REVIEW
https://www.doczj.com/doc/8b5041613.html,/CR Update1of:Use of Solid Catalysts in FriedelàCrafts Acylation Reactions
Giovanni Sartori*,?,?and Raimondo Maggi?,?
?Clean Synthetic Methodologies Group and?National Interuniversity Consortium“Chemistry for Environment”(INCA),Unit PR2, Dipartimento di Chimica Organica e Industriale,Universit a degli Studi di Parma,Parco Area delle Scienze17A,I-43100Parma,Italy This is a Chemical Reviews Perennial Review.The root paper of this title was published in Chem.Rev.2006,106(3),1077à1104,DOI: 10.1021/cr040695c;Published(Web)February14,2006.Updates to the text appear in red type.
CONTENTS
1.Introduction A
2.Acylation of Arenes B
2.1.Acylation with Zeolites B
2.2.Acylation with Clays H
2.3.Acylation with Metal Oxides I
2.4.Acylation with Acid-Treated Metal Oxides I
2.5.Acylation with Heteropoly Acids J
2.6.Acylation with Na?on L
3.Acylation of Aromatic Ethers L
3.1.Acylation with Zeolites L
3.2.Acylation with Clays R
3.3.Acylation with Metal Oxides R
3.4.Acylation with Acid-Treated Metal Oxides S
3.5.Acylation with Heteropoly Acids T
3.6.Acylation with Na?on U
4.Acylation of Aromatic Thioethers V
5.Acylation of Phenolic Substrates V
5.1.Fries Rearrangement V
5.1.1.Fries Rearrangement with Zeolites W
5.1.2.Fries Rearrangement with Heteropoly
Acids X
5.1.3.Fries Rearrangement(Miscellaneous)X
5.2.Direct Acylation Y
5.2.1.Direct Acylation with Zeolites Y
5.2.2.Direct Acylation with Clays AA
5.2.3.Direct Acylation(Miscellaneous)AA
6.Acylation of Heterocycles AB
7.Concluding Remarks AC Author Information AD Biographies AD Acknowledgment AD Dedication AD References AD 1.INTRODUCTION
“The?rst mention of acylation related to the later Al2Cl6 method of Friedel and Crafts appeared in1873in a preliminary communication by Grucarevic and Merz....”1With these words G. A.Olah in an historical review about FriedelàCrafts chemistry2reported the earliest reference on the metal-catalyzed acylation of aromatic compounds.The FriedelàCrafts acylation reaction essentially consists of the production of an aromatic ketone by reacting an aromatic substrate with an acyl component in the presence of a catalyst.3
Since the above communication,an impressive number of papers and books have been published and numerous patents have been registered on this topic.3The reaction quickly became a fundamental pillar of synthetic organic chemistry at both the academic and industrial levels.The great interest in electrophilic acylation studies and in the optimization of preparative processes was spurred by the considerable practical value of the aromatic ketone products.In fact,these compounds constitute funda-mental intermediates in the pharmaceutical,fragrance,?avor, dye,and agrochemical industries.4à6
Conventionally,the electrophilic acylations are catalyzed by Lewis acids(such as ZnCl2,AlCl3,FeCl3,SnCl4,and TiCl4)or strong protic acids(such as HF and H2SO4).In particular,the use of metal halides causes problems associated with the strong complex formed between the ketone product and the metal halide itself which provokes the use of more than stoichiometric amounts of catalyst.The workup commonly requires hydrolysis of the complex,leading to the loss of the catalyst and giving large amounts of corrosive waste streams.For these reasons,during the past decade,the setting up of more ecocompatible FriedelàCrafts acylations has become a fundamental goal of the general “green revolution”that has spread in all?elds of synthetic chemistry7through a revision of the preparation methods mainly based on the exploitation of new and increasingly e?cient catalysts.8
Great e?orts have been made by di?erent research groups to achieve the goal of making the Lewis acid role catalytic in FriedelàCrafts acylation.Interesting results have been achieved,such as the use of catalytic amounts of lanthanide tri?uoromethanesulfonates alone9or microencapsulated on polyacrylonitrile10as reusable catalysts,as well as the more ecocompatible methods based on the use of graphite as a solid catalyst11or even the possibility to perform the reaction without any catalyst.12
Received:November2,2010
Even though these results could suggest some practical developments,they have not led to any very important industrial application.However,maximum e?ort has been directed toward the use of solid acid catalysts.In fact,heterogeneous catalysts can be easily separated from the reaction mixture and reused;they are generally not corrosive and do not produce problematic side products.Di?erent classes of materials have been studied and utilized as heterogeneous catalysts for FriedelàCrafts acylations: these include zeolites,(acid treated)metal oxides,and hetero-poly acids already utilized in the hydrocarbon reactions.13More-over,the application of clays,per?uorinated resinsulfonic acids, and supported(?uoro)sulfonic acids,mainly exploited in the production of?ne chemicals,is the subject of intensive studies in this area.
Owing to the great interest in the argument,minireviews can be found on the use of solid catalysts in FriedelàCrafts acylation. Kouwenhoven and van Bekkum in a chapter of the Handbook of Heterogeneous Catalysis faced the basic problem of the use of zeolites in the reaction.14A further essential overview of the same argument was reported by M e tivier in Fine Chemicals through Heterogeneous Catalysis.15Furthermore,Bezouhanova described the synthetic aspects of the zeolite-catalyzed aromatic ketones preparation.16a Very recently, C ejka et al.reported the develop-ment in the acylation reactions of arenes,aromatic ethers,and phenols catalyzed by zeolites and mesoporous materials.16b The present review deals with the developments,mainly during the past decade,in the use of heterogeneous catalysts for FriedelàCrafts acylation of aromatic compounds.The whole argument is organized in?ve sections,namely,acylation of
arenes,aromatic ethers,aromatic thioethers,phenolic substrates (split up into Fries rearrangement and direct acylation),and heterocycles.It is structured according to a mechanistic point of view,taking into special account the role played by the surface active sites in the activation of reagents as well as in the di?erent modes of regioselectivity encountered in the acylation of arenes, aromatic ethers,and phenols.
Even if the great majority of the papers reviewed concern reactions carried out in batch conditions,where the blocking of pores and active sites can have a negative e?ect on catalyst e?ciency,we particularly stressed results obtained in the gas phase or under continuous?xed-bed reaction conditions,where the continuous removal of products and poisons from the catalyst surface enhances performance.
When we decided to face the problem of writing a review on the FriedelàCrafts acylation reaction,immediately our minds went back to the fruitful discussions on this topic with our mentor Prof.Giuseppe Casnati and to the passionate studies performed under his guidance about the physicochemical factors that control the C-regioselectivity in the acylation of ambidental phenol substrates.17,18For these reasons,with high regard and much a?ection,we dedicate this review to his memory on the occasion of the18th anniversary of his death.
2.ACYLATION OF ARENES
In this section,the FriedelàCrafts acylations of simple arenes (benzene,toluene,xylenes,etc.),condensed arenes,and biphe-nyls are analyzed.These aromatic substrates are examined together since their reactions with acylating reagents follow the same direct mechanism and usually they do not involve second-ary transformations such as transposition and deacylation-reacy-lation processes.The ketones derived from these kinds of arenes represent important chemicals utilized in di?erent areas of applied organic chemistry.19,20
2.1.Acylation with Zeolites
Zeolites are well-known microcrystalline porous materials largely studied and applied in the petrochemical industry for a long time;13more recently they have been utilized in the?ne chemicals industry.21As these materials have been fully described and characterized,we report here(Table1)only the essential data concerning the pore types and dimensions of the zeolites most employed for FriedelàCrafts acylation reactions. Zeolites should be best considered as solid solvents when they are used as catalysts for liquid-phase organic reactions.22,23In fact,adsorption equilibrium constants can be e?ectively consid-ered as partition coe?cients determining the distribution of the reactants and products between the bulk liquid phase and the zeolite“solid solvent”phase.The partitioning of the reactants and products is determined by their nature and relative amount, the type of zeolite,the temperature,and other conventional factors.This statement can account for the di?erent behaviors observed when zeolites are utilized in the liquid-phase FriedelàCrafts acylation.
BEA zeolites are the most useful zeolite catalysts applied at academic and industrial levels for FriedelàCrafts acylation of arenes.24A detailed comparison of the activity of di?erent HBEA zeolites in the acylation of toluene1with acetic anhydride2(1/2 ratio=20)was reported by Corma et al.25(Scheme1).The reaction a?orded p-methylacetophenone(5;p-MAP)with a selectivity close to100%,accompanied by ortho-and meta-isomers3and4,whose amount was less than2%of the total yield in acetylated products.The yield of MAPs increased by increasing the time on stream(TOS),and after120min the constant value of～42%was achieved,suggesting that an Table1.Pore Types and Dimensions of the Zeolites Utilized entry zeolite pore type dimensions
1a Beta(BEA)interconnected channels7.6??6.4?channel
5.5??5.5?channel
2a Y(FAU)interconnected spheres7.4?diameter pore
11.8?diameter cavity
3a ZSM-5(MFI)interconnected channels 5.5??5.6?channel
5.1??5.5?channel
4a Mordenite(MOR)interconnected channels 6.5??7.0?channel
2.6??5.7?channel
5b Nu-10(TON)one-dimensional channels5.5??4.5?channel 6a X(FAU)interconnected spheres7.4?diameter pore
11.8?diameter cavity
a Meier,W.M.;Olson,D.H.Zeolites1992,12,special issue Atlas of Zeolites Strucutre Type.
b Kokotalio,G.T.;Schlenker,J.L.;Dwyer,F.G.; Walyocsik,E.W.Zeolites1985,5,
349.
Scheme1
important deactivation of the catalyst occurred during the reaction.This is probably due to the inhibiting e?ect of MAPs, which can be strongly adsorbed on the catalyst(product inhibition).26Moreover,the adsorbed MAPs can further react, giving larger byproducts(coke)which remain adsorbed and further limit the di?usion of reactants within the channels of the catalyst.The catalyst activity is in?uenced by the Br€o nsted acidity and the SiO2/Al2O3ratio(SAR)of the zeolite;in fact,a low SAR framework led to better yields of MAPs,and a lowering in the catalytic activity was observed when increasing the SAR value. The conclusion is that neither the higher hydrophobicity nor the higher acidity alone produce an important increase of the catalytic activity in the present reaction.On the contrary,the zeolite crystallite size is an important factor and a?ects both conversion and catalyst decay.Thus,use of a sample with very small crystallites(crystal size～0.05μm)and a high density of Br€o nsted acid sites resulted in an important increase in the activity and a decrease of catalyst deactivation,allowing faster di?usion of the products out of the catalyst and minimizing the coke deposition.Similar activity enhancement of microcrystal-line HBEA zeolites was very recently described in a study of the acylation of aromatic and heteroaromatic compounds with di?erent acid anhydrides.27
The e?ect of the pore dimensions and the hydrophobicity of the zeolite catalyst was con?rmed in the acylation of toluene1 with isobutyryl chloride628(1/6ratio=4)(Scheme2).The catalytic activity increased from medium-to large-pore zeolites and from one-to three-dimensional channel systems.The high-est conversion of the acylating reagent was observed with large-pore zeolites such as HBEA(71%)and USY(62%).The reaction rate increased by increasing the hydrophobicity of the zeolite; therefore,the highest initial TOF values were obtained for HBEA zeolite with the lowest concentration of acid sites.With an increase of the zeolite hydrophobicity,toluene can easily di?use to the channels system and adsorb more e?ciently,and also the desorption of the polar ketone product is much easier.
The same catalyst was utilized by Singh et al.29in the reaction of chlorobenzene14with p-chlorobenzoyl chloride(15)to produce4,40-dichlorobenzophenone(16)(14/15ratio=2) (Scheme3).As expected,the process showed a modest conver-sion that was reagent14deactivated toward the electrophilic substitution reaction.Product16was obtained with>88% selectivity at19.8wt%15conversion.Small amounts of2,40-dichlorobenzophenone and dibenzoylated products were also
obtained.It must be stressed that by using HBEA zeolite it was possible to activate not only4-chlorobenzoyl chloride but also the greener and cheaper4-chlorobenozic acid,that,reacting with the more activated toluene(toluene/4-chlorobenozic acid ratio= 300),a?orded4-chloro-40-methylbenzophenone in84%yield.30 Davis et al.31studied the possibility of preparing4,40-diacy-lated biphenyls26and27by regioselective4,40-bisacylation of biphenyl17with carboxylic acids18and19or anhydrides2and 20(17/acylating agent ratio=1)(Scheme4)over HBEA and HY zeolites,with HBEA being the most e?cient one.Unfortu-nately,in the model reaction with acetic anhydride(2),the monoacylated product23was near exclusively formed with a selectivity higher than98wt%,whereas the target diacetylated product26was isolated only in modest yield(8à10%).More-over,acylation of17with hexanoic acid19at150°C a?orded 4-hexanoylbiphenyl(24)with8à14%yield(98%selectivity);an increase in temperature to200°C enhanced the yield of24to 53%,but as frequently observed in similar experiments,a slight lowering in selectivity to92%was observed.
HBEA zeolite was again considerably more active than HZSM-5and HY in the acylation of17with benzoyl chloride 21(17/21ratio=1)(Scheme4)to give4-phenylbenzophenone (25)in41%yield and97.5%selectivity.32In the same reaction, AlCl3showed higher conversion of reagent17but lower selectivity to product25,as a considerable amount of2-phenyl-benzophenone22(～20%)was produced.A lowering of product 25yield(from41to33%)on catalyst recycling was observed. The hydrogen chloride liberated during the reaction probably promotes the extraction of aluminum to some extent from the framework of HBEA.The loss of aluminum and the decrease in crystallinity of the catalyst may be the cause for the lowering of catalytic activity after each cycle,in good agreement with similar experiments carried out with di?erent
zeolites.33,34
Scheme
2
Scheme
3
Scheme
4
Scheme5
The acylation of naphthalene(28)with benzoyl chloride(21) and acetic anhydride(2)was studied in the presence of di?erent zeolites,including HBEA(28/21ratio=2),in comparison with AlCl3(Scheme5).35,36With the number of active sites being equal,HBEA was more e?cient and selective with respect to the production of2-benzoylnaphthalene(32),in comparison with nonshape-selective AlCl3,which preferentially a?ords compound 30because the1-position of naphthalene is more active than the
2-position.37a HBEA showed higher activity with respect to HZSM-type zeolites,which is ascribable to the narrow pore diameter of the latter catalysts which hampers the access of large molecules such as naphthalene to the active sites.In the reaction with acetic anhydride(28/2ratio=2),HBEA still exhibited the highest activity in comparison with some other large-pore zeolites such as HY and HMOR.Signi?cant di?erences in naphthalene conversion over HBEA were found with Decalin or sulfolane as solvents;the di?erent hydrophilicities of these two solvents dramatically in?uence the resulting naphthalene con-version.The hydrophilic sulfolane interacts more strongly with the zeolite surface,blocking the acid sites that are unavailable for the acylation reaction;on the contrary,the hydrophobic Decalin enables the adsorption of acetic anhydride and increases the rate of acylation reaction.Due to the proper structure of the HBEA, the selective formation of isomer31was achieved probably via a restricted transition state selectivity(81%selectivity at35% conversion of28).By comparing HBEA zeolites with di?erent SARs,it was evident that for the best naphthalene conversion an optimum value(37.5)was required;at higher or lower aluminum contents,the catalyst showed lower activity.Moreover,since the catalyst deactivation was attributed to the formation of bulky byproducts that cannot desorb from the zeolite channels,the use of an excess of naphthalene resulted in a decrease of the deactivation rate.
2-Methylnaphthalene was acylated by HBEA zeolite in the absence of any solvent.37b Short-chain acyl chlorides and car-boxylic acids were found not to be the e?ective acylating agents; only acid anhydrides possessed considerable reactivity,which increased with the lengthening of the carbon chain.Butyric anhydride was chosen as a model acylating agent:the catalytic reaction did not proceed at140°C with as low as0.2g of catalyst loading(for50mmol of aromatic substrate),and the conversion of butyric anhydride increased steadily from0to61%as the zeolite amount was raised from0.2to4.0g.Diacylated byproducts emerged when the catalyst amount was higher than1.5g.The best HBEA amount was found to be3.5g.The conversion of the acylating reagent increased steadily up to83%as the temperature was raised from140to200°C;a bit of heavy products,which would block the zeolite channels,were detected when the acylation was conducted above200°C.The best reaction time was1h,and as with the increase of the reaction time,the competing adsorption between reactants and products as well as the emergence of heavy products brought on the deactivation of HBEA.In addition,the equimolar byproduct butyric acid,which was inevitably formed during the acylation reaction,may under-go competitive adsorption with butyric anhydride on the catalyst and consequently lead to its deactivation.
The problem of catalyst deactivation with particular attention to HY and HBEA zeolites was further investigated by Moreau et al.38during studies on the reaction of tetralin(33)with acyl chlorides.In particular,with acetyl chloride(34)(33/34ratio= 0.5)(Scheme6)the reaction led to isomers35(～2%)and36 (～15%)after2h.The36/35ratio remained constant with time,suggesting that both isomers were obtained by parallel reactions. Moreover,studies on the in?uence of the chain length of the acylating agent showed very good conversion of33(higher than 70%after4h of reaction)with octanoyl and butanoyl chloride,in agreement with the results reported by Geneste et al.39To avoid hydrolysis of acetyl chloride,the reaction was performed under a nitrogen atmosphere;however,even if a very fast conversion was obtained leading to a maximum amount of acetyltetralin after only20min(17%yield),di?erent secondary products (naphthalene,ethyltetralin,and acetylnaphthalene)were pro-duced on the surface of the catalyst due to the consecutive reactions of the acetyltetralin.
