Electronic effects are important directing forces in the course of chem. reactions.  Small differences in these effects can bring about considerable changes in the results of very similar reactions.  Thus, although the ambident nucleophiles urea, o-​phenylenediamine and dibenzyl ketone are expected to take comparable double condensation pathway in their resp. reaction with benzil, urea reacts differently by causing benzil-​to-​benzilic acid type rearrangement.  This is attributed to the reduced availability of the lone pair of electrons on nitrogen in urea that is needed for assisting the dehydration of the intermediate

Nagendrappa, G.

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124 RESONANCE  February 2010GENERAL  ARTICLEElectronic Effects in the Cyclocondensation of BenzilG NagendrappaKeywordsBenzil, urea, o-phenylenedi-amine, dibenzyl ketone, conden-sation, cyclo-condensation,hydantoins, quinoxalines.Electronic effects are important directing forces in the courseof chemical reactions. Small differences in these effects canbringaboutconsiderable changes in theresults of very similarreactions. Thus, although the ambident nucleophiles urea, o-phenylenediamine and dibenzyl ketone are expected to takecomparable double condensation pathway in their respectivereactionwithbenzil, ureareactsdifferentlybycausingbenzil-to-benzilic acid type rearrangement. This is attributed to thereduced availability of the lone pair of electrons on nitrogenin urea that is needed for assisting the dehydration of theintermediate.IntroductionApopular experiment performed inMSc organic chemistry labo-ratory classes is the following sequence of simple preparationsstarting from benzaldehyde, which is elaborated schematically in(s1–s6) [1-3].Homocyclic/Heterocyclic compdPhHNO3Ph PhOOHCHO Ph PhOOPh OHOHOPhVit B1OH_or CN_The exercise provides a good opportunity to teach and learnseveral preparativeprocedures anddiverseorganic reactionmecha-nisms. It also offers a chance to train students in the application ofspectroscopic techniques, particularly IR and UV, to followstructural changes and functional group transformations thataccompany the conversion of starting compound to product ineach individual reaction. The conversion of benzaldehyde tobenzoin (s1) was discussed in some detail in an earlier article(Resonance, Vol.13, pp.355–368, 2008),which covered the greenchemistry aspect too [3]. In this article three condensationG Nagendrappa was aprofessor of OrganicChemistry at BangaloreUniversity, Bangalore, andProfessor and Head of theDepartment of MedicinalChemistry, SriRamachandra (Medical)University, Chennai, fromwhere he recently retired.He continues to teach anddo research. His work is inthe area of organosiliconchemistry, synthetic andmechanistic organicchemistry, and clay-catalysed organic reactions(Green Chemistry).GENERAL  ARTICLE125RESONANCE  February 2010reactions of benzil (s4–s6) are taken up for discussionwith a viewto show how subtle differences in electron shift in the reactantwould bring about interesting changes in the reaction course.Benzaldehyde – Umpolung and Benzoin FormationThe benzaldehyde-to-benzoin transformation, (s1), is an excel-lent example of nucleophilic addition of an aldehyde to anotheraldehyde by charge reversal (umpolung) process catalysed byvitamin B1 or other environmental friendly organo catalysts [3].Oxidation – Benzoin to BenzilThe oxidation of benzoin to benzil is effected by concentratednitric acid, (s2), and not by the conventional oxidising agents likepermanganate, dichromate or chromic acid, because in thesecases benzoinproduces benzaldehyde/benzoic acid, but not benzil.Copper sulphate in pyridine also oxidizes benzoin to benzil inSubtle differencesin electron shift inthe reactant wouldbring aboutinterestingchanges in thereaction course.Ph HOPhOHPhOVit B1PhOHPhOPhOPhOHNO3PhOPhOOHPhHOOHOPhPhOPhOPhPhO OH OPhHOPh OH PhPhOPhPhPhPhPhOPhOH2NH2N NHHNPhHOPhHO NNPhPhHNNHOPhOHNNHOPhHOPhHOPhOPhOH2NOH2NOH Ph1 2343 5 8 116 9 127 10 13(s1)(s2)(s3)(s4)(s5)(s6)126 RESONANCE  February 2010GENERAL  ARTICLEgood yield. A green chemical method of oxidation is alsoknown, in which benzoin absorbed on zeolite A is irradiatedwith microwaves to give benzil. From this the student canmeaningfully learn why HNO3 or CuSO4 in pyridine succeedswhile the other oxidising agents produce unwanted products.Base-Catalysed Reaction of BenzilLet us analyse the interesting differences in the base-catalysedcyclocondensation reactions of benzil. Benzil, a bis-acceptorsynthon with 1,2-diketo function but no -hydrogen, reactsefficientlywith two nucleophilic groups. If the two nucleophilicgroups are part of the same molecule, the so-calledcyclocondensation takes place, meaning, a cyclic product isformed, as in the three reactions exemplified in (s4–s6). Butbefore taking it up for discussion, it should be kept