Microwave chemistry and a Design of Experiments (DOE) protocol were employed together in order to rapidly and efficiently optimize a modified Perkin reaction. Microwave heating significantly reduced the reaction time, and the DOE provided a statistically significant understanding of underlying process relationships in a minimum number of experimental runs. In all, the reaction time was reduced from1hour to 2 minutes, factors important to yield were identified, an interesting cross-term interaction was discovered, and it was demonstrated that the more economical sodium acetate trihydrate catalyst was a viable alternative to the more costly anhydrous sodium acetate

McWilliams, Laura

Pace, R. David

ScholarWorks@UARK

Journal of the Arkansas Academy of ScienceVolume 60 Article 152006Perkin Reaction: Rapid and Efficient ProcessOptimization Through a Microwave/Design ofExperiments CoupleR. David PaceLyon College, dpace@lyon.eduLaura McWilliamsLyon CollegeFollow this and additional works at: http://scholarworks.uark.edu/jaasPart of the Physical Chemistry CommonsThis article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able toread, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking priorpermission from the publisher or the author.This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academyof Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu.Recommended CitationPace, R. David and McWilliams, Laura (2006) "Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Couple," Journal of the Arkansas Academy of Science: Vol. 60 , Article 15.Available at: http://scholarworks.uark.edu/jaas/vol60/iss1/15~96 *The Perkin Reaction: Rapid and Efficient Process OptimizationThrough a Microwave/Design of Experiments CoupleR. David Pace ' and Laura McWilliamsiScience Division,Lyon College P.O. Box 2317, Batesville, AR 725032Correspondence: dpace@lyon.eduAbstract.—Microwave chemistry and a Design ofExperiments (DOE) protocol were employed together in order to rapidly andefficiently optimize a modified Perkin reaction. Microwave heating significantly reduced the reaction time, and the DOE provideda statistically significant understanding ofunderlying process relationships in a minimum number ofexperimental runs. In all,thereaction time was reduced from1hour to 2 minutes, factors important to yield were identified, an interesting cross-term interactionwas discovered, and it was demonstrated that the more economical sodium acetate trihydrate catalyst was a viable alternative to themore costly anhydrous sodium acetate.Key words: — Microwave chemistry, Design of Experiments (DOE) protocol, Perkin reaction, sodium acetate trihydrate catalyst,anhydrous sodium acetate.IntroductionThe base-catalyzed condensation of aromatic aldehydeswith acid anhydrides, called the Perkin reaction, is a classicalmethod for the synthesis of a,(3-unsaturated carboxylic acids asshown inEquation 1 (March, 1985). A variation of this reactioninvolves the use ofrhodanine instead of an acid anhydride as aroute to a variety ofbiologically active compounds as shown inEquation 2 (Brown 1961, Foye and Torivich 1977). However,long reaction times and high temperatures (Mayo et al. 1994;Sykes, 1987) and/or exotic base catalysts (Vererkova et al. 1999)are required for the Perkin reaction.Acceleration of the reaction rate using microwaves couldpotentially reduce reaction times from hours to just a fewminutes. Additionally, microwave heating is an efficient energyalternative over the classical thermal sources, which are highlyinefficient.Verekova, et al. (1999) reported that microwaves doaccelerate the Perkin reaction (Equation 1),but their best yieldswere obtained after 10 minutes at 800-Watts using toxiccesiumcatalysts. Although sodium acetate is the most common basecatalyst, reports suggest that it must be anhydrous (Mayo etal. 1994). Given the previous long reaction time (10 minutes)at high microwave power (800 Watts) using a toxic catalyst(Vererkova et al. 1999), we decided to investigate optimizingthis reaction using an efficient statistical approach called Designof Experiments (DOE). The acceleration of reactions usingmicrowave chemistry combined with the resource efficiency ofDOE constitutes a powerful process for optimizing chemicalreactions. Herein, wedemonstrate the utilityofthe microwave-DOE couple through the optimization of the Perkin reaction(Equation 2).DOE is a large area of statistics that provides a way toconsider the effects of all variables of a process on a set ofoutcomes. Itdoes so ina uniform but simultaneous way throughthe construction of a mathematical model that has statisticallysignificant predictive value within a defined design space (Boxet al. 1978, Laird 2002). Chemists in the corporate sectorhave largely embraced DOE as a credible tool for optimizingprocesses, developing