The rare-earth-exchanged HBEA zeolites(REBEA)were studied in the model reaction involving toluene(1)and acetic anhydride(2)(1/2ratio=0.5)(Scheme1)in nitrobenzene.40 The catalysts were prepared by ion exchange with an aqueous solution of the rare earth acetate followed by calcination at 550°C.With HBEA and LaBEA,a maximum conversion was observed after6h(50and66%,respectively)with high selectivity (86à100%)toward para-isomer5.Therefore,the observed di?erence in the catalytic activity could not be attributed to the rare earth content of the zeolite alone.In general,rare-earth-exchanged zeolites display both Lewis and Br€o nsted acidity;this is ascribable to the cation high charge density,which generates acid hydroxy groups inside the zeolitic cavities.Thus,the di?erence in the catalytic activity of these materials might be due to the following reasons:(i)acidity of the sample,(ii)SAR and crystallinity of the sample as the total number of Br€o nsted acid sites decreases with the increase of SAR,25and(iii)cation position in the lattice as cations present at di?erent positions in the lattice result in di?erent acidities depending on their im-mediate environment.Concerning the solvent e?ect,the highly polar solvent nitrobenzene showed the best activity,in agree-ment with the general mechanism of the acylation reaction involving highly polar active species such as the acylium ion and theσ-complex.3
The catalytic activity improvement of HBEA and HY zeolites by metal exchange was further studied by Singh et al.29,32,34,35,41 in the acylation of arenes with benzoyl chloride(arene/benzoyl chloride ratio=5).The isomorphous substitution of Al by Ga and Fe in the HBEA sample resulted in the following order of e?ciency(benzoyl chloride conversion after18h in the reaction with toluene):AlBEA(54.0)>GaBEA(32.8)>FeBEA(19.0). Indeed the acid strength of the exchanged metal decreases in the order Al>Ga>Fe.42Similarly,when HY was transformed ino REY by exchanging with rare earth metals,its catalytic activity was considerably enhanced[for example,compare the TOF values of benzoyl chloride conversion:4.2for HY vs14.2for REY].
Choudary et al.43,44compared the activities of HBEA and HBEA-supported In2O3(In2O3àBEA)(20wt%loading)in the acylation of benzene with benzoyl chloride(benzene/benzoyl chloride ratio=17).In2O3àBEA showed higher
activity(80% Scheme6
benzoyl chloride conversion in1.5h vs50%benzoyl chloride conversion with HBEA in3h).This catalytic activity enhance-ment was explained by considering the activation of benzoyl chloride by both protonic acid and redox sites present in In2O3àBEA.In fact,rare earth metal oxide species are known for their redox properties,which are expected to play a signi?cant role in activating the benzoyl chloride according to the pathway depicted in Scheme7.Thus,the benzoyl cation produced according to the redox process promotes the acylation reaction. Singh et al.45thoroughly studied the vapor-phase acylation of aromatic hydrocarbons with acyl chlorides over di?erent zeolites. Comparison experiments of the acetylation of toluene with acetyl chloride(toluene/acetyl chloride ratio=2)over HZSM-5, HMOR,and REY zeolites showed that HZSM-5was the best catalyst,a?ording p-MAP with60.2%conversion of acetyl chloride(88.3%selectivity).The conversion increased with increasing reaction temperature and toluene to acetyl chloride
molar ratio,while it decreased with the increase of the reaction time,space velocity,Na content,and SAR.
The vapor-phase benzene acylation with acetic anhydride (benzene/acetic anhydride ratio=2)in the presence of CeZSM-5 was studied by Subrahmanyam et al.46This research is a part of a more extensive study on the use of CeY zeolites as catalysts for aromatic acylation with carboxylic acids.39,47,48Comparison experi-ments showed that CeZSM-5was a better catalyst in the reaction (86.4wt%conversion of acetic anhydride,95.0%selectivity to acetophenone)than unmodi?ed HZSM-5(70.6wt%conversion of acetic anhydride,86.4%selectivity to acetophenone).The reaction was favored by Br€o nsted acid sites even if no special mechanistic information is given.
The use of the greener acetic acid in the acetylation of benzene (benzene/acetic acid ratio=2)over HZSM-5was evaluated;the process was carried out in a?ow reactor under atmospheric pressure at275°C,showing quite promising results(76%acetic acid conversion,91.2TOF value,and88.1%selectivity with respect to acetophenone).49,50
Results of studies on the application of HBEA in the anthraquinone(40)synthesis by gas-phase bis-acylation of benzene(37)with phthalic anhydride(38)were reported51 (Scheme8).Compound38reacted even at relatively low temperature(<250°C),and the anthraquinone selectivity was very high(>95%).An increase of phthalic anhydride conversion was observed by increasing the temperature or the TOS,unfortunately accompanied by a lowering in selectivity toward anthraquinone,particularly for temperatures higher than350°C.The main byproducts are benzoylbenzoic acid 39and biphenyl.FT-IR studies showed that at50°C benzene interacts with all bridged silanols and with70%of the unbridged silanols,whereas at250°C these groups are completely free. Thus,at temperatures lower than250°C,a solution of phthalic anhydride in benzene can exist inside zeolite channels,whereas at higher temperatures benzene does not exist in the form of liquid?lm in the zeolite channels and phthalic anhydride forms H-complexes with acid OH groups.At200°C the formation of benzoylbenzoic acid as a H-complex was observed,and above 250°C compound39was decarboxylated.This information allows the conclusion that anthraquinone should be better formed at200°C.
The cycliacylation step39f40was also investigated in the presence of a HZSM-type zeolite;52a at200°C the reaction was complete in100min.Authors assumed that the cyclization takes place within the zeolite cavities.
2-Methylanthraquinone(2MA)can be obtained by liquid-phase cascade reactions through bis-acylation of toluene with phthalic acid.52b The process has been carried out with various zeolitic materials,namely,HBEA,HY and HMOR;HBEA appears to be the best active catalyst in terms of both conversion of phthalic acid and selectivity to2MA.Because of the inter-connected channel architecture,HBEA and HY zeolites allow for an easier di?usion of the products than HMOR.However,the lower SAR value of HY(5.5)compared with that of HBEA(22) will lead to a higher hydrophilicity,which may resulting in the absorption of some produced water;as a result,the HY zeolite can be easily passivated.Both conversion of phthalic acid and selectivity to2MA increase rapidly with the increase of reaction temperature up to250°C,but then they drop-out beyond this. As recently nanomaterials and nanotechnology have received much attention for catalysis application,nanosized HBEA zeolite was prepared and tested in the above process.This nanocatalyst exhibited better catalytic performance in the one-pot synthesis of 2MA than the microsized catalyst,which may be attributed to the former’s additional surface acid sites,larger surface area and pore volume,and shorter pore channels.Because of the shortened pore channel allowing materials and product to di?use smoothly from the body of catalyst to the reaction system(which com-presses the coke formation),there is no obvious decrease in conversion but a slight increase in selectivity after the catalyst is recycled four times.
Acetylferrocene has been prepared by liquid phase acylation reaction over zeolites of ferrocene with acetic anhydride in decahydronaphthalene under an atmospheric pressure at 140°C.52c The exclusive formation of monoacetylferrocene was detected.The conversion of ferrocene in acylation reaction was signi?cantly in?uenced by the zeolite structure,SAR value, and ferrocene/acetic anhydride molar ratio.The lowest ferro-cene conversion was achieved with10-membered ring zeolite, indicating that some steric hindrances limit the formation of acetylferrocene inside the catalyst.Some increase in the conver-sion of ferrocene was observed with12-membered HMOR.The highest conversions of ferrocene were achieved with12-mem-bered HBEA(100%conversion after180min)and HY(80% conversion after300min).Very high selectivity to acetylferro-cene could be explained by the shape-selective properties of these zeolites:because of the steric hindrances imposed by zeolite structures,the formation of more acylated ferrocenes can prob-ably proceed only in the large cavities of zeolite
Y.However, Scheme
7
Scheme8
these bulky products if formed might be strongly retained inside the cages of this zeolite.In addition,the higher concentration of acid sites(despite the structural type of zeolite used),the higher the conversion of ferrocene.To this end,three di?erent types of HBEA zeolite,with di?erent SAR values(25,75,and300)were tested:HBEA(25)achieved100%ferrocene conversion after180 min,while HBEA(75)reached the same conversion in300min; the lowest activity in ferrocene acylation was found for HBEA-(300)(30%after300min).It must be underlined that while total ferrocene conversion was obtained after120min when0.8g of HBEA(25)zeolite was employed,300min of the reaction were not su?cient to reach the same conversion when only half of this amount of catalyst was used.
Strongly dealuminated HY zeolites,prepared from commer-cially available NaY by a triple treatment with NH4NO3followed by calcination(3YH)and further treatment with HNO3 (3YHA),were utilized as catalysts in the acylation of m-xylene (41)with benzoyl chloride(21)and benzoic anhydride(42) (41/acylating agent ratio=2)53,54(Scheme9).3YH and3YHA have a substantial pore volume in mesopores and contain an appreciable amount of nonframework aluminum.Contrary to the results reported by other authors,36the3YH catalyst showed a much higher activity in sulfolane(94%xylene conversion)with respect to decane(46%xylene conversion).To account for these results,it was assumed that a polar solvent like sulfolane enhances the reaction rate by stabilizing ionic species.3However,a more realistic leaching of acid active species in the highly polar medium can help to account for the apparently positive sulfolane e?ect. Acylation of arenes with benzoyl chloride over FeNaY zeolite (arene/benzoyl chloride ratio=5)in comparison with homo-geneous FeCl3was studied by Hutchings et al.55The activity of the heterogeneous catalyst was very similar to that of the homogeneous one(74à99%arene conversion with FeCl3vs 64à96%conversion with FeNaY)even if longer reaction times were needed.Kinetic studies of the reaction show typical product inhibition phenomena.26,35,41
In a series of valuable studies,Geneste et al.39,48,56investigated the activity of various cation-exchanged HY zeolites in the acylation of toluene and xylenes with aliphatic carboxylic acids (arene/carboxylic acid ratio=300).In a model reaction between toluene and octanoic acid(Scheme10)the activity of rare earth, transition metal,and alkaline earth cation exchanged HY zeolites was considered.39
REY exhibited the highest activity(47yield=75%),in agreement with the results published in an earlier study;57on
the contrary,HY showed a lower activity(47yield<40%)and transition metal and alkaline earth exchanged HY were nearly inactive.Figure1shows the dependence of the reaction rate on the cerium content in the Y zeolite.The catalyst activity increased with the degree of exchange of Nations by Ce3t.There is a threshold of exchange(～20%)below which no activity was observed,but above that threshold a rapid increase in activity occurred.A possible explanation for this phenomenon was recognized by the authors in the particular structure of the HY zeolite that contains?ve distinct cation sites which are located respectively at the center of the hexagonal prism(type I),in the sodalite unit(types I0and II0),and in the supercage(types II and III)48(Figure2).When the zeolite is in the hydrate form,all cations are in the supercage because of the solvation by water. However,upon dehydration,the cation position shifts and for low degree of exchange the trivalent cations tend to migrate toward inaccessible sites I and I0,showing very reduced activity.For exchange entities greater than40%,part of the cations remains in the supercage and considerable catalytic activity can be observed.The nature of the acid sites and consequently the catalyst activity depend on the thermal pretreatment.For HY zeolite the activity remains practically constant for calcination temperatures between300and600°C;for CeNaY the maximum acylation activity was obtained at a calcination temperature of 300°C:this relatively low activation temperature may be a consequence of the easier removal of adsorbed water,and the decrease in activity for temperatures above350°C is probably due to dehydroxylation of the lattice and conversion of Br€o nsted acid sites into Lewis ones.These results con?rm that the Br€o nsted rather than Lewis acids are the active sites in the present reaction.A quite interesting behavior was observed by evaluating the activity of CeY in the acylation of toluene with linear carboxylic acids of increasing chain length
(from acetic Scheme
9
Scheme10
Figure1.Dependence of the degree of exchange of Natby Ce3ton the activity of Y-zeolite in the acylation of toluene by octanoic acid at200°C.
[C 2]to behenic acid [C 22])(Figure 3).39The acylation with fatty acids took place with yields higher than 50%.Acylation of toluene showed an extraordinary high para shape-selectivity e ?ect,and in all cases the yield of para -isomer was at least 94%,whereas in classical Friedel àCrafts acylation with AlCl 3,the para -selectivity was ～80%due to the competitive attack at the ortho -position.For short alkyl chain carboxylic acids,the yield increased linearly with the number of carbon atoms,although all molecules could di ?use through the porous network.This phenomenon is not encountered in the homogeneous Friedel àCrafts acylation,and it is probably due to the same reason as previously mentioned,i.e.,the intracrystalline reaction combined with the hydrophobic interaction of reactants with the catalyst surface.
The e ?ect of the catalyst modi ?cation on the activity in the acylation of toluene with acetyl and propionyl chlorides (toluene/acyl chloride ratio =150and 230)was further investi-gated;47two HY zeolites containing di ?erent amounts of lantha-num,namely,La(26)Y and La(70)Y,were utilized,a ?ording the para -isomers as the major products (44and 65%,respectively)accompanied by trace amounts of meta -and ortho -isomers (2à3%).
From a synthetic point of view,REY zeolites were utilized in the preparation of cycloalkanones via intramolecular electrophi-lic acylation of variously substituted arylalkanoic acids (Scheme 11).58CeY catalyzed the reaction,a ?ording bicyclic and tricyclic ketones in satisfactory to good yield (20à72%).As well documented in previous studies,the e ?ciency of the process parallels the lipophilic character of the reagent.
The use of HY and HBEA zeolites in the Friedel àCrafts acylation of aromatics showed some limitations when large-sized molecules were utilized.In fact,due to the dimensions of their pores,the access to the internal active sites of these zeolites is restricted to molecules with kinetic diameter up to 8?.The mesoporous molecular sieve MCM-41,a silicate-type material,possesses an hexagonal arrangement of uniformly sized unidi-mensional mesopores with a diameter which can be system-atically varied from 20to 80?,59and it should,therefore,be an interesting catalyst for reactions involving larger molecules.Choudary et al.60,61a thoroughly investigated the preparation and the use of InCl 3,GaCl 3,and ZnCl 2supported on MCM-41as Lewis acids in Friedel àCrafts acylation of aromatics with acyl
chlorides (arene/acyl chloride ratio =17).The support itself showed no catalytic activity,whereas the highest activity was shown by the supported InCl 3.The order for acylation activity of the supported metal chloride (InCl 3>GaCl 3.ZnCl 2)was quite similar to that of the redox potential of the metals [E °In 3t/In (à0.34V)>E °Ga 3t/Ga (à0.53V)>E °Zn 2t/Zn (à0.74V)]and con ?rms a possible relationship between the redox potential and the catalytic activity of the supported metal chloride,in agree-ment with further studies by the same authors.43,44The reaction could be e ?ciently applied to a variety of aromatic compounds (70à90%yield),con ?rming the moisture insensitivity of the InCl 3/MCM-41catalyst.61a
A good improvement was realized by grafting GaCl 3or a mixture of GaCl 3/AlCl 3on MCM-41.61b The acylation reactions were carried out by magnetically stirring the catalyst,the benzoyl chloride,and the aromatic substrate at 80°C for 2h.No leaching of gallium or aluminum from the catalysts was observed during the acylation reactions.For both catalysts,reaction induction periods,strongly depending on the nature of the aromatic substrate utilized (anisole,cumene,mesitylene,p -xylene,to-luene,benzene,and naphthalene),were found,but with the bimetal catalyst these induction periods are quite small.This was mostly attributed to a synergetic e ?ect produced,due to the presence of strong Lewis acid sites,(àO à)2AlCl and (àO à)3Al,along with the weaker Lewis acid sites,(àO à)2GaCl and (àO à)3Ga.Both the catalysts also showed excellent reusability and stability.
More interesting are the results on the support of In 2O 3,Ga 2O 3,and ZnO on MCM-41.62à64In particular,In 2
O
3/MCM-41
Figure 3.Dependence of the chain length of the linear carboxylic acid on the toluene (b )and p -xylene (9)
acylation yield.
