Ahmad, S., Lockett, A., Shuttleworth, T. A., Miles-Hobbs, A ......ARTICLE Please do not adjust margins Please do not adjust margins Received 00th January 20xx, Accepted 00th January

Ahmad, S., Lockett, A., Shuttleworth, T. A., Miles-Hobbs, A. M.,Pringle, P. G., & Bühl, M. (2019). Palladium-catalysed alkynealkoxycarbonylation with P,N-chelating ligands revisited: a densityfunctional theory study. Physical Chemistry Chemical Physics, 21(16),8543-8552. https://doi.org/10.1039/c9cp01471c

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Pleasedonotadjustmargins


Received00thJanuary20xx,Accepted00thJanuary20xx

DOI:10.1039/x0xx00000x

Palladium–catalysedAlkyneAlkoxycarbonylationwithP,NChelatingLigandsRevisited:ADensityFunctionalTheoryStudyShahbaz Ahmad,a Ashley Lockett,a Timothy A. Shuttleworthb Alexandra Miles-Hobbs,b Paul G.PringlebandMichaelBühl,*a

ArevisedinsitubasemechanismofalkynealkoxycarbonylationviaaPdcatalystwithhemilabileP,N-ligands(PyPPh2,Py=2-pyridyl)hasbeen fully characterisedat theB3PW91-D3/PCM levelofdensity functional theory.Key intermediatesonthis route are acryloyl (η3-propen-1-oyl) complexes that readilyundergomethanolysis.With twohemilabileP,N-ligandsand one of themprotonated, the overall computed barrier is 24.5 kcalmol-1,which decreases to 20.3 kcalmol-1 uponprotonation of the second P,N-ligand. This newmechanism is consistent with all of the experimental data relating tosubstituent effects on relative reaction rates and branched/linear selectivities, including new results on themethoxycarbonylationofphenylacetyleneusing(4-NMe2Py)PPh2and(6-Cl-Py)PPh2ligand.Thisligandisfoundtodecreasecatalytic activity over PyPPh2, thus invalidating a formerly characterised in situ base mechanism.

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Introduction

The regioselective, direct synthesis of fine chemicals fromsustainable and abundant resources is highly desirable forindustrial chemical manufacture. The key challenges within thisarea include the availability of commercially viable catalysts,efficient reaction time and conditions, realistic isolationprocedures,broadsubstratescopeandhighatom-economy.Usingtransition metal catalysts, homogeneously catalysedcarbonylations are important industrial processes1-5 that can beconducted with high chemo- and regioselectivities, efficientlyextending carbon chains.3,6 Transition metal catalysedalkoxycarbonylation(hydroesterification)ofalkynes(Scheme1)isa direct route to the corresponding acrylate esters with 100%atomeconomy.7-14

Scheme1

Methoxycarbonylation of propyne yields methyl methacrylate(MMA),7, 8, 15-21 the precursor to poly(methylmethacrylate), alsoknown as Perspex.22 There is a growing demand in the use ofPerspexforliquid-crystaldisplay(LCD)screens,especiallyintouchscreenelectronics.23

Currently,an important route toMMAonan industrial scale isatwo-step process from ethene. The first step is thehomogeneously catalysed methoxycarbonylation of ethene toyield methyl propionate (MeP) followed by a heterogeneouslycatalysedconversionofMePtoMMA.22,24-27

Due to their hemilabile coordination modes, P,N-ligands are ofconsiderable interest in homogeneous catalysis. Directhomogeneous methoxycarbonylation of propyne under mildconditionsisanattractiverouteforthesynthesisofMMAusingahemilabile Pd(P,N-chelate) catalyst.7-10, 28-30 Drent’s initial worksuggestedacarbomethoxymechanismwithterminationinvolvingintramolecular proton transfer from a protonated 2-pyridyldiphenylphosphine (PyPPh2) ligand.

7Subsequent labelling studiesbyScrivantietal.suggestedthatthecyclemightbeinitiatedbyaprotontransferfromPyPPh2ontocoordinatedalkyne.