predictive models for reactions, andunderstanding complex variable interactions with a minimuriof experiments (e.g., without having to run all possibbcombinations of variables and their levels) (Hendrix 197S ,Owen et al. 2001). Historically, it appears that the academi :sector has been reluctant (Lendrem et al. 2001) to emplo 'DOE methods in chemical research, but this is beginning t >change (Carlson et al. 2001, Carlson 2005). While DOE doe;not provide a comprehensive solution to process optimizatior ,it does offer the chemist several advantages over the classics Ione-variable-at-a-time (OVAT) approach, including erroanalysis of the experimental process as well as the statisticamodel itself, detection ofcomplex interactions between reactioiparameters that influence experimental results, a finite numbeofexperiments to reach research objectives, and the constructioiof a predictive mathematical model of the reaction within th<experimenter-determined boundaries of the design (Bayne amJournal of the Arkansas Academy of Science, Vol. 60, 200696Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006¦97The Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Coupleubin, 1986). Common objections chemists have to the use ofOE for optimization of chemical processes include a lack ofTable 1. Factor Settings for the 2-Level Experiment at 330Watts Microwave Powerafficient material resources or statistics trumping chemicalntuition. Along with these, a host ofother perceived obstaclesiave been adequately addressed inanother forum (Lendrem etil.2001).Materials and MethodsBased on the fundamental chemical nature of this reaction,we believed that a 2-level designed experiment consistingof 4 factors (catalyst loading (A), acetic acid level (B), o-chlorobenzaldehyde level (C), and microwave time (D)) wouldprovide the most information on underlying relationshipsaffecting yield. A 2-level screening experiment is the bestoption forrevealing allmain and two-factor (cross-term) effects.This 2-level, 4-factor DOE translated into24 (16) experiments touniformly cover the design space as shown inTable 1.Inclusion of 6 center point experiments (all factors atmidrange settings) provided a way to measure variability due toexperimenter/process error. Inother words, witha minimumof6 center points, totalerror can be separated into two components:pure error due to the experiment and error due to model lack-of-fit. Table 1shows the experiments carried out.The experimental work was carried out in a domesticPanasonic® NN-S540 microwave oven equipped with aninverter that allowed for the actual lowering ofthe power outputto a selectable level (e.g., 330 Watts; Varma and Namboodiri2001). Allchemicals were used as received without any furtherpurification. A 5-mL conical vial was charged with 0.20 mmolrhodanine (Aldrich) and the appropriate amounts of sodiumacetate trihydrate (Fisher) and glacial acetic acid (Fisher) asshown in Table 1. Using an automatic pipet, the appropriatevolume of o-chlorobenzaldehyde (Aldrich) was added in oneportion to the conical vial (Table 1). The vial was capped andplaced in the microwave at 330 Watts for the appropriate time(Table 1). After microwaving, the vial was removed from theoven and placed in an ice-bath. The resulting yellow crystalswere isolated via vacuum filtration and washed with 2 * 1-mLcold glacial acetic acid followed by 2 * 1-mL cold deionizedwater. Upon air drying, the yield was determined, and theF a c to r S e tting sRun mmol mL mmol MW TimeNaOAc HOAc o-CB sec1_ 0.500 0.500 0.200 302 0.500 0.500 0.200 1203 0.0100 0.500 0.600"30.04"0.0100 0.500 0.200"30.05 0.500 0.500 0.600 30.06 0.0100 2.00 0.200 1207 0.500 2.00 0.600 30.08"0.0100 0.500 0.600"1209 0.255 1.25 0.400 75.010 0.255 1.25 0.400 75.011 0.500 2.00 0.200 30.012 0.0100 0.500 0.200"12013 0.500 2.00 0.600 12014 0.255 1.25 0.400"75.015 0.500 0.500 0.600 12016 0.0100 2.00 0.600 12017 0.0100 2.00 0.600 30.018 0.500 2.00 0.200 12019 0.255 1.25 0.400"75.020 0.0100" 2.00 0.200 30.021 0.255 1.25 0.400"75.022 I 0.255 | 1.25 I0.400]" 75.0melting point and infrared spectrum were obtained.Results and DiscussionThe singular reason why we chose microwave heatingwas to drastically shorten the reaction time. Clearly, withoutany statistical analysis, the efficacy of microwave heating wasaffirmed. However, the recommended 800 Watts ofmicrowaveheating (Verekova et al. 1999) was discovered to be somewhatexcessive. We found that 330 Watts of microwave heatingprovided the energy necessary for this reaction.Another clear result from this set of experiments was theefficacy of the sodium acetate trihydrate catalyst. In general,anhydrous salts are difficult to prepare, hard to handle, and morecostly than hydrates. Therefore, the fact that sodium acetatetrihydrate proved to be a viable catalyst