the solvents and reagents were of analytical grade, purchased from Aldrich (São Paulo, Brazil), Merck (São Paulo, Brazil), or Fluka (Mexico City, Mexico), and used without purification, unless otherwise stated. Benzaldehyde was treated with an aqueous NaHCO3 solution to remove benzoic acid, distilled under reduced pressure, and kept under argon atmosphere [40]. Free-base porphyrins 5,10,15,20-tetrakis(phenylporphyrin) [H2(TPP)] and 5,10,15,20-tetrakis (2,6-difuorophenylporphyrin) [H2(TDFPP)] were previously synthesized by our research group using Lindsey’s method [41] and 5,10,15,20-tetrakis(pentafluorophenylporphyrin [H2(TPFPP)] was prepared by the nitrobenzene method [42]. The free-base ligands were purified by a column chromatography and characterized by UV-Vis, FTIR, and 1H NMR spectroscopies, as previously described [43–45]. Iron (III) complexes were obtained from the Kobayashi procedure [46], purified and characterized by UV-Vis, FTIR, and EPR spectroscopies as previously described for 5,10,15,20-tetrakis(phenylporphyrin) chloride, [Fe(TPP)]Cl (Fe0F)[43], 5,10,15,20-tetrakis (2,6-difluorophenylporphyrin) chloride, [Fe(TDFPP)Cl] (Fe2F)[44], and 5,10,15,20-tetrakis (pentafluorophenylporphyrin) chloride, [Fe(TPFPP)Cl] (Fe5F)[45]. For acetalization reactions of carbonyl compounds, standard experiments were carried out as described: a defined amount of iron porphyrin (the catalyst Fe0F, Fe2F, or Fe5F) was placed in a 1.5-mL screw top vial, followed by addition, in the next sequence, of the solvent (when necessary), the protective group (ethanol, methanol, triethyl orthoformate, ethylene glycol, propylene glycol, glycerol, or cyclooctene oxide) and the carbonyl compound (benzaldehyde or acetophenone). The system was placed in a thermostatic bath and kept under magnetic stirring and open atmosphere. Samples were extracted at different times, diluted in ethyl acetate, and analyzed by gas chromatography (GC), while the products were identified in a mass spectrometer coupled to a gas chromatograph (GC-MS) and quantified by GC by the area normalization method. Details about the load of catalyst, solvent, protective groups, and carbonyl compounds, such as temperature, time reactions, and other experimental parameters, were previously described in the Results and Discussion section. To quantify the products from the catalytic reactions, an Agilent 6850 gas chromatograph (flame ionization detector, or FID) equipped with a DB-WAX capillary column (30 m × 0.25 µm × 0.25 µm; J&W Scientific) was used. During analysis, the oven temperature was set at 80 ◦C for 2 min, and then raised to 220 ◦C at a rate of 20 ◦C min−1, which was kept isothermally for 5 min.

4. Conclusions A systematic study regarding the catalytic activity of iron (III) porphyrins with different levels of fluorine substitution in the meso-aryl porphyrin ring positions for protection of benzaldehyde with ethanol and triethyl orthoformate (TEOF) was successfully performed, showing that the most Catalysts 2019, 9, 334 12 of 14 substituted catalyst produced the highest conversion rates. This may be due to the increasing Lewis acidity of the Fe(III) center caused by the inductive effect of the peripheral electrons withdrawing atoms, if carbonyl activation occurs through coordination to the ferric center. The formation of benzaldehyde diethyl acetal (2a) converged to pseudo-first order kinetic behavior, and it was shown to be temperature-dependent. The presence of 1% mol of Fe5F enhanced the stoichiometric reaction rate 576 times, proving its catalytic activity. The presence of TEOF in the reaction media enhanced the reaction rate, which may have been due to the drying effect of TEOF, which can be hydrolyzed in the presence of water, which is the undesired by-product in the acetalization reaction. It was not necessary to add a drying agent to obtain acetals with different protective groups. Benzaldehyde and acetophenone were converted into acetals in the presence of alcohols, glycols, glycerol, and an epoxide, but selectivity to cyclic acetals from ethylene and propylene glycol was observed, even in competitive reactions against ethanol. The kinetic and thermodynamic features may explain this behavior, even in systems that are more viscous and at lower temperatures. To the best of our knowledge, this is the first report of a systematic investigation of the catalytic activity of metalloporphyrins for acetalization reactions. This work can be a proof-of-concept for further investigations, and the application of Fe(III) and other metalloporphyrins in sequential processes in which one of the steps depends on a Lewis acid or on the protection of carbonyl groups.

Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/9/4/334/s1, Table S1: TOF values in function of a catalyst load in the benzaldehyde acetalization reaction catalyzed by Fe5F. Figure S1: Kinetic behavior for synthesis of 2a in the presence of TEOF, catalyzed by Fe5F at different temperatures: (a) conversion values in function of time and (b) data linearization according to exponential first-order adjustment. Figure S2: Kinetic behavior for benzaldehyde cyclic acetals synthesis catalyzed by Fe5F: (a) conversion to 2d in function of time and (b) linearized data; (c) conversion to 2e in function of time and (d) linearized data. Author Contributions: Conceptualization, G.K.B. Ferreira and S. Nakagaki; investigation, project administration, and data treatment, G.K.B. Ferreira and C. Carvalho; writing—original draft preparation, review, and editing, G.K.B. Ferreira, S. Nakagaki and C. Carvalho; resources, supervision and funding acquisition, S. Nakagaki. Funding: This research was funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, finance code—001) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Shirley Nakagaki/CNPq/n.proc. 305491/2014-8. Acknowledgments: The authors acknowledge financial support obtained from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, finance code 001), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Fundação Araucária. C.C. and G.K.B.F. thank CAPES for PhD scholarships. We also acknowledge the support from UFPR (Universidade Federal do Paraná). Conflicts of Interest: The authors declare no conflict of interest.

References

1. Carvalho, B.M.C.; Brocksom, J.T.; Oliveira, T.K. Tetrabenzoporphyrins: Synthetic developments and applications. Chem. Soc. Rev. 2013, 42, 3302–3317. [CrossRef][PubMed] 2. Castaño, B.C.J.; Vargas, C.C.C.; Brocksom, J.T.; Oliveira, T.K. Porphyrins as Catalysts in Scalable Organic Reactions. Molecules 2016, 21, 310. [CrossRef][PubMed] 3. Groves, J.T. High-valent iron in chemical and biological oxidations. J. Inorg. Biochem. 2006, 100, 434–447. [CrossRef][PubMed] 4. Dawson, J.H.; Sono, M. Cytochrome P-450 and chloroperoxidase: Thiolate-ligand heme enzymes. Spectroscopic determination of their active-site structures and mechanistic implications of thiolate ligation. Chem. Rev. 1987, 87, 1255–1276. [CrossRef] 5. Ortiz de Montellano, P.R. Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes. Chem. Rev. 2010, 110, 932–948. [CrossRef][PubMed] 6. Groves, J.T. Cytochrome P450 enzymes: Understanding the biochemical hieroglyphs. F1000Research 2015, 4, 1–8. [CrossRef] 7. Meunier, B. Metalloporphyrins as versatile catalysts for oxidation reactions and oxidative DNA cleavage. Chem. Rev. 1992, 92, 1411–1456. [CrossRef] Catalysts 2019, 9, 334 13 of 14