in mind thatbenzil, under alkaline conditions, can undergo the so-calledbenzil-benzilic acid rearrangement involving 1,2-migration ofphenyl group to give benzilic acid, (s7).PhOPhOOHPhOPhOOHPhOHOOPhPhOHOOHPh4(s7)The cyclocondensation of benzil with the two -methylenegroups of dibenzyl ketone gives the homocyclic compound,2,3,4,5-tetraphenylcyclopentadienone (also known astetracyclone), (s4). In a comparable manner, 1,2-phenylenedi-amine and urea, using their two -NH2 groups, also condensewiththe two carbonyl groups of benzil to produce the heterocycles,2,3-diphenylquinoxaline(s5), and 5,5-diphenylhydantoin (s6).Mechanism of CyclocondensationLooking at the mechanism of these three reactions, one wouldquickly notice complete resemblance between the reactions ofdibenzyl ketone and 1,2-phenylenediamine, while that of urea isstrikingly different, as the product formation here is preceded byBenzil, a bis-acceptorsynthon with 1,2-diketo function but no-hydrogen, reactsefficiently with twonucleophilic groups.1,2-phenylenediamineand urea, using theirtwo -NH2 groups, alsocondense with the twocarbonyl groups ofbenzil to produce theheterocycles,2,3 diphenylquin-oxaline(s5), and5,5-diphenylhydantoin(s6).127RESONANCE  February 2010GENERAL  ARTICLErearrangement that is reminiscent of benzil to benzilic acid reac-tion. Note that this variation occurs despite the fact that the threereactions are subjected to similar reaction conditions. That is,they are carried out in warm or refluxing ethanol under basicconditions. Therefore we have to look elsewhere for explainingthe dissimilar outcomes, and so let us consider the possiblereasons.pKa – The Key to Difference in NucleophilicityAmong the three reactants, o-phenylenediamine with pKa > 31[4] is a good base and a powerful nucleophile and does not needany additional base as catalyst. On the other hand, urea (pKa =26.8) [4] is a weaker base due to resonance, (s8), and needs theassistance of an added base for enhancing its nucleophilic effi-ciency and later on for deprotonation during dehydration step. Inthe case of dibenzyl ketone, which has no such assistance fromlone pair of electrons and has pKa = 18.7 [4], a strong base isrequired to convert it into a good carbanion nucleophile (s9), toinitiate the addition to benzil C=O and then for deprotonation leddehydration at the final phase of condensation.H2N NH2OH2N NH2ONH2H2NOOHPh PhOPh PhOH2OThe Role of Lone Pair ElectronsTo understand what is probably happening while the reactantstravel through their individual course to transform into products,let us consider only a few important steps, without going intominute details, in order to keep the discussion short but adequateand clear. To begin with, let us presume that in all three casessimilar intermediates 8, 9 and 10 are formed, (s4–s6). This wouldbe followed by the elimination of proton and -OHgroups from theadjacent positions. The removal of proton with the assistance ofa base would occur either before or together with the departure of-OH group. In the case of 8, deprotonation is likely to take placeOne would quicklynotice completeresemblance betweenthe reactions ofdibenzyl ketone and1,2-phenylene-diamine, while that ofurea is strikinglydifferent.Dibenzyl ketone, whichhas no suchassistance from lonepair of electrons andhas pKa = 18.7requires a strong baseto convert it into agood carbanionnucleophile.(s8)(s9)128 RESONANCE  February 2010GENERAL  ARTICLEfirst to form the resonance-stabilized carbanion 14 which willthen push off the -OH group, (s10). In the case of 9 and 10, thelone pair of electrons on the adjacent nitrogen can perform thesame task as the carbanion on 14 in helping the exit of -OHgroup,followed closely by abstraction of proton on nitrogen by base. Itis therefore evident that the participation of nonbonded electronson the adjacent nitrogen is crucial in forcing out the hydroxygroup. Herein lies the secret of the difference between thereactions of urea and o-phenylenediamine. The nonbondedelectrons in urea intermediate 10 are engaged in resonance toconsiderable extent with the adjacent carbonyl group, (s11),similar to the negative charge on carbanion of 14, (s10).OPhHOPhHO-H+PhPhOPhHOPhHO PhPhOPhHOPhHO PhPhOPhPhHO PhPhOPhPhPhPh_8 1114(s10)On the other hand, in the case of o-phenylenediamine intermedi-ate 9 the involvement of the nitrogen lone pair of electrons byresonance with benzene ring will be less significant, and theseelectrons are available to act as the driving force for the departureof -OH group. Because of such subtle differences between them,the intermediates 9 and 10 take different routes in their furthertransformation. Since the -OH in 10 is not removed quickly byintramolecular process, the intermolecular abstraction of proton(on -OH or -NH-) by base becomes a kinetically preferred pro-cess. Because the hydroxy protons (pKa ~16) are