constitutes anothersignificant improvement in this process.The intent ofthe DOE was three-fold: 1) identify underlyingrelationships between factors, 2) develop a first-generationmathematical model of the process, and 3)provide insight forfurther development work. Inthe statistical analysis, the half-normal probability plot revealed that the main effects of all 4factors as wellas several cross-term interactions were significantMicrowave assisted acceleration of organic reactions hasjmerged within the past twenty years as a viable alternativeto conventional thermal methods (Hayes 2002, Marx 2004).Reactions carried out under conventional thermal conditions areoften accompanied bylongreaction times, undesired side productformation, and/or low yields. Microwave methodologies provideviable alternatives to classical thermal approaches for drugdiscovery efforts (Rose 2002), analytical chemistry (Kingstonand Jassie 1988), protein synthesis (Yu et al. 1992), and greenchemistry (Mingos 1994). Microwave techniques often providethe opportunity for carrying out organic transformations in asolventless or solid phase environment (Larhed et al. 2002).Journal ofthe Arkansas Academy ofScience, Vol. 60, 200697Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15http://scholarworks.uark.edu/jaas/vol60/iss1/15I98 IR. David Pace and Laura McWilliamsprocess variability). This, however, is a screening experimei t.Therefore, this experiment only gives us information concernii gfactors and interactions that may be important in explainii gprocess variability of selected responses (/. e., yield) with nthe design space. What is clear is that the sodium aceta elevel, acetic acid volume, o-chlorobenzaldehyde level, and tremicrowave time significantly impacted yield as well as severalinteraction terms. The expression for the predicted yield sgiven as Equation 3.Design- Expert© Software;X Yield Half-Normal Plot« error irom nepuc:A.NaOAc Hydrate6: Acetic AcidCo-CB O DD MWTimea Posrtive Effects i» w¦ Negative Effects -§OBo *0a. DAB?-n d§*on acoOJBCDo DABCDz«S 90XBtc10Yield= 21.1+155 AA+8.85-12.9C -0.03D -1 1 1AAB-362.1 AC-1 A3AD-11.SBC -0.05BD +OACD+206.9 ABC/&°+O.SABD +A.XACD-0.03BCD -2.0ABCD (3)o» 3.ss t.m io.es ioi(Standardized Effect| Interactions are best understood through 3-dimensionalplots. Figure 2 shows three cube plots at the low,medium, andhigh microwave times (30 sec, 75 sec, and 120 sec), which revealthe behavior of the reaction yield at the extremes of the designspace.Fig. 1. Half-normal plot showing main and cross-term effectson the yield.The lower right edges of the cube plots reveal a mostinteresting interaction (the CD interaction shown in Table 2)between o-chlorobenzaldehyde level (C) and microwave time(D). At 30 seconds microwave time, the best yield occurswith 0.50 mol NaOAc, 0.5 mL HOAc, and 0.20 mol (or, oneequivalent) o-chlorobenzaldehyde. On the other hand, at 120seconds microwave time, the best yield occurs with 0.50 molNaOAc, 0.5 mL HOAc, and 0.60 mol (e. g., three equivalents)o-chlorobenzaldehyde. Figure 3 shows this CD cross-terminteraction with two 3-D plots (one at 30 microwave seconds,the other at 120 microwave seconds) of the yield versus NaOAclevel and o-chlorobenzaldehyde level. Clearly, after 30 secondsat 330 Watts, the optimum yieldoccured at the lowest level (1equivalent) of o-chlorobenzaldehyde and the highest level of(Fig. 1). Half-normal probability plot is the fundamentalmethod for selecting 2-level effects. Inother words, the plotof the ordered values ofa sample versus the expected orderedvalues from the true population willbe approximately a straightline. Any terms that turn out to be important for the statisticalmodel show up as outliers.It should be pointed out that many 2-, 3-, and 4-factorterms appear to be significant, but such appearances can bedeceiving. As shown in the ANOVA table (Table 2), effectsthat are significant in explaining process variability are clearlyseparated from effects that are not significant on the basis ofthemagnitude of the p-value. Small p-values (<0.05) suggest thatthere is model effect (e. g, the term is significant inexplaining001 A: NjOAcHyduU 0.S 0.01 A: NiOAeHydrjt* O.S 001 A: NjOAc Hydrit* 0.SFig.2. Cube plots of the yield at the edges of the DOE design spaceJournal of the Arkansas Academy of Science, Vol.60, 200698Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006I99IThe Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Coupleible 2. ANOVATable for the DOE.Opgrees p-valup K innifirant?Sum of Mean—-Source of F-valueSquares Square Prob>F Yes/No!