Scheme 11
proved to be a highly active catalyst for the acylation of aromatic compounds with benzoyl chloride(arene/benzoyl chloride ratio=17)even in the presence of moisture.The activity order of the three supported metal oxides was found to be the same as that for the supported metal halides.63The times requested for the half of the benzene benzoylation in di?erent solvents in the presence of In2O3/MCM-41were in the following order: dichloromethane(2.8h) (6.2h).These results indicate that the catalyst is more active for the reaction in the presence of polar solvents even if a parallel correlation with Reichardt E T N polarity parameters65a[dichloro-methane(0.309),acetonitrile(0.460),heptane(0.012)]was not observed. Several metal tri?ates,La(OTf)3,Ce(OTf)4,Y(OTf)3and Zn(OTf)2,were incorporated into the pores of mesoporous SBA-15.65b The so-obtained catalysts were employed in the acylation of naphthalene using p-toluoyl chloride as acylating agent.The SBA-15with no tri?ate loading showed no measur-able catalytic activity in the naphthalene acylation;with the tri?ate-functionalized mesoporous material,the conversion of naphthalene was found to progressively increase with the in-crease in the tri?ate loading(from35to55%for the increase in the Zn(OTf)2loading from5to30mol%).The2-acyl naphthalene was the major reaction product(～92%selectivity), the minor product being1-acyl naphthalene.This product distribution was almost independent of the supported-metal tri?ate utilized,but the zinc-based catalyst showed much higher catalytic activity.This catalyst can be utilized for?ve-six con-secutive test runs,showing only a5%activity loss in the process. The results of IR studies revealed that,while large tri?ate groups may assist in the geometric con?nement within the pores of the mesoporous SBA-15,the zinc cations are basically responsible for the direct binding of the reactant molecules and hence for the catalytic properties. An interesting catalyst,namely,AlKIT-5,obtained with vary-ing ratios of Si/Al by sol gel procedure through the addition of aqueous HCl to a mixture of tetraethoxysilane,aluminum isopropoxide,and Pluronic F127as template polymer,was utilized in the acylation of ferrocene with acyl chlorides.65c The reaction carried out with1-adamantoyl chloride shows a sub-stantial increase in ferrocene conversion during the?rst30min at 100°C reaching～50%;also with other acyl chlorides the reaction a?ords selectively the monoacylated products.The catalyst can be recycled after?ltration and regeneration by heating to500°C in a stream of air for2h:for four consecutive kinetic runs of ferrocene acylation with1-adamantoyl chloride AlKIT-5catalyst can a?ord the corresponding product with more than40%yield. 2.2.Acylation with Clays From a general point of view,66clays consist of crystalline sheets of aluminosilicate that are negatively charged.These sheets can have a1:1(i.e.,kaolin)or2:1(i.e.,montmorillonite) structure;in the latter case,a central layer of alumina in octahedral coordination with oxygen is sandwiched between two layers of silicon tetrahedrally coordinated with oxygen. Although the ideal aluminosilicate is electrically neutral,random substitutions for the aluminum and silicon resulted in a net negative charge within the sheets;typical substitutions include Al3tfor Si4tand Mg2tfor Al3t.To balance this negative charge, cations such as Nat,Kt,or Ca2tare located in an amorphous interlayer between the sheets.The interlayer also includes water molecules,some of which are complexed to the interlayer cations.Clay particles are composed of alternating sheets and interlayers.Di?erent clay materials(natural,acid-treated,cation-exchanged,67and pillared clays68)are e?ective catalysts for a wide variety of organic reactions,66including FriedelàCrafts acyla-tion;both Br€o nsted and Lewis acidity play a role in the catalytic activity. Among the di?erent applications of modi?ed clays in catalysis, Laszlo et al.69à72described their use in FriedelàCrafts acylation. Two groups of materials were studied in catalytic reactions, namely,clays modi?ed through exchange of the interlamellar cations or through impregnation of metal chlorides.The acid Fe-K10,obtained by exchanging K10montmorillonite clay with Fe(III)ions,gave outstanding results in the acylation of mesity-lene and p-xylene with benzoyl chloride or benzoic anhydride (arene/acylating agent ratio=7)(98à100%yield).The catalyst is described as a material of low cost and low toxicity since the metal ions remain trapped in the double layer.In a comparative study on the acylation of mesitylene and anisole with benzoyl chloride promoted by Fe-K10,70it was observed that mesitylene reacted faster(by a factor of3)when the reactions were carried out separately.However,when the two substrates were reacted jointly,competition favored anisole(by the same factor of3). A tentative explanation for this reversal activity could be based on the assumption that benzoylation of mesitylene and anisole follows two di?erent mechanisms characterized by di?erent levels of interaction of the catalyst surface with the aromatic substrate and the benzoyl cation,the actual electrophilic reagent. In particular,it must be taken into consideration that anisole interacts more strongly than mesitylene with the acid centers of the catalyst and,consequently,both its intrinsic higher reactivity toward the acyl cation can be dramatically lowered and the acid sites are less available for mesitylene acylation reaction. Cation-exchanged montmorillonites were utilized by Geneste et al.73,74in the acylation of aromatics with carboxylic acids.As the clay acidity depends on the nature of the exchanged cation,a series of exchanged montmorillonites was studied in the model acylation of toluene with dodecanoic acid(toluene/ dodecanoic acid ratio=190).Best results were achieved with Al3t-exchanged montmorillonite(60%yield of the ortho-,meta-, and para-isomers).The in?uence of the chain length of di?erent carboxylic acids on the yield of acylation appeared to be similar on clays and on zeolites.39Indeed,acylation of toluene with CH3(CH2)n COOH over Al3t-montmorillonite gave12%yield for n=1,45%for n=6,and80%for n=14. K10montmorillonite impregnated with zinc chloride (ZnK10)was also utilized for similar reactions.Unfortunately, carboxylic acids(i.e.,benzoic acid)were inactive,and benzoic anhydride underwent activation of only one of the two acyl groups.Nevertheless,the reaction was applied at an industrial level.75However,some doubt still remains on the e?ective heterogeneity and reusability of these kinds of catalysts. Scheme12 Some interest shows the results of the study on the use of bentonite-supported polytri?uoromethanesulfosiloxane (B-PTMSS)as catalyst in the acylation of ferrocene with di?erent acyl chlorides76(ferrocene/acyl chloride ratio=0.5)(Scheme12). The catalyst was prepared by mixing the selected bentonite with tetraethyl orthosilicate(TEOS)in water and by adding a solution of tri?uoromethanesulfonic acid in ethanol;the material was then dried at200°C.77The conversions of acyl chlorides increased in the following order:aromatic acyl chlorides(～20%) The in?uence of hydrogen chloride pretreatment of a GaàMg-hydrotalcite anionic clay78on its catalytic activity in the acylation of aromatics by benzoyl chloride(arene/benzoyl chloride ratio=14)was studied by Choudary et al.79,80The hydrotalcite was dried at80°C,and the sample was designated as GaàMgàHT-80.Hydrogen chloride pretreatment of GaàMgàHT-80was performed by bubbling gaseous hydrogen chloride through a mixture of the catalyst and the aromatic substrate,and then?ushing with nitrogen to remove the physically adsorbed or absorbed hydrogen chloride from the reaction mixture.After this pretreatment,the surface area of the catalyst decreased from9.0to2.9m2/g.The fresh GaàMgàHT-80catalyst showed no activity;however,after the hydrogen chloride pretreatment,the catalyst was activated,showing almost no reaction induction period.The activity values measured in terms of the time required for half the reaction for di?erent aromatic substrates followed this order:mesitylene>p-xylene> toluene.The catalyst could be reused repeatedly in the reaction even in the presence of moisture(～90%benzoyl chloride conversion in the model reaction with toluene). 2.3.Acylation with Metal Oxides Metal oxides were utilized in their pure form or in di?erent mixtures as solid catalysts in?ne chemicals preparation since they are commercially available or easily synthesized,they are stable toward moisture,and their properties can be tailored by doping with convenient metal ions.81 Dimethylbenzophenones can be obtained in high yield (88à97%)by reaction between benzoyl chloride and the three isomeric xylenes(xylene/benzoyl chloride ratio=1.5)in the presence of iron(III)oxide,zinc oxide,tin(II)oxide,or moly-bdenum(VI)oxide,with iron(III)oxide showing the greatest activity.82The inertia of some metal oxides,such as those of aluminum and titanium,in the same reaction is puzzling,since all the respective halides are powerful FriedelàCrafts catalysts.3On the basis of comments made by di?erent authors on the leaching of active FeCl3,produced by reaction of iron oxide with HCl,into solution,the possible contribution of the homogeneous iron-based Lewis acid form is strongly suspected. The acylation of toluene with benzoyl chloride(toluene/ benzoyl chloride ratio=40)over ferrous and ferric sulfates previously heat treated at500,700,and900°C was studied by Arata et al.;83the catalysts prepared by calcination of the two sulfates at700°C showed good activity[FeSO4,initial rate=7.7?103(mol/L3min3g);Fe2(SO4)3,initial rate=10.1?103 (mol/L3min3g)].The product distribution was18à22%o-, 2à4%m-and74à78%p-methylbenzophenone.Both ferrous and ferric sulfates are mainly remaining as sulfate forms when calcined at500°C and decompose to form iron oxides containing 0.15%of sulfur at700°C. Thallium oxide supported on di?erent materials was studied by Choudary et al.84as catalyst in the benzene acylation with benzoyl chloride(benzene/benzoyl chloride ratio=17).In general,TlO x deposited on low-surface-area supports showed high catalytic activity(80%benzoyl chloride conversion after ～1.5h),whereas that deposited on high-surface-area supports had almost no activity.This behavior is indicative of a di?erent interaction between TlO x and the supports.Strong metalàsup-port interactions are well-known and are observed for many supported metals;81,85however,the information on the chemical nature of the strong metal oxide-support interaction is scarce.86a In the present case,since TlO x is basic,it can chemically interact with the weak or strong acid hydroxy groups of high-surface-area supports.The low-surface-area supports are highly sintered macroporous materials and hence have no surface hydroxy groups;thus,the supported TlO x keeps unchanged its catalytic properties. P2O5/SiO2catalyst has been employed in the ecoe?cient reaction of carboxylic acids with aromatic substrates to produce the corresponding aryl ketones.86b The acylation reactions were carried out at re?ux under solventless conditions or by using1,2-dichloroethane as solvent.The reactions are so clean that no chromatographic separation was necessary to obtain spectro-scopically pure compounds(except in a few cases).The acylation occurs at the para position with good selectivity;of course,in cases where this position is blocked,the acyl group is introduced at the ortho position.These reactions are rapid even with higher carboxylic acids;as expected,deactivated aromatic rings such as bromobenzene,chlorobenzene,and nitrobenzene gave low or no yields.The present acylation method occurs by in situ generation of a carboxylic anhydride derived from a mixed carboxylic-phosphoric anhydride.Interestingly,in the absence of the siliceous support the yields were lower(average,20%);the e?ect of SiO2may be due to a good dispersion of P2O5on the surface of silica gel leading to signi?cant improvements in its reactivity.In addition,SiO2as a support may also minimize cross contamina-tion between the product and the H3PO4generated during the reaction. The same reaction was also carried out by using Cu x Mn(1-x)-Fe2O4spinel catalyst(benzene/benzoyl chloride ratio=10).87A relationship between the concentration of strong acid sites on the catalyst surface and the reaction rate was shown.Moreover,the incorporation of copper drastically decreased the number of Br€o nsted acid sites;the relatively high catalytic activity of copper-substituted systems for benzene benzoylation is due to the generation of Lewis acid sites at higher copper loadings. 2.4.Acylation with Acid-Treated Metal Oxides Sulfated metal oxide catalysts represent a class of extremely attractive strong solid acids showing widespread application in di?erent areas of chemical transformations.88Arata et al.89,90 reported that sulfated zirconia(SZ),prepared by treatment of zirconia with sulfuric acid or ammonium sulfate,exhibits extre-mely strong acidity and that it is able to catalyze the isomerization of butane to isobutane at room temperature.This behavior represents a unique catalytic performance,compared to those of typical solid acids,such as zeolites,which show no activity for the reaction at such low https://www.doczj.com/doc/8b5041613.html,ing Hammet indicators, Hino and Arata90claimed that SZ is an acid104times stronger than100%sulfuric acid;therefore,SZ,withàH0=16,was considered as the strongest halide-free solid superacid.91à94 However,the superacidity of SZ has been recently questioned by several authors,95à98who claimed that SZ is only a strong solid acid with an acid strength comparable to that of sulfuric acid or some acid zeolites. In an early study,Arata et al.99showed that SZ was catalytically active in the acylation of toluene with acetic and benzoic acids (toluene/carboxylic acid ratio=145).In the latter case,the yield of methylbenzophenones was60%and the product’s distribution was30à35%o-,5%m-,and60à65%p-methylbenzophenone. The same reaction carried out with benzoic anhydride took place readily even at30°C,and it seems to be also accomplished by the benzoic acid produced.The real heterogeneity of the catalyst was con?rmed by the inertia observed when the catalyst was removed from the reaction medium.The acylation of toluene with acetic acid was also performed in a?ow system by passing the vaporized reaction mixture through the SZ catalyst bed at280°C with a nitrogen carrier.The system seems to be quite promising even if no further development of the research was performed(51% acetic acid conversion;89%selectivity with respect to all ketones; ortho-,meta-,and para-isomer selectivity16,13,and71%). Further studies were performed to evaluate the e?ciency of SZ and sulfuric acid-treated alumina(SA)in the acylation of arenes with di?erent benzoylating reagents(arene/benzoyl chloride ratio=10).100à103SZ catalyzed the reaction of p-chlorobenzoyl chloride with benzene,a?ording p-chlorobenzo-phenone in80%conversion and100%selectivity.The catalyst showed partial reusability without any further treatment.The loss of about20%of particles during?ltration can account for the partial loss of https://www.doczj.com/doc/8b5041613.html,parison experiments showed that the activity of SZ was slightly higher than that of SA for the reaction with benzoyl chloride(28%vs22%benzophenone yield after 1h)but much lower for the reaction with benzoic anhydride (45%vs80%benzophenone yield after1h).The authors concluded that strong Br€o nsted acid sites are responsible for the production of the benzoyl cation although the FriedelàCrafts acylation with acyl chlorides is generally known to be catalyzed by Lewis acids. The promoting e?ect of alumina on various types of sulfated metal oxides,namely,sulfated zirconia-alumina(SZA),sulfated titania-alumina(STA),and sulfated iron oxide-alumina(SFA), was reported.104,105The catalyst e?ciency in the acylation of toluene with benzoyl chloride(toluene/benzoyl chloride ratio= 22)was dependent on the content of alumina.For example,in the case of SZA,the catalyst activity increased with alumina content up to a maximum(～3mol%Al2O3)and then decreased as the alumina content was further increased.The yields in isomeric methylbenzophenones of the reactions carried out with the catalysts were in the order SZA(91%)>SFA(78%)>STA (45%).The high or good activity of SZA and STA is consistent with the formation of strong acid sites on the catalyst surface due to the production of AlàOàZr and AlàOàTi bonds in the mixed oxides;these strong bonds lead to an increase of the concentration and thermal stability of the sulfate surface species and generate additional acid sites.On the contrary,the high activity of SFA was explained assuming that the reactions were homogeneously catalyzed by iron chloride formed by reaction of benzoyl chloride or hydrogen chloride evolved with the iron component of the catalyst.106 The catalytic properties of mesoporous zirconias(Zr-TMSs) functionalized with tri?ic acid were studied by Singh et al.107,108 The catalysts were prepared via a postsynthesis method by reaction of Zr-TMS with tri?ic acid;for comparison,the amorphous zirconia[Zr(OH)4]was functionalized in the same manner.Physicochemical analyses revealed that tri?ic acid was bonded in the same fashion on both Zr(OH)4and Zr-TMS at all loading values:tri?ate groups bound via three equivalent oxygen atoms to zirconium atoms forming a tripod structure.Acylation of biphenyl(17)with benzoyl chloride(21)(17/21ratio=1) (Scheme4)showed a comparable low conversion with both unfunctionalized amorphous and mesoporous zirconia(3.1and 3.2%,respectively).The conversion of substrate17increased for both catalysts after the functionalization with tri?ic acid[41.0% for Zr-TMS and20.5%for Zr(OH)4],and the selectivity with respect to product25ranged from93to100%;these results demonstrate that the benzoylation of17essentially needs a porous catalyst with uniform porous size and high acidity.The activity of the same tri?ic acid-functionalized Zr-TMS was studied in the acylation of toluene(1)with p-toluoyl chloride (7)(1/7ratio=1)to give4,40-dimethylbenzophenone(13)(1 conversion=82wt%,9selectivity=21.4wt%,13selectivity= 44.1wt%)(Scheme2).Results of catalyst-recycling studies showed a modest decrease in p-toluoyl chloride conversion after one cycle(from50.7to49.2wt%)which was related to a minor loading of CF3SO3H(from15.0to14.1wt%);this result seems to be rationalized with some leaching of CF3SO3H into the solution during the reaction. 