7,11

The Bühl group has previously applied state-of-the-art densityfunctionaltheory(DFT)studiestounravelthemechanisticdetailsof homogeneous methoxycarbonylation of propyne using ahemilabile Pd(P,N-chelate) catalyst. A number of possiblepathways (previously labelledA - D) were considered, of whichonly one appeared to be consistentwith observed activities andselectivities(pathwayD,Scheme2).29,30Thismechanisminvolvesproton shuttling by the pyridyl groups in the initiation andterminationsteps.Thependantpyridylmoiety(whenprotonated)can act as an in situ acid, protonating coordinated propynefollowed by thermodynamically favoured CO insertion and thendeprotonating coordinated methanol to promote rapid esterformation. The unfavourable steric interaction between thearomatic ringof the ligandandthemethylgroupof thepropynepromotestheobservedhighregioselectivity(Scheme2).

Scheme2.Bühl’spathwayD.29,30

Basedonthismechanism,an increase inbasicityof the2-pyridylmoiety should facilitate the critical proton transfer steps, andindeed it was predicted computationally that the 4-dimethylamino-2-pyridylligand(4-Me2N-Py)PPh2shouldlowertheoverallbarrierofthewholecyclesignificantly,thusincreasingtheoverall catalytic activity.29 In the Pringle groupwe have put thisprediction to the test for the methoxycarbonylation ofphenylacetylene. Rather disappointingly, it transpires that themorebasic ligand(4-Me2N-Py)PPh2doesnot increasetheactivityover the parent PyPPh2 and indeed, a decrease in activity isobserved. We have thus revisited the original mechanismcomputationally and now present a new pathway that isconsistentwithallavailableexperimentalinformation.

ResultsandDiscussion

1.MethoxycarbonylationofPhenylacetyleneTo test the predicted effect of the (4-Me2N-Py)PPh2 ligand, wesynthesised it and used it in the Pd-catalysedmethoxycarbonylationofphenylacetylene.Weusedthissubstraterather than propyne, because it is a liquid at room temperatureand thus more easily handled. We have confirmedcomputationally that our hypothesised mechanism is notdependent on this particular choice of substrate. We haverecomputedpathwayDatthesamelevel,replacingtheMeC≡CHwith PhC≡CH. As documented in the Supporting Information (SI,see Table S1 and Figures S1 and S2) the general shape of thereactionprofile, aswell as keybarriers are very similarongoingfrom propyne to phenylacetylene. Importantly, for bothsubstrates,essentiallythesamelowering intheoverallbarrierofthewholecycleiscomputedongoingfromthePyPPh2tothe(4-Me2N-Py)PPh2 ligand (see SI). Predictions made for propyne assubstrateshouldthusbeentirelytransferabletophenylacetylene.

We had anticipated that the dimethylamino group in (4-Me2N-Py)PPh2wouldbe sufficiently basic to beprotonated in the veryacidic conditions under which the catalysis is carried out andtherefore may not produce the desired electron-rich pyridylgroup.For this reason, inaddition to thepreviously reported (4-

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Me2N-Py)PPh2 we also prepared the p-anisyl ligand (4-MeO-Py)PPh2byasimilarroute(Scheme3)inthebeliefthatthiswouldhavethepropertiesofanelectron-richpyridylsubstituentwithoutasignificantriskofprotonationofthemethoxysubstituent.

Scheme3.Preparationof(4-Me2N-Py)PPh2and(4-MeO-Py)PPh2

The phenylacetylene methoxycarbonylation (Scheme 1, R = Ph)resultsobtainedunderthestandardconditions(MethodA intheExperimental)withthe2-pyridylphosphinesaregiveninTable1.Itis clear that the catalysts derived from (4-Me2N-Py)PPh2 and (4-MeO-Py)PPh2arenotasactiveastheparentPyPPh2.

Table1Catalyticmethoxycarbonylationofphenylacetylene.

Entry Liganda Mb Convat

15minbConvat1hc

Convat4.5hc

Selectivityd

1 PyPPh2 A 99 100 992 (4-Me2N-

Py)PPh2A 51 78 95

3 4-MeO-Py)PPh2 A 86 98 994 PyPPh2 B 88 >995 (6-Cl-Py)PPh2 B 99 >99aPy=2-pyridyl.bReactionconditionsaregivenintheExperimentalSection. Method A was used for Entries 1-3 and Method B forEntries 4-5. cConversion and selectivity determined by 1H NMR.Each result is an average of 2 or more runs. cdThe rest of theproductwasthelinearisomer.

Since these new results do not support our previously proposedmechanism, pathway D, we have revisited the mechanismcomputationally and have uncovered a new pathway which isconsistentwiththeexperimentalresults.ForconsistencywithourpreviousresultswewilllabelthenewpathwayE.