- re (.'damModel 3195.584 15 213.0389"113.814 < 0.0001~YesA-NaOAc Hydrate 88.1721 1 88.1721 4/.10S09 00010 YesB-Acetic Acid 630.5121 1 630.5121 336.845 < 0.0001 YesC-o-CB 15.7609 1"15.7609 8.420109 '0 0337"YesD-MW Time; 331.24 331 24 176.9618 < 0.0001"YesAB 466 9921 1 466 9921 249.486 < 0 0001 YesAC 15.7609 1 15.7609 8.42Q109' 0.0337~ YesAD 8281 1 82.81 44 24044'0.0012 Yes~BC 0.202b 1 0.2025 0, 108184'O./bbii~NoBD 67.9844 1 87 9844 47 00482 0.0010 YesCD 807.6964 1 807 6964 431.504 < 0.0001 YesABC 74 8225 1 74 8225 39 9732 00015"YesABD 0 2304'1"0.2304 0 123089 0 7400"NoACD 213.7444 1 213 7444 114 1909 0 0001'YesBCD "209.0916 1 209.0916 111.7052' ' 0.0001 YesABCD 170.5636 1 170.5636 91.12196 0.0002"YesCurvature 1305.867 1 1305.867 697.6468 < 00001 YesPure Error 9 359083 5 1.871817Cor Total 4510.81 21sodium acetate. Alternatively, after 120 seconds at 330 Watts,the optimum yield occured at the highest level (3 equivalents)ofo-chlorobenzaldehyde and the lowest levelofsodium acetate.The explanation for this unexpected result is not clear at thispoint. However, this CD interaction (or, any other interactionfor that matter) would have gone undetected in the conventionalOVATmethod ofexperimentation.At least three interactions (AB, ABC, and ABCD)identified in the DOE (see Table 2) may partially be explainedby a combination of the facts that sodium acetate/acetic acidconstitute a buffer system and that this modified Perkin reactionis acid catalyzed. Therefore, this suggests the possibility of asubsequent DOE where the levels of sodium acetate and aceticacid may be combined into one buffering pH term.ConclusionsThe DOE clearly identified that all 4 model factors areimportant in explaining the variability of the yield data.Further, an unexpected, but interesting, cross-term interactionwas identified involving o-chlorobenzaldehyde and microwavetime at 330 Watts (CD). Other interactions involving thecoupling of sodium acetate and acetic acid suggest thatcombining these terms in a single buffering pH term may beimportant insubsequent work. Additionally, it was shown thatthe anhydrous sodium acetate catalyst could be replaced by themore economical trihydrate and that high wattage microwavesare not required for this process (330 Watts work as wellas 800Watts).Acknowledgments. —We wouldlike to thank LyonCollegefor providing the chemical, instrumental, and laboratory spaceresources to carry out this research. Additionally,one ofus (DP)would like to thank Dr. Kurt Grafton for his encouragement towrite this paper. Finally, we would like to thank the ArkansasAcademy ofScience for granting us the opportunity to presentthe results ofthis work.0.5mL HOAc (LowLevel)C: d-CB120 seconds MW•g. 3. 3-D plots ofthe yieldwithin the design spaceJournal of the Arkansas Academy ofScience, Vol. 60, 200699Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15http://scholarworks.uark.edu/jaas/vol60/iss1/15100IR. DavidPace and Laura McWilliamsLiterature CitedBayne CK and IB Rubin. 1986. Practical experimentaldesigns and optimization methods for chemists. DeerfleldBeach, FL. VCHPublishers. 205 p.Box GEP, WG Hunter, and JS Hunter. 1978. Statistics forexperimenters. New York: John Wiley &Sons. 653 p.Brown FC. 1961. 4-Thiazolidinones. Chemical Reviews61:463.Carlson R. 2005. Canonical analysis of response surfaces: Avaluable tool for process development. Organic ProcessResearch and Development 9:321-330.Carlson R, J Carlson, and A Grennberg. 2001. A novelapproach for screening discrete variations in organicsynthesis. Journal ofChemometrics 15:455.Foye WO and P Tovivich. 1977. N-Glycosyl-5-aralkylidenerhodanines: antibacterial and antiviral activity. Journal ofPharmaceutical Science 66:1607.Hayes BL.2002. Microwave synthesis: chemistry at the speedof light. Matthews, NC: CEM Publishing, Matthews, NC.293 p.Hendrix CD. 1979. What every technologist should knowabout experimental design. Chemtech 3:167.KingstonHMand LBJassie. 1988. Indroduction tomicrowavesample preparation. Washington, DC: American ChemicalSociety. 20 p.LairdT. 2002. Design ofexperiments (DOE). Organic ProcessResearch and Development 6:337.Larhed M,C Moberg, and AHallberg. 2002. Microwave-accelerated homogeneous catalysis in organic chemistry.Accounts ofChemical Research 35: 717-727.Lendrem D,MOwen, and S Godbert. 2001. DOE (design ofexperiments) indevelopment chemistry: Potential obstacles.Organic Process Research and Development 5:324-327.March J. 1985. Advanced organic chemistry. New York: JohnWiley&Sons. 1346 p.Marx V. 2004. Riding the microwave. Chemical andEngineering News 82:15.Mayo DW, RM Pike, and PK Trumper. 1994. Microscaleorganic laboratory withmultistep and multiscale syntheses,3 rdEd. New York: John Wiley&Sons. 764 p.Mingos DMP. 1994. The application of microwaves inchemistry. Research in Chemical Intermediates 20:85-91.Owen MR,C Luscombe, L-W Lai,S Godbert, DLCrookes,and D Emiabata-Smith. 2001. Efficiency by design:Optimization in process research. Organic ProcessResearch and Development 5:308-323.RoseS. 2002. Statistical design and application to combinatorialchemistry. Drug Discovery Today 7:133-138.SykesP. 1987. Aguidebook tomechanism inorganic chemistry,6thEd. Singapore: Longman Scientific Technical. 416 p.Varma RS and VNamboodiri. 2001. An expeditious solvent-free route to ionic liquids using microwaves. ChemicalCommunications 7:643-644.Vererkova E, E Pacherova, and S Toma. 1999. Examinatic qof the perkin reaction under microwave irradiatio i.Chemistry Papers 53:257.Yu HM,TS Chen, and KT Wang. 1992. Enhanced couplir gefficiency in solid-phase peptide synthesis by microwa\eirradiation. Journal ofOrganic Chemistry 57:4781-4784.Journal of the Arkansas Academy ofScience, Vol. 60, 2006100Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006

Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Couple

UARK (University of Arkansas )

Journal of the Arkansas Academy of Science Volume 60 Article 15 2006 Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Couple R. David Pace Lyon College, dpace@lyon.edu Laura McWilliams Lyon College Follow this and additional works at: https://scholarworks.uark.edu/jaas  Part of the Physical Chemistry Commons Recommended Citation Pace, R. David and McWilliams, Laura (2006) "Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Couple," Journal of the Arkansas Academy of Science: Vol. 60 , Article 15. Available at: https://scholarworks.uark.edu/jaas/vol60/iss1/15 This article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able to read, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academy of Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu. ~96 *The Perkin Reaction: Rapid and Efficient Process OptimizationThrough a Microwave/Design of Experiments CoupleR. David Pace'and Laura McWilliamsiScience Division,Lyon College P.O. Box 2317, Batesville, AR 725032Correspondence: dpace@lyon.eduAbstract.—Microwave chemistry and a Design ofExperiments (DOE) protocol were employed together in order to rapidly andefficiently optimize a modified Perkin reaction. Microwave heating significantly reduced the reaction time, and the DOE provideda statistically significant understanding ofunderlying process relationships in a minimum number ofexperimental runs. In all,thereaction time was reduced from1hour to 2 minutes, factors important to yield were identified, an interesting cross-term interactionwas discovered, and it was demonstrated that the more economical sodium acetate trihydrate catalyst was a viable alternative to themore costly anhydrous sodium acetate.Key words:—Microwave chemistry, Design of Experiments (DOE) protocol, Perkin reaction, sodium acetate trihydrate catalyst,anhydrous sodium acetate.IntroductionThe base-catalyzed condensation of aromatic aldehydeswith acid anhydrides, called the Perkin reaction, is a classicalmethod for the synthesis of a,(3-unsaturated carboxylic acids asshown inEquation 1 (March, 1985). A variation of this reactioninvolves the use ofrhodanine instead of an acid anhydride as aroute to a variety ofbiologically active compounds as shown inEquation 2 (Brown 1961, Foye and Torivich 1977). However,long reaction times and high temperatures (Mayo et al. 1994;Sykes, 1987) and/or exotic base catalysts (Vererkova et al. 1999)are required for the Perkin reaction.Acceleration of the reaction rate using microwaves couldpotentially reduce reaction times from hours to just a fewminutes. Additionally, microwave heating is an efficient energyalternative over the classical thermal sources, which are highlyinefficient.Verekova, et al. (1999) reported that microwaves doaccelerate the Perkin reaction (Equation 1),but their best yieldswere obtained after 10 minutes at 800-Watts using toxiccesiumcatalysts. Although sodium acetate is the most common basecatalyst, reports suggest that it must be anhydrous (Mayo etal. 1994). Given the previous long reaction time (10 minutes)at high microwave power (800 Watts) using a toxic catalyst(Vererkova et al. 1999), we decided to investigate optimizingthis reaction using an efficient statistical approach called Designof Experiments (DOE). The acceleration of reactions usingmicrowave chemistry combined with the resource efficiency ofDOE constitutes a powerful process for optimizing chemicalreactions. Herein, wedemonstrate the utilityofthe microwave-DOE couple through the optimization of the Perkin reaction(Equation 2).DOE is a large area of statistics that provides a way toconsider the effects of all variables of a process on a set ofoutcomes. Itdoes so ina uniform but simultaneous way throughthe construction of a mathematical model that has statisticallysignificant predictive value within a defined design space (Boxet al. 1978, Laird 2002). Chemists in the corporate sectorhave largely embraced DOE as a credible tool for optimizingprocesses, developing predictive models for reactions, andunderstanding complex variable