2.5.Acylation with Heteropoly Acids Heteropoly acids(HPAs)are Br€o nsted acids composed of heteropolyanions and protons as countercations;the most commonly utilized HPA is the phosphotungstic acid (H3PW12O40).HPAs are stronger than many conventional solid acids such as mixed oxides and zeolites.One important advantage of HPAs is that they can be utilized both homogeneously and heterogeneously.The homogeneous reactions occur in polar media at～100°C;on the other hand,when using nonpolar solvents,the reactions proceed heterogeneously.In the latter case,supported HPAs are the catalysts of choice,as bulk HPAs possess a low surface area(1à5m2/g).109The HPA catalysts are easily separated from the heterogeneous reaction mixture by ?ltration and from the homogeneous systems by extraction with water. The use of HPAs and multicomponent polyoxometa-lates as catalysts in liquid-phase reactions was reviewed by Kozhevnikov109in1998.Moreover,an interesting minireview was published in2003by the same author110concerning the FriedelàCrafts acylation of arenes and the Fries rearrangement catalyzed by HPA-based solid acids.111à113The author con-cluded that HPA-based solid acids,including bulk and supported heteropoly acids as well as heteropoly acid salts,are e?cient and environmentally friendly catalysts for all reactions analyzed. The insoluble Cs2.5H0.5[PW12O40]was applied in the acyla-tion of benzene with benzoic anhydride(benzene/benzoic anhydride ratio=180)in100%yield.114The initial rate was almost proportional to the amount of catalyst.Repeated use of the catalyst was possible by washing the used one with benzene. However,the activity gradually decreased after the third run caused by the adsorption of both benzophenone and benzoic acid. The alkali metal and ammonium salts of HPAs were studied by Izumi et al.115à117In the acylation of p-xylene with benzoyl chloride(p-xylene/benzoyl chloride ratio=20),the catalytic activity of sodium and potassium salts decreased with increasing metal content expressed as x in the formula M x H3-x[PW12O40]. For rubidium and cesium salts,however,the activity?rst decreased with increasing x and then jumped to attain a max-imum at x=2.5.Although the acid alkali metal salts,as well as the parent free acid H3PW12O40,are protonic acids in nature,they worked as e?cient catalysts to activate benzoyl chloride.In contrast,typical strong protonic acids such as sulfuric and perchloric acids were quite inactive for the present benzoylation reaction.The reason is that the heteropolyanion PW12O403àhas the ability to stabilize cationic intermediates118a such as benzoyl cations,whereas simple oxoanions such as sulfate and perchlorate anions are unable of stabilizing such cations.However,it is important to take into account that a similar behavior was observed with acid-treated metal oxides.100à103No dissolution of catalytically active species from the salts was observed(the reaction ceased completely if the heterogeneous salt was re-moved from the reactor).Rb2.5H0.5[PW12O40]and Cs2.5H0.5-[PW12O40]are highly porous materials with mesopores showing 2à7nm average diameter;this mesoporous structure seems to favor the benzoylation since the reaction takes place not only on the surface but also in the bulk near the surface,owing to the highly polar nature of benzoyl chloride and the deriving cationic intermediate.It must be underlined that not only can Cs2.5H0.5-[PW12O40]act as an e?cient catalyst for electrophilic acylation with acid chlorides or anhydrides but also,more and more advantageously,it can directly activate the carboxylic acids. The polyvalent transition metal salts of dodecatungstopho-sphate can act as highly e?ective and recyclable heterogeneous catalysts for FriedelàCrafts acylation of both activated and less activated aromatic substrates with carboxylic acids.118b In the model reaction of toluene with dodecanoic acid,H3PW12O40and Cs2.5H0.5PW12O40show low yields(<35%),suggesting that a catalyst with strong Br€o nsted acidity is not able to catalyze this kind of reaction.On the contrary,salts of polyvalent transition metal ions(Fe3t,Ti4t,Sn4t,Zr4t,Bi3t,Ru3t)and PW12O403àshow good to excellent yield(65à94%)with only3mol%of the catalyst;the para isomer was the major product(86à90% selectivity).The highest yield(94%)was achieved in the presence of FePW12O40.This catalyst was found to be truly heterogeneous,and after its separation from the reaction mixture by a simple centrifugation,it can be recycled at least three times keeping excellent yield without any reactivation treatment.The catalyst was also employed to acylate other aromatic compounds with dodecanoic acid:electronrich arenes such as p-xylene and anisole gave the corresponding acylation products in89and97%yield,respectively,but even nonactivated arenes such as benzene and chlorobenzene gave satisfactory yield (53and39%,respectively).Finally,the acylation of toluene with a variety of straight chain C6àC19carboxylic acids and benzoic acid gave the corresponding acylated products in87à94%yield. The yield increases with carbon number of linear carboxylic acids from C2to C6,which suggests that the hydrophobic reactant is more favorable for this reaction.Interestingly,the acylation rate strongly depends on the type of metal cation:the rate increases with electronegativity of cation.This suggests that the catalytic activity increases with Lewis acid strength,originated from the exchanged metal cation.The e?ect of Keggin anions on the activity of Ru salts was also tested;the initial rate and the?nal yield show the following order:PW12O403à>SiW12O404à> PMo12O403à,which is consistent with the order of the acid strength of the proton form of HPAs.From these results,the cooperation of strong Br€o nsted acid sites and Lewis acid sites may be responsible for the high activity of the polyvalent transition metal salts of PW12O403à. It is well-known that one of the major problems associated with HPAs in the bulk form is their low e?ciency due to low surface area,rapid deactivation,and relatively poor stability. Attempts to improve the e?ciency and stability of HPAs were made by using various supports including mesoporous silica,119 mesoporous aluminosilicates,120zirconia,and alumina.121Be-cause of their basic nature,alumina and zirconia tend to decom-pose HPAs,resulting in deformation of the parent Keggin structure,thereby reducing the overall acidity.The use of pure phosphotungstic acid and its cesium salt supported on silica as solid catalysts for the acylation of aromatics48with crotonic acid 49(48/49ratio=85)was studied by Corma et al.122The protonation of crotonic acid in the presence of a Br€o nsted acid produces an electrophilic reactive intermediate that can be either an alkyl or an acyl carbocation which can react with the aromatic ring to produce either the alkylated product50or the acylated product51,respectively(Scheme13).Products50and51can further react either via intramolecular acylation/alkylation reac-tion to produce the corresponding indanone53or via an intermolecular acylation/alkylation process to form the corre-sponding ketone52.Products52and53could be obtained in di?erent proportions depending on the relative rates of the di?erent reactions.Analysis of products obtained with p-and m-xylene showed that all the catalysts were more active for the acylation than for the alkylation reaction.Indeed,indanones54 and55(Figure4)were obtained in65and79%yield.The silica-supported HPA was more active than the unsupported one,due to the increase of the surface area.However,in the case of cesium-exchanged HPA,the surface area concept could not be directly extrapolated since the surface area increased when Scheme13 Figure4.Indanones obtained by FriedelàCrafts reactions of p-and m-xylene with crotonic acid. cesium ions were introduced,but the total Br€o nsted acidity decreased when Htwas replaced by Cst.A good correlation could be,however,observed between the speci?c surface acidity and the catalyst activity.123a Similarly,the catalytic performance of H4SiW12O40supported on silica was tested in the reaction of p-xylene withγ-butyr-olactone to produce the5,8-dimethyl-R-tetralone.123b The pro-cess,carried out in a stainless autoclave at210°C,showed a high activity and selectivity when20wt%H4SiW12O40/SiO2was employed;the unsupported heteropolyacid H4SiW12O40was found to convertγ-butyrolactone but mainly yielded byproducts adhering tenaciously to the catalyst.The reaction of p-xylene with vinylacetic acid to give3,4,7-trimethyl-R-indanone was also performed with the same supported catalyst(40wt%):the process was carried out for4h at190°C and a?orded the product in44%yield. As already underlined by Kozhevnikov,109,110it is quite evident that HPAs and related compounds represent materials to be e?ciently utilized as catalysts in organic reactions,including FriedelàCrafts acylation.However,a serious problem with the use of these compounds as heterogeneous catalysts is their deactivation because of coking.In fact,conventional regenera-tion by calcining at500à550°C,which is routinely used in the case of oxides and zeolites,cannot be applied to HPAs because their thermal stability is not high enough.However,some tricks useful in alkane isomerization processes,that include doping with transition metal ions(i.e.,Pd)and controlled addition of water to the catalyst,can be successfully utilized to prolong the lifetime of HPA catalysts. 2.6.Acylation with Nafion The use of Na?on,a solid per?uorinated resinsulfonic acid, was reported early by Olah et al.124for the acylation of toluene with benzoyl chlorides(toluene/benzoyl chloride ratio=2).The reaction could be simply carried out by heating under re?ux the mixture of the reagents with the solid catalyst,a?ording sub-stituted benzophenones in81à87%yield.The optimum catalyst amount was30wt%,as higher quantities signi?cantly decreased the yields due to adsorption of appreciable amounts of products and starting materials.Concerning the isomeric composition of methylbenzophenones,when benzoyl chloride was employed as acylating agent,the reaction gave predominantly para-and ortho-substitution(in accordance with the typical electrophilic aro-matic reaction),but the o/p ratio(2.34à4.81)was,in general, higher than that obtained under homogeneous(AlCl3)catalysis (0.02à0.62).The reaction could be applied to p-nitrobenzoyl chloride and various substituted benzenes,giving the corre-sponding benzophenones in60à90%yield. More problems resulted with the acetylation of aromatic compounds;in fact,with acetyl chloride the preferential forma-tion of ketene degradation products was observed,whereas neither acetic anhydride nor acetic acid alone proved to be e?ective.On the contrary,when an equimolecular mixture of acetic acid and acetic anhydride was re?uxed with toluene,m-xylene,or mesitylene in the presence of Na?on,the correspond-ing acetophenones were isolated in3,21,and72%yield, respectively. Na?on was also successfully utilized as catalyst for the intramolecular FriedelàCrafts acylation.125,126The cyclization of diphenylethane-2-carboxylic acid(56)(Scheme14)was carried out in re?uxing p-xylene,a?ording the10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one(57)in nearly quantitative yield.The procedure was then applied to other aromatic carboxylic acids by using1,2-and1,3-dichlorobenzene as solvent, and the cyclization products were isolated in82à95%yield.The reactivity of the aliphatic carboxylic acids58-60was also in-vestigated(Scheme15).Even though the yield of1-indanone (61)from3-phenylpropionic acid(58)was very low(～5%), 4-phenylbutyric acid(59)and5-phenylvaleric acid(60)a?orded the corresponding R-tetralone(62)and1-benzosuberone(63) in90and83%yield,respectively. 3.ACYLATION OF AROMATIC ETHERS Aromatic ethers are described to be very reactive substrates toward electrophilic substitution and are therefore successfully acylated by using catalysts that normally show modest activity with arenes.However,this statement must be carefully consid-ered each time,since the alkoxy group represents a good donor for the acid sites of the catalyst and it can interact so strongly with the catalyst itself that the original activity of both aromatic ether and catalyst can be greatly lowered.The FriedelàCrafts acylation of aromatic ethers has attracted considerable interest in organic synthesis and in industrial chemistry because of the widespread application of the corresponding ketones as valuable intermedi-ates in?ne chemistry.26,127à130An example is the selective acetylation of2-methoxynaphthalene(2MN)at the carbon in position6owing to the great interest in2-methoxy-6-acetyl-naphthalene(2Ac6MN),an intermediate in the preparation of the anti-in?ammatory drug(S)-Naproxen.58,131 3.1.Acylation with Zeolites Derouane et al.reported the acylation of anisole(64)with acetic anhydride(2)(64/2ratio=2)over HBEA zeolite.22The reaction a?orded p-methoxyacetophenone(65)as the sole Scheme 14 Scheme 15 Scheme16 aromatic product(Scheme16).Compound65and acetic acid18 were produced in equal amounts at short reaction times,con-?rming that reagent2was not noticeably hydrolyzed under the reaction conditions.However,a de?cit of acetic acid was observed at long reaction times,probably due to its reaction with the silanols of the zeolite,ultimately resulting in the deal-umination of the zeolite framework.This partial and uncontrol-lable dealumination led to the irreversible loss of acid sites,giving rise to an irreversible catalyst deactivation.The inhibition of the catalyst in the batch reaction was also shown by detailed kinetic analyses using a LangmuiràHinshelwood model that allowed the authors to quantify its nature and extent.The adsorption equilibrium constant for product65exceeded by a factor of at least6the adsorption equilibrium constant for any reactant,and the occupancy of the intracrystalline volume of the zeolite by compound65increased rapidly with conversion,thereby redu-cing the access of reactants to the catalytic sites and resulting in a catalyst deactivation as the conversion increased.132 The origin of the HBEA deactivation in the same reaction was further investigated by the research groups of Derouane23,133and Guisnet.26The authors showed that,by performing the model reaction(64/2ratio=1)under batch conditions,a rapid catalyst deactivation occurred,which could be attributed,to a