much moreacidic than the amide protons (pKa ~24), the proton that isremoved in 10 is the one from the -OH group, and not from -NH-group. This results in the formation of the alkoxide ion 15, theconsequence of which is the same as in benzil-benzilic acidrearrangement, that is the 1,2-migration of the phenyl group tofinallygive5,5-diphenyl-2,4-imidazolidinedione, (s12), also called5,5-diphenylhydantion or phenytoin.Phenytoin is one of the oldest drugs used and still in use in thetreatment of seizures (epilepsy) and irregular heart beats orIn the case of 9and 10, the lonepair of electronson the adjacentnitrogen canperform the sametask as thecarbanion on 14 inhelping the exitof -OH group.Because the hydroxyprotons (pKa ~16)are much more acidicthan the amideprotons (pKa ~24),the proton that isremoved in 10 is theone from the -OHgroup, and not from-NH- group. Thisresults in theformation of thealkoxide ion 15, theconsequence ofwhich is the same asin benzil-benzilic acidrearrangement..129RESONANCE  February 2010GENERAL  ARTICLEcardiac arrhythmia in medical parlance [5,6]. Quinoxaline de-rivatives show a variety of biological activities. They possessanti-HIV activity and are being tested for treatingHIV infections.They also find use as herbicides, fungicides and insecticides.Quinoxaline moiety occurs as part of a number of natural prod-ucts [7,8].HNNHOPhHOPhHOHNNHOPhHOPhHOHNNHOPhHOPhHO_ _1010 13HNNHOPhHOPhHOHNNHOPhOPhHOHNNHOPhPhOH__O154NHHNOPhPhO13H2NH2NOOHOHPhPhOA Possible Alternative MechanismAt this stage a question arises, namely, whether the product 13would have formed by the reaction of urea with benzilic acid(s13), which can initially be formed by the rearrangement ofbenzil with alkali present in themedium, as in (s7). However, wefound in an independent experiment that benzilic acid, whentreatedwith urea under identical experimental conditions, did notreact but was recovered without change. This shows that thecyclo-condensation of urea with benzil follows the mechanisticpathway given in (s6) and (s12) taken together, and furtherindicates that urea reacts faster with benzil than hydroxide ionand therefore it is a better nucleophile.An Educative ExerciseThis exercise demonstrates howeven a small variation in electrondistribution can have profound effect on the course of a reaction(s11)(s12)(s13)Phenytoin is one ofthe oldest drugsused and still inuse in thetreatment ofseizures (epilepsy)and irregular heartbeatsBenzilic acid, whentreated with ureaunder identicalexperimentalconditions, did notreact but wasrecovered withoutchange.130 RESONANCE  February 2010GENERAL  ARTICLEAddress for CorrespondenceG NagendrappaEmail:gnagendrappa@gmail.comleading to structurally distinct products. Also note that a goodknowledge of electronmovement and application of pKa data arevery useful in the proper understanding of the apparently intrigu-ing reaction mechanism.The IR spectroscopy can be very effectively employed here topursue the structural changes occurring through the whole se-quence. The carbonyl stretching band is one of the mostrecognisable absorption frequencies. The C=O peak is sensitiveto a varietyof electronic and steric effects. Its absence or presenceand position are convincing evidence in confirming the structureof the molecule in question. Therefore this absorption peak canserve as a good guidance to track the success of a particularreaction in the sequence. The O-H and N-H stretching bands canprovide additional information.Considering all these points it is evident that this is a highlyinstructive and worthy set of experiments for MSc classes. Thecomplete exercise may take about 3–4 laboratory hours.Suggested Reading[1] B S Furniss, A J Hannaford, P W G Smith and A R Tatchell, Vogel’sTextbook of Practical Organic Chemistry, 5th edition (Pearson edition),p.1101, p.1153, p.1190, 1980.[2] JMarch, Advanced Organic Chemistry, 4th edition, John-Wiley, pp.1080,1992.[3] G Nagendrappa, Resonance, Vol 13, pp.355–368, 2008.[4] Bordwell pKa Table, http://www.chem.wise.edu/areas/reich/pkatable/kacont.htm[5] J H Black and J M Beale Jr.,Wilson and Grisvold’s Text Book of OrganicMedicinal and Pharmaceutical Chemistry, 11th edition, LWWpublisher,pp.504, 2004.[6] T Nogrady and D F Weaver, Medicinal Chemistry – A Molecular andBiochemical Approach, 3rd, Oxford University Press, pp.122, 1988.[7] M R Islami and Z Hassani, ARKIVOC, pp.280–287, 2008.[8] RMAdlington, J EBaldwin,DCatterickandGJPritchard, J.Chem. Soc.,Perkin Trans., Vol.1, pp.668–679, 2001.A good knowledge ofelectron movementand application ofpKa data are veryuseful in the properunderstanding of theapparently intriguingreaction mechanism.

Electronic effects in the cyclocondensation of benzil

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Electronic effects in the cyclocondensation of benzil

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