interactions with a minimuriof experiments (e.g., without having to run all possibbcombinations of variables and their levels) (Hendrix 197S ,Owen et al. 2001). Historically, it appears that the academi :sector has been reluctant (Lendrem et al. 2001) to emplo'DOE methods in chemical research, but this is beginning t >change (Carlson et al. 2001, Carlson 2005). While DOE doe;not provide a comprehensive solution to process optimizatior ,it does offer the chemist several advantages over the classics Ione-variable-at-a-time (OVAT) approach, including erroanalysis of the experimental process as well as the statisticamodel itself, detection ofcomplex interactions between reactioiparameters that influence experimental results, a finite numbeofexperiments to reach research objectives, and the constructioiof a predictive mathematical model of the reaction within th<experimenter-determined boundaries of the design (Bayne amJournal of the Arkansas Academy of Science, Vol. 60, 200696Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006¦97The Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Coupleubin, 1986). Common objections chemists have to the use ofOE for optimization of chemical processes include a lack ofTable 1. Factor Settings for the 2-Level Experiment at 330Watts Microwave Powerafficient material resources or statistics trumping chemicalntuition. Along with these, a host ofother perceived obstaclesiave been adequately addressed inanother forum (Lendrem etil.2001).Materials and MethodsBased on the fundamental chemical nature of this reaction,we believed that a 2-level designed experiment consistingof 4 factors (catalyst loading (A), acetic acid level (B), o-chlorobenzaldehyde level (C), and microwave time (D)) wouldprovide the most information on underlying relationshipsaffecting yield. A 2-level screening experiment is the bestoption forrevealing allmain and two-factor (cross-term) effects.This 2-level, 4-factor DOE translated into24 (16) experiments touniformly cover the design space as shown inTable 1.Inclusion of 6 center point experiments (all factors atmidrange settings) provided a way to measure variability due toexperimenter/process error. Inother words, witha minimumof6 center points, totalerror can be separated into two components:pure error due to the experiment and error due to model lack-of-fit. Table 1shows the experiments carried out.The experimental work was carried out in a domesticPanasonic® NN-S540 microwave oven equipped with aninverter that allowed for the actual lowering ofthe power outputto a selectable level (e.g., 330 Watts; Varma and Namboodiri2001). Allchemicals were used as received without any furtherpurification. A 5-mL conical vial was charged with 0.20 mmolrhodanine (Aldrich) and the appropriate amounts of sodiumacetate trihydrate (Fisher) and glacial acetic acid (Fisher) asshown in Table 1. Using an automatic pipet, the appropriatevolume of o-chlorobenzaldehyde (Aldrich) was added in oneportion to the conical vial (Table 1). The vial was capped andplaced in the microwave at 330 Watts for the appropriate time(Table 1). After microwaving, the vial was removed from theoven and placed in an ice-bath. The resulting yellow crystalswere isolated via vacuum filtration and washed with 2 * 1-mLcold glacial acetic acid followed by 2 * 1-mL cold deionizedwater. Upon air drying, the yield was determined, and theF a c to r S e tting sRun mmol mL mmol MW TimeNaOAc HOAc o-CB sec1_ 0.500 0.500 0.200 302 0.500 0.500 0.200 1203 0.0100 0.500 0.600"30.04"0.0100 0.500 0.200"30.05 0.500 0.500 0.600 30.06 0.0100 2.00 0.200 1207 0.500 2.00 0.600 30.08"0.0100 0.500 0.600"1209 0.255 1.25 0.400 75.010 0.255 1.25 0.400 75.011 0.500 2.00 0.200 30.012 0.0100 0.500 0.200"12013 0.500 2.00 0.600 12014 0.255 1.25 0.400"75.015 0.500 0.500 0.600 12016 0.0100 2.00 0.600 12017 0.0100 2.00 0.600 30.018 0.500 2.00 0.200 12019 0.255 1.25 0.400"75.020 0.0100" 2.00 0.200 30.021 0.255 1.25 0.400"75.022 I 0.255 | 1.25 I0.400]" 75.0melting point and infrared spectrum were obtained.Results and DiscussionThe singular reason why we chose microwave heatingwas to drastically shorten the reaction time. Clearly, withoutany statistical analysis, the efficacy of microwave heating wasaffirmed. However, the recommended 800 Watts ofmicrowaveheating (Verekova et al. 1999) was discovered to be somewhatexcessive. We found that 330 Watts of microwave heatingprovided the energy necessary for this reaction.Another clear result from this set of experiments was theefficacy of the sodium acetate trihydrate catalyst. In general,anhydrous salts are difficult to prepare, hard to handle, and morecostly than hydrates. Therefore, the fact that sodium acetatetrihydrate proved to be a viable catalyst constitutes anothersignificant improvement in this process.The intent ofthe DOE