large extent,to the inhibiting e?ect of the product.However,when the reaction was performed in a?xed bed reactor,the catalyst deactivation was much slower,particularly when an anisole-rich mixture(64/2molar ratio=5)was used,with product65being obtained in high selectivity(>98%).The conclusion is that the use of an excess of anisole enhances the catalyst stability and limits both retention of product65and formation of polyacety-lated byproducts which deactivate the catalyst even if,as pre-viously underlined,the reaction product65continued to be the major poison of the catalyst.A possible acylation mechanism was proposed in which the acylating agent2reacts?rst with the zeolite to form an acyl cationàzeolite complex68(Scheme17) which then acts as acylating reagent. Controlled dealumination was reported134a as an instrument to enhance the activity of zeolites by tailoring their acidity.Deal-uminated HBEA showed,in the same reaction(64/2ratio=1), higher activity in the initial period compared to the case of untreated HBEA(48.1%vs26.4%anisole conversion after15min),whereas at longer reaction times the same conversion was achieved(～70% after240min).Dealumination provokes changes in acidity and in pore distribution;the initial higher activity of the dealuminated HBEA zeolite could be due to the improved di?usion;this e?ect continues until coking reactions dominate.However,the spent catalyst restored its activity upon exposure to fresh reaction mixture, which was likely able to extract the deposited higher molecular weight compounds,or by calcination in air at500°C for4h,which removed coke by oxidation.After the above treatments,the catalyst could be reused in the model reaction of Scheme16for at least four cycles,showing quite unchanged activity(product65yield= 75%).130Therefore,two types of coke exist in the channels system and in the external surface:(i)extractable(“reversible”)and(ii) nonextractable(“irreversible”)coke.On the basis of these conclu-sions,the authors tried a further increase of the catalyst activity by using the reactor in Figure5.134a In this Soxhlet-like extractor-reactor,the zeolite was placed in the re?ux chamber containing the condensing reaction mixture.However,the conversion was lower compared to that obtained in batch experiments(30%vs70%after 240min),probably due to the di?erent vapor pressures of both reactants. In the same model acylation reaction,the catalytic activity of cation-exchanged NaY zeolites was found to be strongly in?u-enced by the nature of the exchanged cation.134b Rare earth cation(Ce3t,La3t,and Nd3t)exchanged zeolites exhibit the highest activity showing66,24,and21%anisole conversion, respectively.Among the various zeolites studied,HBEA showed the highest catalytic activity(81%anisole conversion).The correlation of the catalytic activity with acidity(evaluated by FT-IR and DSC studies)revealed that the Br€o nsted acid sites in the zeolite are responsible for the anisole acylation. Acylation of anisole(64)with carboxylic acids69(64/69ratio= 45),in particular with octanoic acid(Scheme18),was studied by Beers et al.135,136over variously activated HBEA zeolites.Treat-ment of HBEA with steam or acid did not result in any signi ? cant Scheme17 Figure5.Trickle bed reactor.Reprinted with permission from ref134a. Copyright1999Elsevier. change in the surface area and pore volume.However,treating the zeolite with oxalic acid after steaming resulted in a signi?cant decrease of the surface area(from670to500m2/g)and an increase of the bulk SAR(from13to51).This led to an increase in activity and selectivity:in fact,HBEA itself exhibited an activity,de?ned as the initial apparent?rst-order constant k,of 0.03L/g cat3h and a selectivity toward compound70(R= C7H15)of80%at50%conversion,whereas a great activity increase(k=0.12L/g cat3h)and a selectivity improvement(up to 95%)were observed with the acid-treated catalyst.It was reported54that the activity enhancement observed in steamed zeolites could be due to the migration of the extraframework aluminum(EFAL)into the reaction mixture,hereby acting as an homogeneous catalyst.However,the model reaction did not continue after hot?ltration,137a indicating that no active species were leached from the zeolite during the reaction.More likely, the activity and selectivity enhancement could be due to the increased accessibility or participation of active sites,rather than the formation of additional active species.Indeed,removal of EFAL and,in general,of“site-blocking”species resulted in an increase of the number of active sites that are accessible. The acylation of anisole with long chain carboxylic acids (hexanoic,octanoic,and decanoic acid)has been also investi- gated by Mayadevi et al.over large pore zeolites HBEA,HFAU, and HMOR with di?erent SAR(in brackets).137b According to Scheme18,the products of the acylation with hexanoic acid(69, R=C5H11)are the ketone70(major),the ester71(minor),and a trace amount of the ortho-isomer.The activity of HBEA increases with dealumination(according to previous studies). This is again attributed to the generation of mesopores during dealumination and the corresponding ease di?usion of the reactants and products.The conversion of hexanoic acid after6 h at140°C follows the order HFAU(6)>HBEA(15)> HMOR(11),whereas for decanoic acid the order was HBEA(15) >HFAU(6)>HMOR(11).In the acylation of anisole with hexanoic acid,the reaction rate constant of zeolites showing a SAR value of49reveals that HBEA is about seven times more active than HMOR but only slightly more active(by about17%) than HFAU. The handling of unsupported zeolites in batch reactions frequently shows some drawbacks since these materials have a colloidal form and the small size of the particles renders di?cult their recovery and puri?cation.The transformation of powders into extrudates or tablets requires the introduction of binders such as R-Al2O3that can increase the di?usion barrier between the reactants and the active sites.For these reasons,di?erent groups devoted their e?orts to the preparation of zeolites supported over special materials to obtain a macroscopic shaping easily recoverable from the reaction mixture and more utilizable in a?xed bed reactor.138,139To this end,HBEA zeolite supported on macroscopic preshaped SiC material(HBEA/SiC)was investigated as a high-performance catalyst for benzoylation of anisole(64)with benzoyl chloride(21)(64/21ratio=1.5) (Scheme19).140The SiC support exhibited high thermal con-ductivity,high resistance toward oxidation,high mechanical strength,and chemical inertness,properties required for a good support.HBEA zeolite was synthesized and in situ deposited on SiC extrudates previously prepared by a reported technology.141a A high-magni?cation SEM image showed the presence of small zeolite particles homogeneously dispersed on the entire surface of the support.The deposition of HBEA on the SiC surface signi?cantly increased the overall surface area of the material from25(for pure SiC)to more than100m2/g(for HBEA/SiC) along with a large microporous contribution(～60m2/g).This composite catalyst showed relatively high activity with a total 71%conversion of benzoyl chloride after24h on stream(95% selectivity with respect to ketone66and less than5%selectivity for ketone73).The catalyst could be reused after washing with methylene chloride,showing quite similar results for three tests. Similar experiments carried out with unsupported more highly acidic HBEA showed that in the?rst cycle similar activity and ketone selectivity were achieved,but signi?cant catalyst deactiva-tion was observed during the second cycle.The higher activity of the HBEA/SiC was tentatively attributed,by authors,to the dispersion of the zeolite on the support surface,leading to a larger contact surface with reactants. The zeolite deactivation during electrophilic acylation was attributed to the site blockage due to the accumulation of heavier products.Moreover,the aromatic ketones(i.e.,p-meth-oxybenzophenone)are the main inhibitors for the FriedelàCrafts reaction due to their strong adsorption on the active sites. Temperature programmed oxidation(TPO)analysis carried out on the commercial HBEA catalyst clearly highlights the impor-tant coke formation when compared to that which was observed on the SiC supported HBEA catalyst,that is,7instead of 1.25wt%.141b In addition,coke formed on the bulk zeolite catalyst also exhibits a higher resistance toward combustion(i.e., maximum combustion peak at600instead of400°C for the supported zeolite).The dispersion of the zeolite crystals on the SiC support also allows a high di?usion rate of ketones out of the pores of the HBEA-SiC catalyst,thus lowering the deactivation rate as a function of TOS when compared to that observed on the bulk HBEA. With the aim of achieving a supported HBEA with higher performance,the same authors142prepared HBEA zeolite nano-wire material by using mesoporous multiwalled carbon nano-tubes(MWNTs)as directing templates.The catalyst was obtained by growing the BEA zeolite in the presence of carbon nanotubes favoring the formation of carbon templates.It was assumed that the con?nement e?ect inside the tubes could Scheme 18 Scheme19 induce an increase in pressure,thus promoting the synthesis of nanoparticles of BEA zeolite by replacing the hydrothermal pressure increase by the internal pressure increase.The?nal carbon template was removed by submitting the sample to calcination in air at750°C.The as-prepared BEA zeolite was then converted into the H-form,and it was employed in the acylation of anisole(64)with benzoyl chloride(21)(64/21ratio =8),showing a satisfactory activity(anisole conversion～65%) and selectivity toward p-methoxybenzophenone(～95%).How-ever,it must be emphasized that similar and even better results could be obtained in the same reaction promoted by simpler and less expensive catalysts. The preparation and use of active catalysts coated on a structure packing represents a further attractive replacement for conventional catalysts in randomly packed beds or slurry reactions.143A method was developed in which catalytically active and selective HBEA coatings could be prepared on ceramic monoliths constituted either of pure silica or of cordierite (2Al2O335SiO232Mg)(Figure6a)and on metallic wire gauze packings144(Figure6b).The average loading values of the HBEA coatings were the following:silica monolith,6.6wt%;cordierite monolith,5.4wt%;silica precoated wire gauze packing,5.6wt%. The activity of the coated structures was measured batchwise in the acylation of anisole(64)utilized as solvent-reagent with octanoic acid(64/octanoic acid ratio=45)(Scheme18).The liquid reaction mixture was carried through the monoliths using a nitrogen?ow.The silica monolith showed the highest activity (k=0.05L/g cat3h),which was only10%lower than that of HBEA particles in slurry.The activities of the coated cordierite monolith and the metal wire gauze packing were much lower than that of the HBEA particles in slurry.All monoliths gave a similar selectivity of about77à85%toward the main para-isomer 70(R=C7H15)compared to the84%selectivity of the original HBEA tested in slurry.Since,in the solid acid-catalyzed acylation with carboxylic acids,inhibition of the active sites occurred due to water adsorption,a monolithic structured reactor could make it possible to remove water in situ by a stripping operation using a gas?ow through the reactor.The HBEA-coated monoliths could be reused after regeneration by washing with acetone,drying at 120°C(16h),and calcining at450°C for4h. The HZSM-5zeolite was utilized as catalyst in the acylation of anisole(64)with various linear carboxylic acids69(64/69ratio =4)(Scheme18),showing some interesting results.145As expected,a drop in activity from propanoic(92%)to stearic acid (0%)was observed;this order of activity,reversed to that previously described by Geneste39in the presence of REY zeo-lites,is evidently due to the small micropore size of HZSM-5,in which the formation of large product molecules was di?cult(in the case of pentanoic to octanoic acids)or impossible(in the case of longer chain carboxylic acids).Only two kinds of products were obtained in all experiments,namely,the4-acylanisoles70 and the carboxylic acid phenyl esters71.The selectivity for the C-acylated products70increased from0.5%with acetic acid to 80%with butanoic acid and then remained constant for C5àC7 acids.A great e?ect of temperature on both the conversion and selectivity of the reaction with acetic,propanoic,and butanoic acids was evidenced:phenyl esters71were mainly produced at lower temperature(<130°C),while at higher temperature (>130°C)4-acylanisoles70were the predominant products. Detailed studies on the characterization of acylating inter-mediates formed on HZSM-5with acetic acid,acetic anhydride, and acetyl chloride were performed.146In the case of acetic acid,the molecules are primarily hydrogen bonded to the Br€o nsted sites,whereas,in the case of acetic anhydride and acetyl chloride, a reaction easily occurs at the Br€o nsted sites,forming an acetyl-zeolite intermediate.The comparison of interaction between the Br€o nsted sites in HZSM-5and the three above-mentioned acylating reagents and other polar organic compounds,such as ketones,shows that molecules having a gas-phase proton a?nity equal to or greater than that of ammonia are protonated by HZSM-5;on the contrary,molecules that have a proton a?nity less than that of ammonia tend to form hydrogen bonds with Br€o nsted sites and the strength of the hydrogen bonding appears to vary in a regular manner with the proton a?nity of the adsorbate.These results lead the authors to the conclusion that the acylium-ion-like acetyl-zeolite intermediate is completely analogous to the carbenium-ion-like alkoxide intermediate formed at Br€o nsted acid sites by an alkylating reagent.In conclusion,HZSM-5is readily capable of forming the acy-lium-ion-like intermediates required for the FriedelàCrafts acylation reaction;the main problem of the reaction carried out with this catalyst is still the interaction of ketone products and byproducts with the catalyst active sites.These continuous interactions are well-known to produce coke in the zeolite, leading to deactivation of active sites.A possible way to over-come these problems should be the investigation of materials that are less acidic but more resistant to coke formation,such as HZSM-5zeolites containing Fe3tin place of Al3tin the framework,that are reported to e?ectively produce less coke in butene isomerization.147a Acylation of aromatic ethers with carboxylic acids smoothly proceeds at190à230°C in the presence of zeolite catalyst under microwave irradiation(maximum power300W)to e?ciently a?ord aromatic ketones.147b HY(30à80)and HBEA(40)zeo-lites were active for this acylation giving the aromatic ketones in good yields(Scheme19bis).Hexanoic and butyric acid smoothly underwent the acylation,while propanoic acid showed lower reactivity;anisole gave the para-acylation products nearly selectively.2,3-Dihydrobenzofuran also reacted at the para-position with respect to the oxygen atom,predominantly.The microwave assisted reactions were,in general, faster than the Figure6.Examples of a structured reactor packing:(a)monolithic packing;(b)wire gauze packing.Reprinted with permission from ref144.Copyright 2003Elsevier. Scheme19bis conventional oil bath heated reactions and gave higher yields in the acylation products. Corma et al.148showed that the activities of HY zeolites with di?erent levels of Natexchange in the acylation of anisole with phenylacetyl chloride(anisole/phenylacetyl chloride ratio=1) were independent of their acid strength distributions;on the contrary,a linear dependence between the Nat-exchange level of the zeolite and the initial rate for the ketone formation(r0)was observed(Figure7).The linearity suggests that all the acid sites with weak,medium,and strong acidity are active in the present reaction.This was also con?rmed by the small increase in the TON values(from73to90based on anisole)when the SAR framework changed from9to24,with the zeolites with higher silica content being slightly more active.This behavior can be explained by taking into account that hydrolysis and acylation are competitive processes,both being catalyzed by the zeolite. Since in the heterogeneous catalysis the real reaction medium is the solid surface,and the concentration of water is lower in the more