8. Groves, J.T.; Nemo, T.E.; Myers, R.S. Hydroxylation and epoxidation catalyzed by iron-porphine complexes. Oxygen transfer from iodosylbenzene. J. Am. Chem. Soc. 1979, 101, 1032–1033. [CrossRef] 9. Collman, J.; Zhang, X.; Lee, V.; Uffelman, E.; Brauman, J. Regioselective and enantioselective epoxidation catalysed by metalloporphyrins. Science 1993, 261, 1404–1411. [CrossRef][PubMed] 10. Groves, J.T.; Haushalter, C.R.; Nakamura, M.; Nemo, E.T.; Evans, J.B. High-Valent Iron-Porphyrin Complexes Related to Peroxidase and Cytochrome P-450. J. Am. Chem. Soc. 1981, 103, 2884–2886. [CrossRef] 11. Dolphin, D.; Traylor, T.G.; Xie, L.Y. Polyhaloporphyrins: Unusual ligands for metals and metal-catalyzed oxidations. Acc. Chem. Res. 1997, 30, 251–259. [CrossRef] 12. Chang, K.C.; Ebina, F. NIH Shift in Haemin-Iodosylbenzene -mediated Hydroxylations. J. Chem. Soc. Chem. Commun. 1981, 778–779. [CrossRef] 13. Jiang, G.; Liu, Q.; Guo, C. Biomimetic oxidation of hydrocarbons with air over metalloporphyrins. In Biomimetic Based Applications; George, A., Ed.; InTech: Rijeka, Croatia, 2011; pp. 31–58. 14. Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, I.; Khajehzadeh, M.; Kosari, F.; IV Araghi, M. High-valent [Sn (Br8TPP)(OTf)2] as a highly efficient and reusable catalyst for selective methoxymethylation of alcohols and phenols: The effect of substituted bromines on the catalytic activity. Polyhedron 2010, 29, 238–243. [CrossRef] 15. Climent, M.J.; Corma, A.; Velty, A.; Susarte, M. Zeolites for the Production of Fine Chemicals: Synthesis of the Fructone Fragrancy. J. Catal. 2000, 196, 345–351. [CrossRef] 16. Chang, J.W.; Jang, D.P.; Uang, B.J.; Liao, F.L.; Wang, S.L. Enantioselective Synthesis of α-Hydroxy Acids Employing (1S)-(+)-N,N-Diisopropyl-10-camphorsulfonamide as Chiral Auxiliary. Org. Lett. 1999, 1, 2061–2063. [CrossRef] 17. Mattarei, A.; Azzolini, M.; Carraro, M.; Sassi, N.; Zoratti, M.; Paradisi, C.; Biasutto, L. Acetal Derivatives as Prodrugs of Resveratrol. Mol. Pharm. 2013, 10, 2781–2792. [CrossRef] 18. Corma, A.; Climent, M.J.; García, H.; Primo, J. Formation and hydrolysis of acetals catalysed by acid Faujasites. Appl. Catal. 1990, 59, 333–340. [CrossRef] 19. Leonard, N.M.; Oswald, M.C.; Freiberg, D.A.; Nattier, B.A.; Smith, R.C.; Moahn, R.S. A simple and versatile method for the synthesis of acetals from aldehydes and ketones using bismuth triflate. J. Org. Chem. 2002, 67, 5202–5207. [CrossRef] 20. Corma, A.; García, H. Lewis acids: From conventional homogeneous to green homogeneous and heterogeneous catalysis. Chem. Rev. 2003, 103, 4307–4365. [CrossRef] 21. Trifoi, A.R.; Agachi, P.¸S.;Pap, T. Glycerol acetals and ketals as possible diesel additives. A review of their synthesis protocols. Renew. Sustain. Energy Rev. 2016, 62, 804–814. [CrossRef]

22. Shimizu, K.; Hayashi, E.; Hatamachi, T.; Kodama, T.; Kitayama, Y. SO3H-functionalized silica for acetalization of carbonyl compounds with methanol and tetrahydropyranylation of alcohols. Tetrahedron Lett. 2004, 45, 5135–5138. [CrossRef] 23. Rodriguez, I.; Climent, M.; Iborra, S.; Fornés, V.; Corma, A. Use of delaminated zeolites (ITQ-2) and mesoporous molecular sieves in the production of fine chemicals: Preparation of dimethylacetals and tetrahydropyranylation of alcohols and phenols. J. Catal. 2000, 192, 441–447. [CrossRef] 24. Nakagaki, S.; Ferreira, G.K.B.; Ucoski, G.M.; Castro, K.A.D.F. Chemical Reactions Catalyzed by Metalloporphyrin-Based Metal-Organic Frameworks. Molecules 2013, 18, 7279–7308. [CrossRef] 25. Suda, K.; Sashima, M.; lzutsu, M.; Hino, F. Metalloporphyrin-catalysed Rearrangement of Oxaziridines: An Efficient and Regioselective Synthesis of Lactams Using Ring-enlargement of N-Phenyl-spirooxaziridines. J. Chem. Soc. Chem. Commun. 1994, 0, 949–950. [CrossRef] 26. Takamini, T.; Hirabe, R.; Ueno, M.; Hino, F.; Suda, K. Metalloporphyrin as an Efficient Catalyst in the Regioselective Isomerization of Epoxides to Carbonyl Compounds. Chem. Lett. 1996, 1031–1032. [CrossRef] 27. Firouzabadi, H.; Sardarian, A.R.; Khayat, Z.; Karimi, B.; Tangestaninejad, S. Nitrogen Ligand Complexes of Metal Chlorides as Effective Catalysts for the Highly Regioand Chemoselective Silylation of Hydroxyl Groups with Hexamethyldisilazane (HMDS) at Room Temperature. Synth. Commun. 1997, 27, 2709–2719. [CrossRef] 28. Tangestaninejad, S.; Mirkhani, V. Iron(III) 5,10,15,20-tetrakis(pentafluorophenyl)-porphyrin as an efficient catalyst for conversion of epoxides to thiiranes. J. Chem. Res. 1999, 0, 370–371. [CrossRef] Catalysts 2019, 9, 334 14 of 14