was three-fold: 1) identify underlyingrelationships between factors, 2) develop a first-generationmathematical model of the process, and 3)provide insight forfurther development work. Inthe statistical analysis, the half-normal probability plot revealed that the main effects of all 4factors as wellas several cross-term interactions were significantMicrowave assisted acceleration of organic reactions hasjmerged within the past twenty years as a viable alternativeto conventional thermal methods (Hayes 2002, Marx 2004).Reactions carried out under conventional thermal conditions areoften accompanied bylongreaction times, undesired side productformation, and/or low yields. Microwave methodologies provideviable alternatives to classical thermal approaches for drugdiscovery efforts (Rose 2002), analytical chemistry (Kingstonand Jassie 1988), protein synthesis (Yu et al. 1992), and greenchemistry (Mingos 1994). Microwave techniques often providethe opportunity for carrying out organic transformations in asolventless or solid phase environment (Larhed et al. 2002).Journal ofthe Arkansas Academy ofScience, Vol. 60, 200697Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15https://scholarworks.uark.edu/jaas/vol60/iss1/15I98 IR. David Pace and Laura McWilliamsprocess variability). This, however, is a screening experimei t.Therefore, this experiment only gives us information concernii gfactors and interactions that may be important in explainii gprocess variability of selected responses (/. e., yield) with nthe design space. What is clear is that the sodium aceta elevel, acetic acid volume, o-chlorobenzaldehyde level, and tremicrowave time significantly impacted yield as well as severalinteraction terms. The expression for the predicted yield sgiven as Equation 3.Design- Expert© Software;X Yield Half-Normal Plot« error irom nepuc:A.NaOAc Hydrate6: Acetic AcidCo-CB O DD MWTimea Posrtive Effects i» w¦ Negative Effects -§OBo *0a. DAB?-n d§ *on acoOJBCDo DABCDz«S 90XBtc10Yield= 21.1+155 AA+8.85-12.9C-0.03D-1 1 1AAB-362.1 AC-1 A3AD-11.SBC -0.05BD +OACD+206.9 ABC/&°+O.SABD +A.XACD-0.03BCD -2.0ABCD(3)o» 3.ss t.m io.es ioi(Standardized Effect| Interactions are best understood through 3-dimensionalplots. Figure 2 shows three cube plots at the low,medium, andhigh microwave times (30 sec, 75 sec, and 120 sec), which revealthe behavior of the reaction yield at the extremes of the designspace.Fig. 1. Half-normal plot showing main and cross-term effectson the yield.The lower right edges of the cube plots reveal a mostinteresting interaction (the CD interaction shown in Table 2)between o-chlorobenzaldehyde level (C) and microwave time(D). At 30 seconds microwave time, the best yield occurswith 0.50 mol NaOAc, 0.5 mL HOAc, and 0.20 mol (or, oneequivalent) o-chlorobenzaldehyde. On the other hand, at 120seconds microwave time, the best yield occurs with 0.50 molNaOAc, 0.5 mL HOAc, and 0.60 mol (e. g., three equivalents)o-chlorobenzaldehyde. Figure 3 shows this CD cross-terminteraction with two 3-D plots (one at 30 microwave seconds,the other at 120 microwave seconds) of the yield versus NaOAclevel and o-chlorobenzaldehyde level. Clearly, after 30 secondsat 330 Watts, the optimum yieldoccured at the lowest level (1equivalent) of o-chlorobenzaldehyde and the highest level of(Fig. 1). Half-normal probability plot is the fundamentalmethod for selecting 2-level effects. Inother words, the plotof the ordered values ofa sample versus the expected orderedvalues from the true population willbe approximately a straightline. Any terms that turn out to be important for the statisticalmodel show up as outliers.It should be pointed out that many 2-, 3-, and 4-factorterms appear to be significant, but such appearances can bedeceiving. As shown in the ANOVA table (Table 2), effectsthat are significant in explaining process variability are clearlyseparated from effects that are not significant on the basis ofthemagnitude of the p-value. Small p-values (<0.05) suggest thatthere is model effect (e. g, the term is significant inexplaining001 A: NjOAcHyduU 0.S 0.01 A: NiOAeHydrjt* O.S 001 A: NjOAc Hydrit* 0.SFig.2. Cube plots of the yield at the edges of the DOE design spaceJournal of the Arkansas Academy of Science, Vol.60, 200698Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006I99IThe Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Coupleible 2. ANOVATable for the DOE.Opgrees p-valup K innifirant?Sum of Mean— -Source of F-valueSquares Square Prob>F Yes/No!