dealuminated samples,it is expected that acylation be-comes comparatively favored over hydrolysis when more hydro-phobic catalysts are used.The results con?rm that a good catalyst does not need very strong acid sites,but a high-SAR framework is better in order to achieve an appreciable hydrophobicity and consequently a good catalytic performance. LaY zeolites showed enhanced activity with respect to the starting HY sample in the acylation of anisole with acetyl chloride and acetic anhydride(anisole/acylating agent ratio=140).149 The enhancement of the Br€o nsted acid strength of the LaY was attributed to the presence of La2t(OH)ions which may be formed during the calcination[La3t(H2O)n(O-zeolà)3f La2t-(H2O)n-1(OH)(O-zeolà)2tHO-zeol].150 Some attractive results deserving of further attention and development were reported by Wang et al.151concerning the acylation of anisole with alkanoic acids,alkanoic anhydrides,and aromatic carboxylic acids(anisole/acylating agent ratio=4)over di?erent HY and HZSM-5zeolites.Results achieved with one HZSM-5zeolite(SAR=60)and four HY zeolites(SAR= 5.8à18.4)in the acylation of anisole with propanoic acid showed an order of activity consistent with the order of the Lewis sites’strengths and opposite to the order of the Br€o nsted sites’strengths.The byproducts formed were phenyl propionate and 2-hydroxypropiophenone,originated respectively from the at-tack of the propionic acid at the oxygen atom of anisole and from the Fries rearrangement of phenyl propionate.C-acylation was preferentially catalyzed by Lewis acid sites,and instead,the esteri?cation reaction was promoted by strong Br€o nsted sites, which were at?rst absent in all HY zeolites but were produced from the Lewis acid sites by reaction with water coming from the carboxylic acid.The reaction showed a quite interesting synthetic application in the benzoylation of anisole with a series of substituted benzoic acids.In general,the substituted benzophe-nones were produced with satisfactory yield(20à80%);how-ever,a great e?ect of the substituent groups at the aromatic ring of the benzoic acid was observed:in particular,the conversion decreased when the electron-donating nature of the substituent decreased(for example:87%conversion of p-methoxybenzoic acid vs60%conversion of p-bromobenzoic acid). The limitation imposed by small pore dimensions could be overcome,as already observed in the acylation of arenes,by using MCM-41mesoporous materials.The preparation of mesopor-ous aluminosilicate MCM-41-type material was performed from HBEA zeolite seeds.152This catalyst was utilized in the acylation of anisole(64)with octanoyl chloride(72)(64/72ratio=45) (Scheme19)with the aim of improving the transport of the reactants,especially for the relatively hindered molecules such as 72.The catalyst showed a good activity,with product74being obtained in90%yield after1h.As commonly observed,the use of the carboxylic acid as acylating agent resulted in a slower process (～20%yield after26h)due to its lower electrophilicity and to the production of water that inhibits the active sites of the zeolite, as previously observed by Beers et al.144 The regioselective propanoylation of veratrole(75)to3,4-dimethoxypropiophenone(77)with propanoyl chloride(76) (75/76ratio=1)was explored by Singh et al.127over HBEA, HMOR,HY,and REY zeolites in comparison with AlCl3 (Scheme20,n=1).In all experiments,3,4-dimethoxypropio-phenone was the main product accompanied by small amounts of other(consecutive)https://www.doczj.com/doc/8b5041613.html,pared with AlCl3,all zeolites showed higher selectivity(90à100%vs70%),and HBEA catalyzed the reaction more e?ciently than other zeolite catalysts (40%vs10%veratrole conversion for HY).The catalyst could be recycled after washing with acetone and calcining at500°C for 16h in air;its activity,however,progressively decreased to a small extent on recycling,but the selectivity remained nearly unaf-fected(93.4%fresh catalyst,95.8%in the second cycle). The activities of some HY zeolites showing di?erent Lewis and Br€o nsted acid site densities were studied by Sartori et al.153in the acylation of dimethoxyarenes(with particular attention to vera-trole,Scheme20)with di?erent acyl chlorides(dimethoxyarene/ acyl chloride ratio=5)as a function of zeolite acidity and chain length and lipophilic nature of the acyl chlorides.Due to the particularly soft reaction conditions, 3,4-dimethoxyphenyl Scheme20 ketones77were the sole isomers recognized in the reaction mixture.Results of the catalytic tests(yield of compounds77) con?rm that the best catalyst was the HY zeolite with a SAR value of14,characterized by an optimum ratio between Lewis and Br€o nsted acidity(medium-strength acid site densities for Lewis and Br€o nsted acids=17.0and11.0mmol/g py respectively), whereas more strongly or weakly acidic materials gave lower yields.This evidence suggests that the reaction requires both a delicate balance between the Lewis and Br€o nsted acid sites and a low density of hydrophilic hydroxy groups that can strongly and preferentially interact with methoxy and carbonyl groups,result-ing in the pore-blocking by product molecules.The chain length e?ect of the acyl chloride on the ketone yields showed the typical trend already reported by Geneste et al.39 The remarkable e?ect of pore dimensions and structural properties on zeolite e?ciency was further con?rmed by Moreau et al.154,155in the acylation of veratrole with acetic and benzoic anhydrides(veratrole/anhydride ratio=1).The following r0 value order was observed with some commonly utilized zeolites: HY(0.125)>HBEA(0.050)>HMOR(0.015).These results can be directly related to the microporous structures of the di?erent catalysts,for which the pores of the tridimensional HY framework allow a readier di?usion of both substrate and product than those of the interconnected channel architecture of HBEA and those of the bidimensional HMOR framework. Extensive studies were carried out to investigate the electro-philic acylation of2MN(78)with acetic anhydride(2)in the presence of di?erent zeolites(Scheme21)mainly for two reasons:(i)2Ac6MN(83)represents,as underlined in the introduction of this section,a valuable intermediate in pharma-ceutical chemistry and(ii)reagent78represents a suitable model substrate since it can a?ord di?erent isomeric ketones via direct acylation or isomerization and consequently it makes it possible to evaluate the e?ect of the catalyst properties and experimental conditions on the regioselectivity of the reaction. Acetylation of78generally occurs at the kinetically controlled 1-position,leading to1-acetyl-2-methoxynaphthalene(1Ac2MN (80).However,over acid zeolites a di?erent product distribution was frequently obtained,mainly depending on the type of the framework,solvent,and temperature.156 In a series of independent studies the research groups of H€o lderich,157Guisnet,158à160and Lenarda161thoroughly inves-tigated the acetylation of2MN with acetic anhydride in the presence of HBEA zeolites with particular attention to the acid-treated materials.Concerning the special activity of HBEA,in addition to its generally large outer surface,157,162à164it pos-sesses particular acid properties related to local defects,i.e., aluminum atoms which are not fully coordinated to the framework.164à166The reactions performed over this catalyst showed a common behavior:initially,isomer80was largely predominant between the reaction products;however,it dis-appeared afterward at the bene?t of isomers83and,in a minor amount,86;the higher the reaction temperature,the faster this disappearance.This transformation is due both to direct isomer-ization of80into83and86and to deacetylation-transacetylation reactions in an intermolecular mechanism.From molecular modeling and analysis of the compounds entrapped in the zeolite pores during isomerization,Guisnet et al.160concluded that acetylation and isomerization mainly occurred inside the zeolite pores.2Ac6MN was obtained in80%yield at relatively high temperature(g170°C)and in the presence of a polar solvent such as nitrobenzene.The positive e?ect of solvent polarity was also exploited in the industrial acylation of2MN with a series of carboxylic acid anhydrides(C2àC5).167 H€o lderich et al.157deeply analyzed the in?uence of the acid pretreatment of HBEA on its activity in the model reaction between2MN and acetic anhydride.The contribution of the inner and outer surfaces of the catalyst was examined by considering the selectivity with respect to the bulky product 1Ac2MN and the linear product2Ac6MN,which were assumed to be formed on the outer surface and on both the inner and the outer surfaces,respectively,as also evidenced by the research groups of Fajula,168Davis,169and Lee.170Authors showed that the production of EFAL species located in the micropores of HBEA subjected to high heating rate calcination provoked the increase in the selectivity of the less hindered2Ac6MN since the formation of the bulky1Ac2MN was sterically hampered.On the contrary,acid treatment increased the catalytic activity of the outer surface due to the extraction of the catalytically active EFAL species out of the micropores,leading to the preferential formation of the bulky1Ac2MN. Competitive adsorption studies of a mixture of reagent78, product80,and sulfolane or1,2-dichlorobenzene over HBEA zeolite showed that compound80can be formed inside the pores by acetylation of78.Isomerization of80into83was also shown to occur inside the zeolite micropores,with the desorption of83 being slower than its production.Moreover,these experiments con?rmed that highly polar solvents such as sulfolane(E T= 0.410;r0=184mmol/h3g)limited the entrance into the zeolite micropores of reactant78(which is less polar)and hence the rate of the acetylation;on the contrary,solvents of intermediate polarity such as1,2-dichlorobenzene(E T=0.225;r0=224.5 mmol/h3g)favored the reaction,in good agreement with results reported by Guisnet et al.160 Acetyl chloride was tested in the comparative acylation of78 (78/acetyl chloride ratio=1)over HBEA,HY,and HMOR zeolites.171All three catalysts showed about30à40%conversion of78in sulfolane in the temperature range100à150°C.At 100°C HY showed higher activity than the other two catalysts. However,as the reaction temperature was raised to150°C,the initial high conversion dropped rapidly,indicating faster deacyla-tion of the primary product80.HBEA and HMOR zeolites also showed some deacylation at higher temperatures,but the drop in conversion was not as sharp as that observed with HY.At150°C yields of isomer83were found to be similar with all three catalysts(70à80%)due to the faster isomerization of compound 80. The SAR value,which directly a?ects some properties of the zeolite,such as the surface polarity,lipophilicity,and acidity,is expected to play a major role in the distribution of isomers80,83, and86in the reaction between2MN(78)and acetic anhydride2 (78/2ratio=0.5).In a comparative study with three HY zeolites, namely,HY-15,HY-40,and HY-100,an increase of the initial activity was observed with the increase of the SAR value.172 Scheme21 These results con?rm that the activity does not come from an increase of the acid strength of the catalyst173and suggest,in agreement with some conclusions by Corma,148that the catalytic activity could be better related to a more hydrophobic character of dealuminated HY zeolites.In all cases,the reaction led to the formation of compound80as major product(95%yield),83 (obtained only up to4%yield),and traces of86.These products were formed by a parallel reaction since the80/83ratio remained constant to a value of24even after24h. Acylation of78with di?erent anhydrides(78/anhydride ratio =2)at low temperature(100°C)in the presence of the moderately protic acid MCM-41mesoporous zeolite was studied by van Bekkum et al.174a The selectivity for isomer80was practically100%with the less bulky acetic anhydride whereas with the more bulky isobutyric anhydride a small amount of isomer85was produced.At higher temperature(～130°C)the reversibility of the acylation at the1-position played a funda-mental role in the distribution of products and a decrease in the selectivity for the1-position was observed.The catalyst could be recycled three times;after each cycle,the catalyst was?ltered, washed,dried,and reactivated by calcination for2days at450°C, showing quite similar conversion(～40%)and selectivity (～97%)with respect to isomer80. H€o lderich et al.studied the acylation of2MN with acetic anhydride over Na?on/silica composite(SAC5-80)ion-ex-changed with Lewis acids.174b The higher the Na?on content, the higher conversion and selectivity(up to69%)to the desired 2Ac6MN.Unpolar solvents such as toluene or methylene chloride favor the formation of1Ac2MN,while polar solvents such as nitrobenzene or sulfolane promote the2Ac6MN forma-tion.The di?erence between SAC-13in the Htform and the metal-exchanged SAC-13was in the ratio between the selectivity of2Ac6MN and1-acetyl-7-methoxynaphthalene(1Ac7MN). The best results in terms of selectivity toward2Ac6MN were achieved with SAC-80(Cu)(49%)and SAC-80(Ag)(69%). The tridimensional large pore zeolite named ITQ-7was formerly prepared in the silica form not useful in catalysis.175 More recently,Corma et al.176developed a methodology to perform the synthesis of ITQ-7with di?erent T III and T IV elements isomorphically incorporated into the framework,such as Al-ITQ-7;this zeolite has two channels of6.2??6.1?and a third one of6.3??6.1?,which are smaller than the two major channels of the HBEA zeolite(7.2??6.2?).Al-ITQ-7was studied as a catalyst in the reaction of Scheme21(R=Me)(78/2 ratio=2)in comparison with HBEA.177,178Both catalysts showed quite similar activity(～70%2MN conversion),but Al-ITQ-7decays much faster due to its smaller pore dimension. 3.2.Acylation with Clays Thermally activated rare-earth chlorides or oxychlorides de-posited on clays and silica showed high activity in the acylation of aromatic ethers with acyl chlorides(aromatic ether/acyl chloride ratio=0.6).179Among the supports used,K10montmorillonite gave the more e?ective catalysts,as the clay itself has its own activity.All the rare-earth-supported catalysts were active in the benzoylation of anisole;ScK10showed the best activity(～98% anisole conversion in20h),whereas the untreated K10mon-tmorillonite showed a good anisole conversion(～95%)but with a lower reaction rate(～60h). Envirocat EPIC(commercially available FeCl3-exchanged montmorillonite)was utilized as a catalyst for the benzoylation of anisole with aromatic carboxylic acids(anisole/aromatic carboxylic acid ratio=35).180The reaction showed limited applicability,with the yield ranging from20to70%.No information is reported on the possible recycling of the catalyst and on the leaching phenomena. Yadav et al.181,182compared the activity of ZnK10with those of some cesium-substituted HPAs on K10clay(CsHPAK10)in the acylation of anisole(64)with benzoyl chloride(21)(64/21 ratio=7)(Scheme19).p-Methoxybenzophenone was the sole iso-mer produced,and ZnK10showed the higher activity;nevertheless, the reusability of this catalyst was found to be unfavorable,whereas the CsHPAK10catalyst showed an excellent reusability for at least three times(36,35,and33%anisole conversion for each cycle). Choudary et al.79,80,183described the preparation of cation-exchanged clays and their use in FriedelàCrafts acylation of aromatic ethers with anhydrides(aromatic ether/anhydride ratio =0.5).The best results were obtained with Fe3t-and Zn2t-exchanged clays.In the case of the reaction of2MN(78)with acetic anhydride(2)(Scheme21),1Ac2MN(80)was selectively formed and only small amounts of the thermodynamically favored6Ac2MN(83)were produced(82%yield,90%1Ac2MN selectivity,8%6Ac2MN selectivity).The higher activity of Fe3t-and Zn2t-exchanged montmorillonites can be ascribed to the synergistic e?ect of Br€o nsted and Lewis acidities. A further application of metal-exchanged K10clay is repre-sented by the preparation of ketones of benzo crown ethers by reaction of crown ether89with acetyl chloride(34)184(89/34 ratio=0.2)(Scheme22).The best catalyst in the reaction was SnK10,which a?orded product90in90%yield after30min.The redox mechanism depicted in Scheme7could represent an alternative pathway for the formation of acyl cation,that can account for the higher activity of the SnK10. 