29. Konishi, K.; Makita, K.; Aida, T.; Inoue, S. Highly Stereoselective Hydrogen Transfer from Alcohols to Carbonyl Compounds Catalysed by Aluminium Porphyrins. J. Chem. Soc. Chem. Commun. 1988, 0, 643–645. [CrossRef] 30. Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Shaibani, R. Rapid and efficient ring opening of epoxides catalyzed by a new electron deficient tin(IV) porphyrin. Tetrahedron 2004, 60, 6105–6111. [CrossRef] 31. Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, I.; Taghavi, S.A. High-valent IV tin(IV) porphyrin, Sn (TPP)(BF4)2, as an efficient catalyst for the ring-opening of epoxides. Catal. Commun. 2007, 8, 2087–2095. [CrossRef] 32. Taghavi, S.A.; Moghadam, M.; Mohammadpoor-Baltork, I.; Tangestaninejad, S.; Mirkhani, V.; Khosropour, A.R.; Ahmadi, V. Investigation of the catalytic activity of an electron-deficient vanadium(IV) tetraphenylporphyrin: A new, highly efficient and reusable catalyst for ring-opening of epoxides. Polyhedron 2011, 30, 2244–2252. [CrossRef] 33. Kozuch, S.; Martin, J.M.L. “Turning over” definitions in catalytic cycles. ACS Catal. 2012, 2, 2787–2794. [CrossRef] 34. Evans, M.G.; Polanyi, M. Some applications of the transition state method to the calculation of reaction velocities, especially in solution. Trans. Faraday Soc. 1935, 31, 875–894. [CrossRef] 35. Eyring, H. The activated complex in chemical reactions. J. Chem. Phys. 1934, 3, 107–115. [CrossRef] 36. Stearn, A.E.; Johnston, H.P.; Clark, C.R. The Significance of activation entropy in catalytic mechanisms. J. Chem. Phys. 1939, 7, 970–971. [CrossRef] 37. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, UK, 2012; pp. 342–348. ISBN 978-0199270293. 38. Lide, D.R. (Ed.) CRC Handbook of Chemistry and Physics, Internet Version 2005, 85th ed.; CRC Press: Boca Raton, FL, USA, 2005; pp. 6-186–6-190. ISBN 0-8493-0485-7. 39. Olea, A.F.; Thomas, J.K. Rate constants for reactions in viscous media: Correlation between the viscosity of the solvent and the rate constant of the diffusion-controlled reactions. J. Am. Chem. Soc. 1988, 110, 4494–4502. [CrossRef] 40. Armarego, W.L.F.; Perrin, D.D. Purification of Laboratory Chemicals, 4th ed.; Butterworth-Heinemann: Oxford, UK, 2000; p. 56. ISBN 978-0750637619. 41. Lindsey, J.S.; Schreiman, I.C.; Hsu, H.C.; Kearney, P.C.; Marguerettaz, A.M. Rothemund and Adler-Longo reactions revisited: Synthesis of tetraphenylporphyrins under equilibrium conditions. J. Org. Chem. 1987, 52, 827–836. [CrossRef] 42. d’A Gonsalves, A.M.R.; Varejão, J.M.T.B.; Pereira, M.M. Some new aspects related to the synthesis of meso-substituted porphyrins. J. Heterocycl. Chem. 1991, 28, 635–640. [CrossRef] 43. Halma, M.; Wypych, F.; Drechsel, S.M.; Nakagaki, S. Synthesis, characterization and catalytic behavior of iron porphyrins immobilized in layered double hydroxides. J. Porphyr. Phthalocya. 2002, 6, 502–513. [CrossRef] 44. Machado, G.S.; Castro, K.A.D.F.; Lima, O.J.; Nassar, E.J.; Ciuffi, K.J.; Nakagaki, S. Aluminosilicate obtained by sol–gel process as support for an anionic iron porphyrin: Development of a selective and reusable catalyst for oxidation reactions. Colloids Surf. A 2009, 349, 162–169. [CrossRef] 45. Castro, K.A.D.F.; Simões, M.M.Q.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S.; Wypych, F.; Nakagaki, S. Glycol metalloporphyrin derivatives in solution or immobilized on LDH and silica: Synthesis, characterization and catalytic features in oxidation reactions. Catal. Sci. Technol. 2014, 4, 129–141. [CrossRef] 46. Kobayashi, H.; Higuchi, T.; Kaizu, Y.; Osada, H.; Aoki, M. Electronic spectra of tetraphenylporphinatoiron(III) methoxide. Bull. Chem. Soc. Jpn. 1975, 48, 3137–3141. [CrossRef]

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