- re (.'damModel 3195.584 15 213.0389"113.814 < 0.0001~YesA-NaOAc Hydrate 88.1721 1 88.1721 4/.10S09 00010 YesB-Acetic Acid 630.5121 1 630.5121 336.845 < 0.0001 YesC-o-CB 15.7609 1"15.7609 8.420109'0 0337"YesD-MW Time; 331.24 331 24 176.9618 < 0.0001"YesAB 466 9921 1 466 9921 249.486 < 0 0001 YesAC 15.7609 1 15.7609 8.42Q109'0.0337~ YesAD 8281 1 82.81 44 24044'0.0012 Yes~BC 0.202b 1 0.2025 0, 108184'O./bbii~NoBD 67.9844 1 87 9844 47 00482 0.0010 YesCD 807.6964 1 807 6964 431.504 < 0.0001 YesABC 74 8225 1 74 8225 39 9732 00015"YesABD 0 2304'1"0.2304 0 123089 0 7400"NoACD 213.7444 1 213 7444 114 1909 0 0001'YesBCD "209.0916 1 209.0916 111.7052''0.0001 YesABCD 170.5636 1 170.5636 91.12196 0.0002"YesCurvature 1305.867 1 1305.867 697.6468 < 00001 YesPure Error 9 359083 5 1.871817Cor Total 4510.81 21sodium acetate. Alternatively, after 120 seconds at 330 Watts,the optimum yield occured at the highest level (3 equivalents)ofo-chlorobenzaldehyde and the lowest levelofsodium acetate.The explanation for this unexpected result is not clear at thispoint. However, this CD interaction (or, any other interactionfor that matter) would have gone undetected in the conventionalOVATmethod ofexperimentation.At least three interactions (AB, ABC, and ABCD)identified in the DOE (see Table 2) may partially be explainedby a combination of the facts that sodium acetate/acetic acidconstitute a buffer system and that this modified Perkin reactionis acid catalyzed. Therefore, this suggests the possibility of asubsequent DOE where the levels of sodium acetate and aceticacid may be combined into one buffering pH term.ConclusionsThe DOE clearly identified that all 4 model factors areimportant in explaining the variability of the yield data.Further, an unexpected, but interesting, cross-term interactionwas identified involving o-chlorobenzaldehyde and microwavetime at 330 Watts (CD). Other interactions involving thecoupling of sodium acetate and acetic acid suggest thatcombining these terms in a single buffering pH term may beimportant insubsequent work. Additionally, it was shown thatthe anhydrous sodium acetate catalyst could be replaced by themore economical trihydrate and that high wattage microwavesare not required for this process (330 Watts work as wellas 800Watts).Acknowledgments.—We wouldlike to thank LyonCollegefor providing the chemical, instrumental, and laboratory spaceresources to carry out this research. Additionally,one ofus (DP)would like to thank Dr. Kurt Grafton for his encouragement towrite this paper. Finally, we would like to thank the ArkansasAcademy ofScience for granting us the opportunity to presentthe results ofthis work.0.5mL HOAc (LowLevel)C: d-CB120 seconds MW•g. 3. 3-D plots ofthe yieldwithin the design spaceJournal of the Arkansas Academy ofScience, Vol. 60, 200699Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15https://scholarworks.uark.edu/jaas/vol60/iss1/15100IR. DavidPace and Laura McWilliamsLiterature CitedBayne CK and IB Rubin. 1986. Practical experimentaldesigns and optimization methods for chemists. DeerfleldBeach, FL. VCHPublishers. 205 p.Box GEP, WG Hunter, and JS Hunter. 1978. Statistics forexperimenters. New York: John Wiley &Sons. 653 p.Brown FC. 1961. 4-Thiazolidinones. Chemical Reviews61:463.Carlson R. 2005. Canonical analysis of response surfaces: Avaluable tool for process development. 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DOE (design ofexperiments) indevelopment chemistry: Potential obstacles.Organic Process Research and Development 5:324-327.March J. 1985. Advanced organic chemistry. New York: JohnWiley&Sons. 1346 p.Marx V. 2004. Riding the microwave. Chemical andEngineering News 82:15.Mayo DW, RM Pike, and PK Trumper. 1994. Microscaleorganic laboratory withmultistep and multiscale syntheses,3 rdEd. New York: John Wiley&Sons. 764 p.Mingos DMP. 1994. The application of microwaves inchemistry. Research in Chemical Intermediates 20:85-91.Owen MR,C Luscombe, L-W Lai,S Godbert, DLCrookes,and D Emiabata-Smith. 2001. Efficiency by design:Optimization in process research. Organic ProcessResearch and Development 5:308-323.RoseS. 2002. Statistical design and application to combinatorialchemistry. Drug Discovery Today 7:133-138.SykesP. 1987. Aguidebook tomechanism inorganic chemistry,6thEd. Singapore: Longman Scientific Technical. 416 p.Varma RS and VNamboodiri. 2001. An expeditious solvent-free route to ionic liquids using microwaves. ChemicalCommunications 7:643-644.Vererkova E, E Pacherova, and S Toma. 1999. Examinatic qof the perkin reaction under microwave irradiatio i.Chemistry Papers 53:257.Yu HM,TS Chen, and KT Wang. 1992. Enhanced couplir gefficiency in solid-phase peptide synthesis by microwa\eirradiation. Journal ofOrganic Chemistry 57:4781-4784.Journal of the Arkansas Academy ofScience, Vol. 60, 2006100Journal of the Arkansas Academy of Science, Vol. 60 [2006], Art. 15Published by Arkansas Academy of Science, 2006

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Perkin Reaction: Rapid and Efficient Process Optimization Through a Microwave/Design of Experiments Couple

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