3.3.Acylation with Metal Oxides The regioselective acylation of aromatic ethers with carboxylic acids(aromatic ether/carboxylic acid ratio=1)was performed in the presence of an equimolecular mixture of tri?uoroacetic anhydride adsorbed on the surface of alumina without any solvent.185The process could be applied,with nearly quantitative yields,to anisole and the three isomeric dimethoxybenzenes by using cyclic and C2àC16linear carboxylic acids.Authors outlined that in the case of anisole the acylation occurred selectively at the position para to the methoxy group.The reaction required a large amount of alumina and tri?uoroacetic anhydride,and conse-quently,it could only be applied at the laboratory scale. A merely synthetic application was reported concerning the acylation of aromatic ethers with acyl chlorides(aromatic ether/ acyl chloride ratio=1)in the presence of hydrated zirconia.186 Thus,anisole,2-methoxynaphthalene,and3,5-dimethoxyto-luene were reacted with acetyl or benzoyl chloride in the presence of zirconium oxide.The corresponding ketones were produced in60à80%yield.Unfortunately,no comments are made concerning the isomeric distribution. Scheme22 Mixed oxides WO3/ZrO2showed catalytic activity in the acetylation of anisole with acetic anhydride(anisole/acetic anhydride ratio=9).187a These catalysts have both Br€o nsted and Lewis acid sites;the maximum Br€o nsted acidity and catalytic activity was achieved with a WO3loading of19wt%.The highest conversion(89%with92%selectivity)was obtained when the reaction was carried out at100°C;higher reaction temperature and increasing the WO3loading on ZrO2resulted in a lower activity. P2O5/SiO2catalyst,simply prepared by mixing equal amounts of the two reagents at room temperature,can be e?ciently used for the acylation of methoxyarenes.86b The reactions were performed by re?uxing for1à5h an excess of the liquid aromatic reagent,the carboxylic acid,and the solid catalyst;in a few cases methylene chloride was utilized as solvent.Aromatic ketones were obtained in satisfactory to good yields according to the reactivity rules of the electrophilic substitution.Lower yields were obtained by performing the reaction with P2O5alone.The positive e?ect of the support is probably due to the dispersion of P2O5on the surface of the silica. Quite similar results were achieved by using a mixture of P2O5 and alumina.187b Similar solid acid catalysts WO3/ZrO2,pre-pared by wet impregnation method using zirconium dichloride and ammonium metatungstate,were utilized in the acylation of veratrole with acetic anhydride.187b The most active catalyst, which contains15wt%of WO3calcined at800°C,gave67% conversion of acetic anhydride at70°C with a veratrole/ acylating agent=2and a reaction time of4h.The catalyst was reused without appreciable loss of activity by calcination. 3.4.Acylation with Acid-Treated Metal Oxides SZ was reported by Deutsch et al.188to show high perfor-mance in the acylation of anisole with benzoic anhydride or benzoyl chloride(anisole/acylating agent ratio=10).The authors compared the activity of several solid acid catalysts in the reaction with benzoic anhydride(42)(Scheme16).They showed that SZ exhibited a dramatically higher activity with respect to those of HBEA and HMOR;in addition,they found that the performance of SZ in the reaction of the sterically demanding benzoic anhydride was less dependent on the acidity level and more dependent on the pore https://www.doczj.com/doc/8b5041613.html,parative experiments surprisingly con?rmed that benzoyl chloride(21) (Scheme19)(yield of73t66=52%)was less active than benzoic anhydride(yield of73t66≈100%);this result would require further investigations.However,the method showed synthetic utility since the anisole acylation with carboxylic acid anhydrides and chlorides(anisole/acylating agent ratio=10) over SZ189à192a a?orded the corresponding ketones in88à96% yield and94à99%selectivity. Signoretto et al.showed that in the benzoylation of anisole with benzoic anhydride catalyzed by SZ,the calcination tem-perature as well as the precipitation pH applied in the preparation of the catalyst played an important role in the catalyst activity.192b Thus,calcination at temperatures higher than550°C resulted in a nearly quantitative conversion of anhydride,with a70à80% selectivity and a o/p ratio=97:3;lower temperatures led to incomplete conversion.The precipitation pH had a minor in?uence,pH10being slightly better than pH8in terms of yield(70and64%yield,respectively).Activation temperature was demonstrated to have a strong e?ect on the selectivity:lower activation temperatures(150à300°C)led to catalysts able to promote high benzoic anhydride hydrolysis rate at the expense of the acylation(～30%yield).On the contrary,73%yield was achieved with a catalyst activated at450°C.The di?erent catalytic activity is related to the combination of di?erent phenomena such as physisorbed water elimination,dehydroxyla-tion,sulphating agent decomposition,phase transition and sulfate species removal. According to the positive results achieved with di?erent solid catalysts,the metal ion doping of SZ was tried with the aim of improving the catalytic performance of the parent material.Thus, the so-called metal-promoted SZs were prepared by impregna-tion of SZ with a solution of the selected metal salt.Iron-promoted SZ samples were synthesized by freeze-drying as well as by conventional and aerogel synthesis followed by impregna-tion with Fe(NO3)3and Mn(NO3)2,and their catalytic e?ciency was evaluated in the anisole(64)acylation with benzoyl chloride (21)(64/21ratio=40)(Scheme19).193Besides the ketones, benzoic acid and phenyl benzoate were formed as side products; p-and o-methoxybenzophenones were obtained in95and5% selectivity.Again,pure zirconia was catalytically inactive,and all modi?ed samples showed good acylation activity(68à85% yield).This catalytic behavior might be mainly due to the large pore volume.An increase of the catalytic activity of SZ was also observed after promotion with iron(63vs42%anisole con-version),whereas no such e?ect was observed for manganese-promoted samples(41%anisole conversion).The product inhibition and coke deposition still represent the major drawback of these catalysts;194a nevertheless,the catalytic activity of the spent SZ could be completely restored by burning o?the deposited carbonaceous materials. SZs supported on MCM-41silica promoted with metal oxides (Ga2O3and Fe2O3)were employed in the catalytic acylation of veratrole with acetic anhydride.194b In the preparation of the catalyst,SZ was supported on MCM-41silica by incipient wetness impregnation.The metal promoted catalysts were prepared by impregnation of MCM-41silica with a methanol solution of Zr(SO4)2and M(NO3)339H2O(M=Ga or Fe).All catalysts were active in the mentioned reaction(70à78%yield, 88à93%selectivity).A marked enhancement in catalytic activity was observed as the veratrole/anhydride molar ratio was in-creased.For example,with the gallium-promoted catalyst,at a molar ratio5:1,the anhydride conversion was72%after3h reaction;as the molar ratio was increased to20:1,the conversion was complete after30min.The gallium-promoted catalyst was the best catalyst beause of the presence of Lewis acid sites,absent in the sample promoted by iron oxide.On the other hand,the presence of Fe2O3was important because it enhances the redox properties of the catalytic system,allowing the complete restora-tion of the catalytic activity by calcination at450°C even after three catalytic runs. Kemnitz et al.195reported the preparation and use of borate zirconia catalyst(B2O3/ZrO2),prepared from zirconyl nitrate and boric acid,in the same reaction(64/21ratio=0.8).Phenyl benzoate,formed by O-benzoylation,was still found to be the major side product.The activity of the catalyst was almost constant during three cycles(data not reported).It was found that the stronger surface acid sites were mainly responsible for the catalytic reaction and the weaker sites were active at higher reaction temperatures.The advantage of B2O3/ZrO2over SZ may be that it is a suitable catalyst because of the presence of weaker surface sites that lead to a longer catalyst life.There is also evidence to con?rm the assumption that the acylation occurred exclusively at Br€o nsted acid sites which can activate the acylating agent through a hydrogen bond(Figure8).In fact,by comparing acylation with1-butene isomerization as a probe of Br€o nsted acid-catalyzed reactions,high catalytic activity in the acylation was observed for samples that showed high conversion degrees in the1-butene isomerization.Therefore,it can be concluded that both reactions take place on the same kind of acid sites of the SZ sample used. The acylation1-methoxynaphthalene(1MN)with acetic anhydride(1MN/acetic anhydride ratio=0.5)was performed by Deutsch et al.196in the presence of SZ.The catalyst exhibited a higher performance than other mesoporous solid acids such as Cs2.5H0.5[PW12O40],Na?on on SiO2,Amberlyst-15,and K10. Indeed,1-acetyl-4-methoxynaphthalene was isolated in nearly quantitative yield after3h.The formation of very reactive acylating species and thermodynamically favored leaving groups on the catalyst surface may explain the high catalytic performa-nces of SZ. Sulfonic acids supported on mesostructured SBA-15silica were studied as catalysts in the acylation of anisole and2MN with acetic anhydride(aromatic ether/acetic anhydride ratio= 0.95).197a The catalysts were prepared by hydrolyzing a mixture of TEOS and3-mercaptopropyl trimethoxysilane in the presence of hydrogen peroxide.These catalysts showed a greater activity as compared to those of other homogeneous and heterogeneous sulfonated materials.The selectivity toward p-methoxyacetophe-none was higher than95%for all catalysts regardless of the pore size,showing that it would not be the consequence of a shape selectivity e?ect but rather that of the speci?c anisole reactivity. The supported catalysts displayed the highest activity(TON= 85à93)with respect to both heterogeneous Amberlyst-15 (TON=40)and homogeneous p-toluenesulfonic acid (TON=5)catalysts.The signi?cant decrease of conversion rate per acid center observed with Amberlyst-15could be related to the low accessibility of the acid sites arising from its low speci?c surface area(45m2/g). High activity in the acylation of anisole with acetic anhydride has been observed by using propylsulphonic acid supported on MCM-41mesoporous silica as catalyst.197b The catalyst was produced through a solàgel method by using a mixture of TEOS and bis(3-trimethoxysilylpropyl)tetrasul?de followed by oxida-tion with bromine/hydrogen chloride.The material showed a mesoporous highly ordered structure.The anisole conversion was98%,accompanied by the same yield of p-methoxyaceto-phenone.Lower activity was observed in the same reaction performed with a catalyst produced by using a mixture of TEOS and mercaptopropyl trimethoxysilane followed by oxidation (68%conversion,65%yield). In a comparative study,di?erent solàgel silica immobilized tri?ate compounds such as La(OTf)3,tert-butyldimethylsilyl tro?uoromethanesulfonate(BDMST)and tri?ic acid(TfOH) were tested in the acylation of2MN with acetic anhydride (Scheme21)leading to1Ac2MN as the major product.197c The reaction proceeded with good yield only on silica supported BDMST and TfOH.In particular,the reaction performed at 50°C for4h in the presence of silica supported BDMST(30mg for5mmol of2MN)without solvent a?orded1Ac2MN with 89%conversion and98%selectivity.Quite interestingly,the TOF was superior to that reported in the literature for other heterogeneous catalysts and even for homogeneous tri?ates. An e?cient MCM-41-based catalyst(SO42à/Al-MCM-41) was set up by impregnating sulfuric acid on Al-MCM-41;198a this composite material showed a good catalytic e?ciency in the preparation of2Ac6MN(83)by acetylation of78with acetic anhydride(2)(78/2ratio=1à0.25)(Scheme21),giving a 43.3%yield of83and a60%conversion of reagent78. 3.5.Acylation with Heteropoly Acids The sustainable heterogeneous acid catalysis by HPAs in di?erent carbonàcarbon bond forming reactions,including electrophilic acylation of aromatics and oxidations,has been recently reviewed by Kozhevnikov.198b The acylation of anisole with C2àC12carboxylic acids (anisole/carboxylic acid ratio=1)was carried out with HPAs and multicomponent polyoxometalates a?ording the corre-sponding products in62à65%yield.These solid acids were superior in activity to the conventional acid catalysts such as sulfuric acid and zeolites.The HPA catalysts could be reused after a simple workup,albeit with reduced activity.110,199 Silica-supported HPA catalysts were also studied in the acylation of anisole with acetic anhydride(anisole/acetic anhy-dride ratio=0.33),200a showing very high anisole conversion (～90%)combined with high selectivity in p-methoxyacetophe-none(90%).Nevertheless,the catalyst seemed to deactivate after 0.5h.Cleaning the spent catalyst by washing with dichloro-methane restored its activity,indicating that the active HPA was not fairly leached from the silica support;however,a slower but progressive coking completely deactivated the catalyst. The silica-supported HPA with a loading of30wt% (HPW30),prepared using an incipient wetness method by slurring the phosphono-12-tungstic acid with silica,has been compared with the lanthanum-exchanged HYzeolite(LaY)and SZ in the model acylation of anisole with dodecanoic acid under conventional heating and microwave stimulation.200b The micro-wave irradiated experiments exhibited increased reaction rates, the extent of which was dependent upon the nature of the catalyst and in general the activity order was HPW30>SZ>LaY under microwave irradiation and HPW30>LaY>SZ under conven-tional heating.The origin of the microwave enhancement has been attributed to the selective desorption of water from the surface of the catalyst. The activities of two HPA catalysts,one supported on a commercial silica(HPA/SiO2)and the other supported on a silica-zirconia mixed oxide(HPA/SiZr),were compared in the same reaction(anisole/acetic anhydride ratio=10).201Both supported catalysts and the SiZr support were active,even if the maximum yield(65%)was observed with HPA/SiO2,whereas low yields(～20%)were obtained with SiZr and HPA/SiZr. Di?erences in the nature and number of the acid sites were recognized,and dispersion of HPA over the silica surface resulted in the generation of a catalyst possessing Br€o nsted acid proper-ties.However,addition of HPA to a support with inherent Lewis and Br€o nsted acid properties modi?es the number and distribu-tion of the acid sites usually by increasing their number and Figure8.Hydrogen bond activation of acyl chloride by Br€o nsted sites of SZ. 第四章酰化技术 本章教学设计 工作任务 通过本章的学习及本课程实训,完成以下三个方面的工作任务: 1、围绕典型产品的生产过程,完成以羧酸、羧酸酯为酰化剂制备酰胺类产品; 2、围绕典型药品生产过程,完成以酸酐、酰氯为酰化剂生产酰胺类产品; 3、围绕典型药物的生产过程,完成用羧酸法、酯交换法、酸酐法、酰氯法生产酯类产品。 学习目标 1、掌握羧酸、羧酸酯、酸酐、酰氯酰化剂的特点、适用范围、使用条件及其N-酰化、酯化中的应用; 2、掌握根据不同的被酰化物,正确选择酰化剂、反应条件的方法; 3、掌握生产中操作及注意事项; 4、掌握Friedel-Crafts酰化反应的基本原理、影响因素以及在药物合成中的应用,在生产中的应用及注意事项 5、理解Hoesch反应、Gattermann反应、Vilsmeier反应的用途、适用条件及在药物合成中的应用; 6、掌握活性亚甲基化合物α位C-酰化的原理、使用条件及在药物合成中的应用; 7、了解新型酰化剂及其在医药科研、生产中的新技术与应用 学时安排 课堂教学10学时 现场教学6学时 实训项目 项目一:对氯苯甲酰苯甲酸的制备 项目二:扑热息痛的制备 项目三:草酸二乙酯的制备 学习目标 ● 掌握羧酸酰化剂、羧酸酯酰化剂的特点、适用范围、使用条件及其N-酰化中的应用; ● 掌握根据不同的被酰化物,正确选择酰化剂、反应条件的方法。 ● 掌握生产中操作及注意事项 ● 了解新型酰化剂及其在医药科研、生产中的新技术与应用 第四章 酰化技术 第一节 概述 一、酰化反应 1． 概念 酰化反应就是指有机物分子中与氧、氮、碳、硫等原子相连的氢被酰基取代的反应。酰基 就是指从含氧的有机酸、无机酸或磺酸等分子中脱去羟基后所剩余的基团。 2． 反应通式 R Z O R S O H Z (式中RCOZ 为酰化剂,Z 代表X,OCOR,OH,OR ˊ,NHR ″等;SH 为被酰化物,S 代表R ˊO 、R ″、Ar 等。)二、常用酰化剂及其活性 ★1.常用酰化剂:羧酸、羧酸酯、酸酐、酰氯等酰化剂的活性规律:当酰化剂(RCOZ)中R 基相同时,其酰化能力随Z —的离去能力增大而增加(即酰化剂的酰化能力随离去基团的稳定性增加而增大)★常用酰化试剂的酰化能力强弱顺序:酰氯 >酸酐 > 羧酸酯 > 羧酸 > 酰胺 三、酰化反应在化学制药中的应用 永久性酰化 制备含有某些官能团的药物 保护性酰化 第二节 N-酰化 常用酰化剂:羧酸酰化剂、羧酸酯酰化剂、酸酐酰化剂与酰氯酰化剂 一、羧酸酰化剂 1、反应过程 氟氯取代苯胺类酰基硫脲衍生物的结构、性质及相互作用研究本文以相转移催化法合成了 14种氟氯取代的酰基硫脲衍生物,除化合物Ⅷ外,其他物质均未见文献报道。通过元素分析、红外光谱、核磁1H、13C谱和X-射线单晶衍射技术对产物进行了结构鉴定,并得到了 10个化合物的单晶结构。 具体如下:单晶:系列一:Ⅰ N-(4-甲基苯甲酰基)-N’-(2,3-二氟苯基)硫脲Ⅱ N-(3-甲基苯甲酰基)-N’-(2,3-二氟苯基)硫脲Ⅳ N-(3-甲基苯甲酰基)-N’-(2,3,4-三氟苯基)硫脲Ⅴ N-(2-甲基苯甲酰基)-N’-(2,3,4-三氟苯基)硫脲ⅥN-(3-甲氧基苯甲酰基)-N’-(2,3-二氟苯基)硫脲系列二:Ⅸ N-(4-甲基苯甲酰基)N’-(4-氯-3-三氟甲基苯基)硫脲Ⅹ N-(3-甲基苯甲酰基)-N’-(4-氯-3-三氟甲基苯基)硫脲Ⅺ N-(2-甲基苯甲酰基)-N’-(4-氯-3-三氟甲基苯基)硫脲ⅩⅢ N-(4-氯苯甲酰基)-N’-(4-氯-3-三氟甲基苯基)硫脲ⅩⅣ N-(4-溴苯甲酰基)-N’-(4-氯-3-三氟甲基苯基)硫脲粉末:系列一:Ⅲ N-(2-甲基苯甲酰基)-N’-(2,3-二氟苯基)硫脲Ⅶ N-(4-氯苯甲酰基)-N’-(2,3-二氟苯基)硫脲Ⅷ N-(4-氯苯甲酰基)-N’-(2,3-二甲基苯基)硫脲系列二:Ⅻ N-(4-氟苯甲酰基)-N’-(4-氯-3-三氟甲基苯基)硫脲从获得的单晶结构数据,分析比较了酰基硫脲衍生物的结构参数、中心基团(-CO-NH-CS-NH-)的构象、空间堆积方式以及分子间相互作用等。并通过引入Hirshfeld表面以及相应的二维指纹图进一步研究了硫脲分子间的弱相互作用。 结果表明,硫脲衍生物中存在着C-H…S、N-H…S和C-H…F等氢键相互作用和π-π堆积作用,除此之外还存在如H…H、C…H、C…S、F…C1和C1…H等弱相互作用。这些相互弱相互作用能够显著增加酰基硫脲衍生物的抗真菌活性。 另一方面,通过菌丝生长速率法和分子对接技术,筛选出具有良好抗真菌活 第七章 多环芳烃 1、 联苯及其衍生物 2、 稠环芳烃：萘、蒽、菲及其衍生物的结构和化学性质 1、 芳香体系与休克尔规则 基本要求： 1.熟练掌握稠环芳烃萘蒽等衍生物的命名。 2.熟练掌握萘的化学性质及萘环上亲电取代产物的定位规律。 3.掌握H ückel 规则，理解芳香性的概念，能应用H ückel 规则判断环状化合物的芳香性。 分子中含有多个苯环的烃称作多环芳烃。多环芳烃可分如下三种： 联苯和联多苯类：这类多环芳烃分子中有两个或两个以上的苯环直接以单键相联结。 稠环芳烃：这类多环芳烃分子中有两个或两个以上的苯环以共用两个碳原子的方式相互稠合。 多苯代脂肪类：这类多环芳烃可看作是脂肪烃中两个或两个以上的氢原子被苯基取代。 7.1联苯及其衍生物 联苯是两个苯环通过单键直接连接起来的二环芳烃。 其结构为： 联苯为无色晶体，熔点70℃，沸点254℃。不溶于水而溶于有机溶剂。因其沸点高和具有很好的热稳定性，所以工业上常用它作热传导介质（热载体）。 联苯的化学性质与苯相似，在两个苯环上均可发生磺化、硝化等取代反应。联苯环上碳原子的位置采用下列所示的编号来表示： 联苯可看作是苯的一个氢原子被苯基取代，而苯基是邻对位定位基，所以，当联苯发生取代反应时，取代基进入苯的对邻位和对位。但由于邻位上的空间位阻较大，主要生成对位产物。 7.2稠环芳烃 有多个苯环共用两个或多个碳原子稠合而成的芳烃称为稠环芳烃。简单的稠环芳烃如萘、蒽、菲等。稠环芳烃最重要的是萘。 7.2.1萘(naphthalene) 萘的结构:平面结构，所有的碳原子都是sp 2杂化的，是大π键体系。 分子中十个碳原子不是等同的，为了区别，对其编号如下： 萘的一元取代物只有两种，二元取代物两取代基相同时有10种，不同时有14种。 萘的物理性质：萘是白色晶体，熔点80.5℃，沸点218℃，有特殊气味，易升华，不溶于水，易溶于热的气醇及乙醚，常用作防柱剂。萘在染料合成中应用很广，大部分用于制造邻苯二甲酸酐。 12345678109αβααα βββ1、4、5、8位又称为 位αβ2、3、6、7位又称为 位电荷密度αβ> 傅-克反应 傅里德-克拉夫茨反应，简称傅-克反应，是一类芳香族亲电取代反应，1877 年由法国化学家查尔斯傅里德(Friedel C)和美国化学家詹姆斯克拉夫茨(Crafts J)共同发现。该反应主要分为两类：烷基化反应和酰基化反应。 (* ch° gj * Mc, 傅-克反应:(1)傅-克烷基化反应；(2)傅-克酰基化反应 傅-克烷基化反应 傅-克烷基化反应在强路易斯酸的催化下使用卤代轻对一个芳环进行烷基化。 假设使用无水氯化铁作为催化剂，在氯化铁的作用下，卤代物产生碳正离子，碳正离子进攻苯环并取代环上的氢，最后产生烷基芳香族化合物和氯化氢。总反应式如下： 傅-克烷基化机理 这类反应有个严重缺点：由丁烷基侧链的供电性，反应产物比起原料具有更高的亲核性，丁是产物苯环上的另一个氢继续被烷基所取代，导致了过烷基化现象而形成了众多副产物。由丁这类反应是可逆的，还可能出现烷基被其他基团所取代的副产物(例如被氢取代时，也称为傅-克脱烷基化反应);另外长时间的反应也会导致基团的移位，通常是转移至空间位阻较小、热力学稳定的问位产物。另外如果氯不是处丁三级碳原子(叔碳原子)上，还有可能发生碳正离子重排反应，而这取决丁碳正离子的稳定性：即三级碳＞二级碳＞一级碳。空间位阻效应可以被利用丁限制烷基化的数量，比如1, 4-二甲氧基苯的叔丁基化反应。 1,4-二甲氧基苯的叔丁基化 烷基化的底物并不局限丁卤代轻类,傅-克烷基化可以使用任何的碳正离子中问体参与反应，如一些烯轻，质子酸，路易斯酸，烯酮，环氧化合物的衍生物。如合成1-氯-2-甲基-2-苯基丙烷就可以从苯与3-氯-2-甲基丙烯进行反应： 1-氯-2-甲基-2-苯基丙烷的合成 通过烯轻的傅-克烷基化 在这个反应中三氟甲磺酸使被认为在卤离子形成中活化了NBS的供卤素能 力。 傅-克去烷基化反应 傅-克烷基化是一个可逆反应。在逆向傅-克反应或者称之为傅-克去烷基化反应当中烷基可以在质子或者路易斯酸的存在下去除。例如，在用漠乙烷对苯的多 重取代当中，由丁烷基是一个活化基团，原来期待能够得到邻对位取代的产物。然而真正的反应产物是1,3,5-三乙基苯，即所有烷基取代都是问位取代。热力学反应控制使得该反应产生了热力学上更稳定的问位产物。通过化学平衡，问位产 物比起邻对位产物降低了空间位阻。因此反应最终的产物是一系列烷基化与去烷基化共同作用的结果。 1,3,5-三乙基苯的合成 傅-克酰基化反应 傅-克酰基化反应是在强路易斯酸做催化剂条件下，让酰氯与苯环进行酰化的反应。此反应还可以使用埃酸酎作为酰化试剂，反应条件类似丁烷基化反应的条 傅克反应 傅-克反应 傅里德-克拉夫茨反应，简称傅-克反应，是一类芳香族亲电取代反应，1877年由法国化学家查尔斯·傅里德（Friedel C）和美国化学家詹姆斯·克拉夫茨（Crafts J）共同发现。该反应主要分为两类：烷基化反应和酰基化反应。 傅-克反应:(1)傅-克烷基化反应;(2)傅-克酰基化反应 傅-克烷基化反应 傅-克烷基化反应在强路易斯酸的催化下使用卤代烃对一个芳环进行烷基化。假设使用无水氯化铁作为催化剂，在氯化铁的作用下，卤代物产生碳正离子，碳正离子进攻苯环并取代环上的氢，最后产生烷基芳香族化合物和氯化氢。总反应式如下： 傅-克烷基化机理 这类反应有个严重缺点：由于烷基侧链的供电性，反应产物比起原料具有更高的亲核性，于是产物苯环上的另一个氢继续被烷基所取代，导致了过烷基化现象而形成了众多副产物。由于这类反应是可逆的，还可能出现烷基被其他基团所取代的副产物（例如被氢取代时，也称为傅-克脱烷基化反应）；另外长时间的反应也会导致基团的移位，通常是转移至空间位阻较小、热力学稳定的间位产物。另外如果氯不是处于三级碳原子（叔碳原子）上，还有可能发生碳正离子重排反应，而这取决于碳正离子的稳定性：即三级碳>二级碳>一级碳。空间位阻效应可以被利用于限制烷基化的数量，比如1，4-二甲氧基苯的叔丁基化反应。 1,4-二甲氧基苯的叔丁基化 烷基化的底物并不局限于卤代烃类，傅-克烷基化可以使用任何的碳正离子中间体参与反应，如一些烯烃，质子酸，路易斯酸，烯酮，环氧化合物的衍生物。如合成1-氯-2-甲基-2-苯基丙烷就可以从苯与3-氯-2-甲基丙烯进行反应: 1-氯-2-甲基-2-苯基丙烷的合成 曾有研究实例表明亲电试剂还能选用由烯烃和NBS生成的溴离子。 通过烯烃的傅-克烷基化 在这个反应中三氟甲磺酸钐被认为在卤离子形成中活化了NBS的供卤素能力。 傅-克去烷基化反应 傅-克烷基化是一个可逆反应。在逆向傅-克反应或者称之为傅-克去烷基化反应当中烷基可以在质子或者路易斯酸的存在下去除。例如，在用溴乙烷对苯的多重取代当中，由于烷基是一个活化基团，原来期待能够得到邻对位取代的产物。然而真正的反应产物是1,3,5-三乙基苯，即所有烷基取代都是间位取代。热力学反应控制使得该反应产生了热力学上更稳定的间位产物。通过化学平衡，间位产物比起邻对位产物降低了空间位阻。因此反应最终的产物是一系列烷基化与去烷基化共同作用的结果。 教学目标：了解键状共轭多烯烃的电环化反应 教学重点：共轭二烯烃电环化反应的特点 教学按排：F >F24;45min 19— 在化学反应过程中，化学键的断裂和形成同步进行的反应称做协同反应，通过环状过渡态的协同反应又称做周环反应。周环反应有两个特点：第一，反应受加热或光照制约，加热和光照的反应结果不同，不受极性溶剂、试剂、酸、碱、催化剂和自由基引发剂的影响；第二，产物有高度的立体选择（立体专属）性。产物的立体化学只与反应物的结构和加热或光照有关。 链状共轭多烯烃两端的π电子形成一个σ-键，其余的π电子进行相应地组合，形成环状不饱和化合物的反应或其逆反应称为电环化反应，电环化反应属周环反应。 一、共轭二烯的电环化反应 1,3-丁二烯在热或光的作用下发生电环化反应都得到环烯。而两端二取代共轭二烯烃在热或光作用下，得到收式或反式环丁烯。例如： （2Z,4E）-2,4-己二烯在热作用下得到顺-3,4-二甲基环丁烯；在光作用下得到反-3,4-二甲基环丁烯。(E，E)-2,4-己二烯在热作用下，得反-3,4-二甲基环丁烯，在光作用下得顺-3,4-二甲基环丁烯，两者的结果相反: 二、电环倾反应机理 1．分子轨道对称守恒原理 伍德和霍夫曼提出化学反应的分子轨道对称守恒原理认为：化学反应是分子轨道重亲组合的过程，对一些由分子轨道的对称性控制反应进行的周环反应过程来说，反应过程中分子轨道的对称性必须是守恒的，即反应分子轨道的对称性必须与产物分子轨道的对称性保持一致，才能容易进行，称为对称性允许，反之，不能保持一致，反应就难进行或不能进行，称为对称性禁阻。 2．分子前沿轨道学说 化学家福井谦一根据形成分子时只有原子介电子变化的概念，提出化学反应与分子前沿轨道有关的分子前沿轨道学说：在化学反应中，分子轨道要重新组合，这种组合主要发生在分子前沿轨道上，即发生在HOMO和LUMO之间。 分子前沿轨道学说和分子轨道对称守恒原理，是近代有机化学理论研究的重大成果之一，获得诺贝尔化学奖，这两个理论结合揭示了周环反应的机理问题。 3．电环化反应机理 在电环化反应中，共轭二烯的两端碳原子的P轨道变成环烯烃的σ键，因此应考察这两个P轨道在反应过程中的对称性与σ键的对称性。2,4-己二烯的π分子轨道与1,3-丁二烯的π分子轨道相同： 2,4-己二烯的π电子轨道图 热反应只与基态有关，在反应过程中起关键作用的是HOMO轨道ψ 2。 第 七 章 甾体类化合物 甾体——化学结构中都具有甾体母核----环戊烷骈多氢菲。 甾体类在结构中都具有环戊烷骈多氢菲的甾核。甾类是通过甲戊二羟酸的生物合成途径转化而来。 天然甾类化合物的分类 C 21甾: 是含有21个碳的甾体衍生物。以孕甾烷或其异构体为基本骨架。 C 5、C 6——多具双键 C 17 ——多为α-构型,少为β-构型 C 20——可有>C=O 、-OH C 11——可有α-OH C-3、8、12、14、17、20——可能有β-OH 强心苷 ： 是存在于植物中具有强心作用的甾体苷类化合物，由强心苷元和糖缩合而产生的一类苷。 海洋甾体化合物 ：不少海洋甾体化合物具有显著的抗肿瘤活性。海洋甾体化合物具有活性强、结构复杂的特点。 第一节 强心苷（考点；结构类型，甲乙型） 强心苷是存在于植物中具有强心作用的甾体苷类化合物，由强心苷元和糖缩合而产生的一类苷。 强心苷是治疗室率过快心房颤动的首选药和慢性心功能不全的主要药物。 第一节、 结构和分类 1.基本结构：强心苷是由强心苷元与糖二部分构成。 一.强心苷元部分：强心苷元是由甾体母核与C 17取代的不饱和内酯环组成 。 （1）苷元母核 ： 苷元母核A 、B 、C 、D 四个环的稠合构象对强心苷的理化及生理活性有一定影响。 2. 结构类型：根据C 17位侧链的不饱和内酯环不同分为：甲型：C 17位侧链为五元环的△αβ-γ内酯 （五元不饱和内酯环）； 乙型：C 17位侧链为六元环的△αβ-γδ -γ内酯（六元不饱和内酯环） 这两类大都是β-构型，个别为α-构型，α-型无强心作用。 二、糖部分 根据C 2位上有无-OH 分为α-OH （2-OH ）糖及α-去氧糖（2-去氧糖）两类。后者主要见于强心苷。 强心苷中，多数是几种糖结合成低聚糖形式再与苷元的C 3-OH 结合成苷，少数为双糖苷或单糖苷。糖和苷的连接方式有三种： Ⅰ型:苷元-(2,6-去氧糖)X -(D-葡萄糖)Y Ⅱ型:苷元-(6-去氧糖)X -(D-葡萄糖)Y Ⅲ型：苷元-（D-葡萄糖）Y X=1-3; Y=1-2 一般初生苷其末端多为葡萄糖。 天然存在的强心苷多数属于Ⅰ型和Ⅱ型，Ⅲ型较少。 (区别题 1.2.3. ) 强心苷的结构与活性的关系（考点） 强心苷的化学结构对其生理活性有较大影响。强心苷的强心作用取决于苷元部分，主要是甾体母核的立体结构、不饱和内酯环的种类及一些取代基的种类及其构型。糖部分本身不具有强心作用，但可影响强心苷的强心作用强度。强心苷的强心作用强弱常以对动物的毒性（致死量）来表示。 甾体基本母核 A B C D CH 220CH 321H 孕甾烷 傅-克烷基化反应 姓名：许峰班级：制药0601 学号：060801344 指导老师：韩莹 摘要 傅克烷基化反应是对芳香化合物衍生化的最为有效的方法之一。本文就是以 邻二甲苯和苯乙烯在路易酸FeCl3的作用下，不采用另外的溶剂进行傅-克烷基化反应，是绿色化学反应。 关键词：邻二甲苯苯乙烯傅-克烷基化反应绿色化学反应 Abstract Friedel—Crafts alkylation is one of the most efi cient methods for the derivatization of aromatic compounds．This paper is to o-xylene and styrene under the influence of Louis acid FeCl 3 conduct Friedel—Crafts alkylation. Key words： o-xylenev styrene Friedel—Crafts alkylation Green Chemical Reaction . 引言： 碳一碳键形成反应是有机合成化学中最为重要的反应，其中傅克反应则是构建与芳香化合物直接相连的碳一碳键最有效的方法之一【1】，自从Friedel Crafts 报道了首例傅克反应后【2】，一百多年来，傅克反应受到了众多化学工作者的关注，而且被越来越多地应用于复杂分子的合成中去。 可以与苯发生傅克反应的最开始的为卤代烷，后来发现烯或者醇在路易斯酸 的催化下也可以发生烷基化反应。而对于路易斯酸的选择，除了FeCl 3 ，其他的 路易斯酸催化剂诸如AlCl 3，SbCl 5 ，也都有催化作用。 绿色化学反应是指化学反应过程尽量不使用额外的溶剂和辅料，不产生额外的对环境有较大污染然的物质。 对于一般的傅-克烷基化反应我们使用的溶剂都是二氯甲烷，四氢呋喃等一些溶剂。而本文的反应物都是液体，故可以不使用额外的溶剂，减少了试剂用量和减少对环境的影响，所以是属于绿色化学反应范畴的。 实验步骤： 1.实验原理： 由于傅-克烷基化反应是卤代烷、烯或者醇在酸催化下形成由碳正离子引起的，如果形成的碳正离子不稳定，就会很容易发生碳正离子的重排，从而得到重排产物。本实验中的苯乙烯在形成的碳正离子，就以形成的叔碳正离子稳定性较 第七章 醛酮醌 思考与练习 7-1 写出分子式为C 5H 10O 的醛、酮的所有异构体。 7-2 命名下列化合物。 ⑴ 2,4-二甲基己醛 ⑵ 5-甲基-4-己烯-3-酮 ⑶ 1-环己基-2-丙酮 ⑷ 4-苯基-2-戊烯醛 ⑸ 3-氯-2,5-己二酮 ⑹β-萘甲醛 7-3 写出下列化合物的构造式。 ⑴ ⑵ ⑶ ⑷ ⑸ ⑹ 7-4 试用合适的原料合成下列化合物。 可用相应醇氧化或用付—克酰基化反应制得。 7-5 将下列化合物的沸点按由高到低的顺序排列，并说明理由。 丙醇＞丙酮＞甲乙醚＞丙烷 主要考虑：有无氢键形成和分子极性的大小。 7-6 乙醛能与水混溶，而正戊醛则微溶于水，为什么？ 低级醛和酮在水中有相当大的溶解度，这是因为醛和酮分子中羰基上的氧原子可以与水分子中的氢原子形成氢键。但随着分子中碳原子数的增加，羰基在分子中所占的比例减小，形成氢键难度加大，醛和酮在水中溶解度也逐渐减小。 7-7 羰基化合物和哪些试剂容易发生加成反应？遵循什么规律？ 羰基化合物与HCN 、NaHSO 3、ROH 、RMgX 、H 2N-Y 等试剂易发生加成反应。遵循亲核加成反应规律，即羰基中的碳原子形成反应的正电中心，受到亲核试剂的进攻。 7-8在与氢氰酸加成反应中，丙酮和乙醛哪一个反应比较快？为什么？ 乙醛快；比较醛和酮羰基加成反应的难易，通常考虑两个方面：①由于烷基的给电性，羰基上连接的烷基越多，给电性越强，羰基碳原子正电性越小，越不利于亲核试剂的进攻，使得加成反应速度减慢。②羰基上连接的烃基越大，则位阻效应越大，亲核试剂就越不容易接近，反应也不易进行。所以在许多亲核加成反应中，酮一般不如醛活泼。 7-9 醛和酮与格氏试剂加成反应主要适用于哪些物质的合成？ 醛和酮与格氏试剂（RMgX ）加成，可生成比原来醛或酮增加了碳原子的伯、仲、叔醇。 7-10 下列化合物哪些能和HCN 发生加成反应？并写出其反应产物。 ⑴、⑵、⑶、⑸； ⑴ CH 3CH 2CH 2CH 2CHO CH 3CH 2CHCHO CH 3CH 3CHCH 2CHO CH 3CH 3C CH 3CH 3 CHO CH 3C O CH 2CH 2CH 3 CH 3C O CHCH 3 CH 3 CH 3CHCH 2CHO 3CH CHCHO O C 2H 5 CH 3CH 3CH 3CH CHCHBr C O CH 3CHO OH CH 2 C O OH CH 2CHCH 2CHO CH 2CHCH 2 CHCN CH 3CH 2CCH 2CH 3 O 傅克反应 傅-克反应 傅-克(傅瑞德尔-克拉夫茨)反应：芳香烃在无水AlCl3作用下，环上的氢原子也 能被烷基和酰基所取代。这是一个制备烷基烃和芳香酮的方法，称为Friedel —Crafts 反应，简称傅-克反应。苯环上有强吸电子基（如－NO2 、－SO3H 、－COR） 时，不发生傅-克反应。 a、烷基化反应：卤代烷在AlCl3的作用下生成C+，C+在进攻苯环之前会发 生重排成稳定的C+（三个C以上） 烷基化反应的缺点是副反应的发生 b、硝基化反应：常用的硝基化试剂是酰卤，此外还可以用酸酐。优点是产物 较纯。 一般用Clemmensen还原法可以得到丙苯。 济南盛信达科技有限公司 燕山学院工作室最新招聘信息加入时间：2008-3-13 11:24:44 单位信息 单位名称：济南盛信达科技有限公司单位所在地：山东省济南市高新区 成立时间：单位性质：其他企业 所属行业：制造业 单位简介 济南盛信达科技有限公司,国家重点高新技术企业，具有自营进出口权。为外向型科集研发、外贸、营销于一体.公司几大产品均为国内首创或专利产品。公司先后获得“国省高新技术企业”等荣誉称号。 --------------------------------------------------------------------------- 职位信息 职位名称：其它科研人员类职位招聘时间： 2008-03-13 至 2008-05-20 招聘人数： 2 工作经验： 工作地点：山东省济南市 职位描述：家在济南优先 专业要求：应用化学 ------------------------------------------------------------------------职位名称：企业后勤管理招聘时间： 2008-03-13 至 2008-04-10 招聘人数： 1 工作经验： 工作地点：山东省济南市 职位描述： 专业要求：工商企业管理 ------------------------------------------------------------------------职位名称：企业/业务发展经理招聘时间： 2008-03-13 至 2008-05-01 招聘人数： 2 工作经验： 工作地点：山东省济南市 职位描述： 环化第三章 第三章作业 1. 重金属类污染物在环境中可以发生哪些迁移和转化行为？ 2. 有机污染物的主要理化参数有那些？ 3. 简述有机污染物的主要环境行为及其参数。 4. 什么是光化学反应? 可以分为哪几类? 5. 简述光吸收过程的基本原理。 6. 简述光物理过程和光化学过程 7. 简述光化学的基本定律。 答案 第三章： 1. 重金属类污染物在环境中可以发生哪些迁移和转化行为？ 答：重金属类污染物的环境行为有：它们在环境中可以以游离态形式溶解，非溶解的可以挥发进入另一环境介质，也可以与某些物质形成沉淀，也可以发生氧化与还原作用，同时也可以与环境介质中某些物质形成配合物，还可以被动植物摄取，沿食物链进行迁移，难降解的物质可以富集在生物体内，同时重金属类物质还可以经过烷基化，吸附和淋溶作用在环境中进行迁移和转化。 2. 有机污染物的主要理化参数有那些？ 答：共有12个参数，分别是： (1)土壤（沉积物）有机碳吸附系数(K oc )：K oc = K p /X oc ，K p =C s /C w ，其中C s 和C w 分别表示污染 物在土壤（沉积物）和水中达到平衡时的浓度，K p 为分配系数，X oc 为沉积物中有机碳的含量。 (2)正辛醇/水分配系数(K OW )：分配平衡时，某一 有机化合物在辛醇相中的浓度(C O )与其在水相中非离解形式浓度(C W )的比值。 (3)水溶解度 (S W )：在一定温度下，该物质溶解在单位量的纯水中的最大量。 (4)正辛醇/空气分配系数(K OA )：分配平衡时，某 一有机化合物在正辛醇中的浓度与空气中该化合物浓度的比值。 (5)空气颗粒物/空气分配系数(K P )：某有机物在 单位浓度TSP 中颗粒物中的浓度与在空气相中的浓度的比值。 (6)蒸气压P ：某物质，当气相与其纯净态(液体或固体)达到平衡时的气压。 (7)酸解离常数K a ：定义为 a [H ][A ][HA] K +-= （对反应 HA A H -+ ?+），为了表示方便，K a 通常以负对数 Friedel-Crafts反应机理 摘要：本文总结了傅-克反应提出以来，化学研究人员对该反应的机理方面的研究，包括动力学研究、中间体结构和性质的。提出傅一克反应机理目前存在的疑问及机理动力学的发展方向。 关键词：傅-克反应；动力学；中间体；反应机理 1、傅-克反应的发现 傅-克反应在整个化学发展史上是最为古老的化学之一[1]。1869年德国化学家Zincke[2]首次报道了在苯环上引入烷基的反应．这个反应的发现来源于一个偶然，当时Zincke想从苄氯和氯乙酸(以苯作为溶剂)出发，在铜粉(或银粉)和密封加热的条件下，通过类似Wurtz反应的方法制各苯丙酸，但他发现在反应过程中有大量的氯化氢产生，同时也生成了二苯甲烷。他意识到这是苄氯和溶剂苯发生反应产生的。为此，在接下来的几年里，他开始研究这类苯环上引入取代基的反应。Zincke的发现引起了化学家们的广泛关注，他们用不同芳烃进行反应，并且得到了相应芳烃的烷基化和酰基化产物．至此，他们一致认为铁、铜、银或锌等金属粉末可以作为此类反应的催化剂，这个反应也因此被命名为Zincke反应。 1877年，Friedel和Crafts[3-4]试图通过Gustavson反应将1，1，1一三氯乙烷(苯作溶剂)在铝粉和碘单质存在条件下转化为1，1，1．三碘乙烷，但出乎意料的是他们再次得到了Zincke反应的产物。经过他们的不断研究，他们又对各种金属卤化物、各种卤代烃以及各种酰卤分别进行了研究，表明Zincke提出的各种金属确实不是此类反应的催化剂，它们的卤代物才是真正意义上的催化剂。至此傅一克反应被正式提出，包括傅一克烷基化反应和傅一克酰基化反应。 REVIEW https://www.doczj.com/doc/8b5041613.html,/CR Update1of:Use of Solid Catalysts in FriedelàCrafts Acylation Reactions Giovanni Sartori*,?,?and Raimondo Maggi?,? ?Clean Synthetic Methodologies Group and?National Interuniversity Consortium“Chemistry for Environment”(INCA),Unit PR2, Dipartimento di Chimica Organica e Industriale,Universit a degli Studi di Parma,Parco Area delle Scienze17A,I-43100Parma,Italy This is a Chemical Reviews Perennial Review.The root paper of this title was published in Chem.Rev.2006,106(3),1077à1104,DOI: 10.1021/cr040695c;Published(Web)February14,2006.Updates to the text appear in red type. CONTENTS 1.Introduction A 2.Acylation of Arenes B 2.1.Acylation with Zeolites B 2.2.Acylation with Clays H 2.3.Acylation with Metal Oxides I 2.4.Acylation with Acid-Treated Metal Oxides I 2.5.Acylation with Heteropoly Acids J 2.6.Acylation with Na?on L 3.Acylation of Aromatic Ethers L 3.1.Acylation with Zeolites L 3.2.Acylation with Clays R 3.3.Acylation with Metal Oxides R 3.4.Acylation with Acid-Treated Metal Oxides S 3.5.Acylation with Heteropoly Acids T 3.6.Acylation with Na?on U 4.Acylation of Aromatic Thioethers V 5.Acylation of Phenolic Substrates V 5.1.Fries Rearrangement V 5.1.1.Fries Rearrangement with Zeolites W 5.1.2.Fries Rearrangement with Heteropoly Acids X 5.1.3.Fries Rearrangement(Miscellaneous)X 5.2.Direct Acylation Y 5.2.1.Direct Acylation with Zeolites Y 5.2.2.Direct Acylation with Clays AA 5.2.3.Direct Acylation(Miscellaneous)AA 6.Acylation of Heterocycles AB 7.Concluding Remarks AC Author Information AD Biographies AD Acknowledgment AD Dedication AD References AD 1.INTRODUCTION “The?rst mention of acylation related to the later Al2Cl6 method of Friedel and Crafts appeared in1873in a preliminary communication by Grucarevic and Merz....”1With these words G. A.Olah in an historical review about FriedelàCrafts chemistry2reported the earliest reference on the metal-catalyzed acylation of aromatic compounds.The FriedelàCrafts acylation reaction essentially consists of the production of an aromatic ketone by reacting an aromatic substrate with an acyl component in the presence of a catalyst.3 Since the above communication,an impressive number of papers and books have been published and numerous patents have been registered on this topic.3The reaction quickly became a fundamental pillar of synthetic organic chemistry at both the academic and industrial levels.The great interest in electrophilic acylation studies and in the optimization of preparative processes was spurred by the considerable practical value of the aromatic ketone products.In fact,these compounds constitute funda-mental intermediates in the pharmaceutical,fragrance,?avor, dye,and agrochemical industries.4à6 Conventionally,the electrophilic acylations are catalyzed by Lewis acids(such as ZnCl2,AlCl3,FeCl3,SnCl4,and TiCl4)or strong protic acids(such as HF and H2SO4).In particular,the use of metal halides causes problems associated with the strong complex formed between the ketone product and the metal halide itself which provokes the use of more than stoichiometric amounts of catalyst.The workup commonly requires hydrolysis of the complex,leading to the loss of the catalyst and giving large amounts of corrosive waste streams.For these reasons,during the past decade,the setting up of more ecocompatible FriedelàCrafts acylations has become a fundamental goal of the general “green revolution”that has spread in all?elds of synthetic chemistry7through a revision of the preparation methods mainly based on the exploitation of new and increasingly e?cient catalysts.8 Great e?orts have been made by di?erent research groups to achieve the goal of making the Lewis acid role catalytic in FriedelàCrafts acylation.Interesting results have been achieved,such as the use of catalytic amounts of lanthanide tri?uoromethanesulfonates alone9or microencapsulated on polyacrylonitrile10as reusable catalysts,as well as the more ecocompatible methods based on the use of graphite as a solid catalyst11or even the possibility to perform the reaction without any catalyst.12 Received:November2,2010 傅克反应总结材料 傅克反应总结材料 1. 傅克反应的发现： 在这些反应中，以制备芳烃和芳酮是主要的。 2. 傅克反应的反应机理 注意以下三种情形下的反应： A. 烷基正离子的重排(稳定性：叔>仲>伯) 因此反应中都有异构体产物的出现。如： B. 烷基取代不会停留在一取代阶段 于烷基是供电子基团，已取代后芳环上电子云密度增大，使得亲电取代反应更容易进行，所以取代还会继续进行下去，最后可以全部取代。如： 但是有些基团于位阻关系，只能得到已取代的产物。 如果取代基团是酰基，于酰基是吸电子基团，使得芳环电子云密度减小，使得亲电取代反应比较困难，反应一步后会停下来，所以傅克酰化合成芳酮更为有用。 C. 定文问题： 下面的例子将让我们更好的去理解定位问题： 3. 傅克反应的催化剂 路易氏酸，强酸，酸酐，酰氯和一些中性化合物和元素等。 特别需要注意以下及点： A.不同催化剂产生不桶产物： B.不同催化剂产率有很大的差别： C. 氯化物作为催化剂要无水，但是绝对无水活性反而不大，甚至不能进行。有些反应还需要把催化剂暴露在空气中吸水几分钟后，才能催化反应的进行。 4. 傅克反应所用的烷基化剂 A. 常用的是氯化物，活泼性次序RCl>RBr>RI B. 烯类也是很好的烷基化剂，催化剂用BF3和HF效果很好。 C. 醇类也可作为烷基化剂，但是催化剂用BF3和HF效果最好。 5. 酰基取代剂 A. 酰卤 活性顺序为： B. 酸酐也是很好的酰化剂，但是它需要比酰卤多50%的氯化铝。 C. 羧酸也可以直接用作酰化剂，但催化剂不宜用氯化铝，而要用硫酸，磷酸，最好是氟化氢。 6. 芳环 芳环和杂环化合物都能参加F-C反应，其中并环和稠环更易发生反应，杂环中，呋喃类，吡咯类等虽对酸敏感，但在适当情况下也可发生F-C反应。 如环上有供电子基团，可用较若的反应条件。如有吸电子基团，则要用较强的反应条件。 稠环的定位问题： 7. 芳酸的环化 首先要考虑形成环的稳定性，一般是6元环>5元环>7元环 8. 实验操作: 傅克反应总结材料 1. 傅克反应的发现： 在这些反应中，以制备芳烃和芳酮是主要的。 2. 傅克反应的反应机理 傅克反应 摘要：本文总结了傅-克反应提出以来，化学研究人员对该反应的机理方面的研究，包括动力学研究、中间体结构和性质的。提出傅一克反应机理目前存在的疑问及机理动力学的发展方向。 关键词：傅-克反应；动力学；中间体；反应机理 1、傅-克反应的发现 傅-克反应在整个化学发展史上是最为古老的化学之一[1]。1869年德国化学家Zincke[2]首次报道了在苯环上引入烷基的反应．这个反应的发现来源于一个偶然，当时Zincke想从苄氯和氯乙酸(以苯作为溶剂)出发，在铜粉(或银粉)和密封加热的条件下，通过类似Wurtz反应的方法制各苯丙酸，但他发现在反应过程中有大量的氯化氢产生，同时也生成了二苯甲烷。他意识到这是苄氯和溶剂苯发生反应产生的。为此，在接下来的几年里，他开始研究这类苯环上引入取代基的反应。Zincke的发现引起了化学家们的广泛关注，他们用不同芳烃进行反应，并且得到了相应芳烃的烷基化和酰基化产物．至此，他们一致认为铁、铜、银或锌等金属粉末可以作为此类反应的催化剂，这个反应也因此被命名为Zincke反应。 1877年，Friedel和Crafts[3-4]试图通过Gustavson反应将1，1，1一三氯乙烷(苯作溶剂)在铝粉和碘单质存在条件下转化为1，1，1．三碘乙烷，但出乎意料的是他们再次得到了Zincke反应的产物。经过他们的不断研究，他们又对各种金属卤化物、各种卤代烃以及各种酰卤分别进行了研究，表明Zincke提出的各种金属确实不是此类反应的催化剂，它们的卤代物才是真正意义上的催化剂。至此傅一克反应被正式提出，包括傅一克烷基化反应和傅一克酰基化反应。 傅一克反应虽然说是非常古老的化学，但是直到现在其应用依然非常的广泛[5-6]。一直以来，许多化学工作者对傅一克反应机理的研究非常感兴趣，同时也做了许多工作。目前有关该反应机理方面的报道相对较少，直至现在还是没有非常清楚地指明该反应的机理，最主要的是至今仍然没有明确提出该反应实际的反应活性中间体．这未免有些遗憾，但研究者们出色的工作还是给出了大量的信息，为傅一克反应机理的进一步探索做出了巨大贡献。 2、傅-克反应的发展及应用概况 傅-克反应自从被发现以来，大量的论文、书籍或者专利介绍这类反应，它在学术或者工业领域上迅速成为有机合成化学的基础反应。 由于傅一克酰基化反应是实现碳碳成键的最有效方式之一，并且是制备各种芳基酮，杂环芳烃酮等的重要手段，所以它在医药、农药、染料、香料等工业生产中具有非常广泛的应用，因此化学家们对傅一克酰基化反应一直怀有很高的兴趣。一般来讲，傅一克酰基化反应使用的是路易斯酸，如氯化锌、氯化铝、氯化铁、四氯化锡、四氯化钛等或者是很强的质子酸，如氢氟酸、硫酸等．在反应结束以后，这些路易斯酸与产物配位从而以配合物的形式存在，所以在水解后才可以得到目标产物，这就会造成环境的污染[7，8]．所以，在过去的几十年里，傅一克酰基化反应一直努力朝着绿色化学的方向发展．通过开发更加有效的催化剂，比如催化量的Ln(OTf)3．使得反应效率得到提高，或者优化反应条件，如微波条件下，离子液体中的傅一克酰基化反应，实现催化剂的回收再利用；抑或是使用石墨作为固体催化剂，以及各种异相催化剂的发展都使得傅一克酰基化反应不断地向前推进。 3.1傅-克烷基化反应 傅-克烷基化反应的反应机理与磺化、硝化类似，首先在催化剂的作用下产酰化反应原理与实例解析
氟氯取代苯胺类酰基硫脲衍生物的结构、性质及相互作用研究
第七章 多环芳烃
傅克反应
傅克反应资料讲解
有机化学电环化反应
第七章 甾体化合物
傅-克烷基化反应
高职高专《有机化学》课后习题答案 第七章
傅克反应
环化第三章
傅克反应机理
F-C酰基化反应
傅克反应总结材料
傅克反应机理
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