2.RevisedInSituBaseMechanism(E)2.1GeneralMechanism.AmoredetailedconformationalanalysisofthePyPPh2ligandsinintermediates1-9hasnowrevealedthatsomerotamerswithdifferentorientationofthePysubstituentareslightly lower in energy than the ones reported previously. Inaddition, we have located the transition states of all steps thatinvolveadditionofreactantsordissociationofproduct,whichhadbeenneglectedbefore.Noneoftheserefinementsresultedinanyqualitative changesof themechanism.Suchaqualitative changewasfound,however,whentheacylintermediate(4ainScheme2)was scrutinised further. What has been revealed is that anisomeric acryloyl complex is accessible (complex 4 discussedbelow),whichisslightlyhigherinenergythan4aby1.1kcalmol-1.OnpathwayD,migratoryCO insertion into4aaffordeda looselyboundMMAproductthatwaseasytodissociatefromthemetal.In contrast, migratory insertion in the new complex 4 affords averystableproductcomplexwithstronglyboundMMA(complex7discussedbelow).ThisnewthermodynamicsinkonpathwayD,whichhadbeenoverlookedbefore,would raise theoverall free-energyspanof thewholecycle from22.9kcalmol-1 29, 30 to41.5kcalmol-1(addingthefree-energydifferencebetweenthepresent

isomer 7 and the previous TS5–6), which would seem to bedifficult to overcome even at the elevated experimentaltemperature.However,anewmechanismformethanolysisoftheacryloylcomplexwasfoundwithasignificantlylowerbarrierthanthatoftheacylcomplex(7ainScheme2),whichmakesthewholeprocessviableagain.Basedonthesefindingswehavenowtracedacompletecycle(termedpathwayE),whichisdiscussedindetailbelow.

Inaddition,anotherisomerofcomplex1hasbeenlocated,which

isstabilisedthroughanintramolecularNH...Nhydrogenbond(1a,Figure 1), and which is now taken as the zero point of all ourenergies.Before initiating thewhole reactionbyprotonating thecoordinated alkyne, 1a first must rearrange to Pd(II) complex 1(ΔG1a!1 = 7.8 kcal mol

-1 and ΔG‡1a!1 = 14.4 kcal mol-1). The

protonation of propyne in complex 1 gives rise to an agosticintermediate2i(ΔG1!2i=-5.4kcalmol

-1andΔG‡1!2i=5.7kcalmol-

1).AlowkineticbarrierviaTS2i–2suggestsafastconversionof2iinto2 (ΔG2i!2 = -9.5 kcalmol

-1 andΔG‡2i!2 = 0.8 kcalmol-1). CO

displaces the chelating nitrogen of the pyridylmoiety via TS2–3forming intermediate3 (ΔG2!3=-3.4kcalmol

-1andΔG‡2!3=8.6kcalmol-1) through a large enthalpic gain (Figure 1). This part isessentially identical to thepreviouspathwayD, except for someminor modifications of the energetics from the differences inconformations.

Figure 1. Free energy profile using methanol as the model solvent for initial proton transfer and CO uptake (B3PW91-D3/ECP2/PCM level). Energies (ΔHandΔG) are in kcal mol-1 relative to 1a.

Thekeystepisnowthedirectformationoftheacyloylcomplex4throughmigratoryCOinsertion(Figure2,theelectronicstructureofthiscomplexisdiscussedbelow).Thefinalstepofmethanolysishas now been divided into two sub-steps, the one that leads totheproductionofMMAandtheotherthatdissociatesMMAfromthe catalytic system (Figure 2 and Figure 3, respectively). In thefirst sub-step, MeOH associates to the complex via a hydrogenbondingMeO–H.....N interactiontothenitrogenofoneof the2-PyPPh2moietiesgivingrisetoanintermediate5(ΔG4!5=1.5kcal

N

Z

Li N

Z

PPh2

ClPPh2

Z = NMe2 or OMe

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mol-1).Then,theacryloylgrouprearrangesviaTS5–6(ΔG5!6=2.9kcal mol-1 and ΔG‡5!6 = 3.6 kcal mol

-1) to form a very reactiveketene-like intermediate. The associated MeOH can easilyperform a nucleophilic attack at the activated acyl group of theketeneviaTS6–7,assistedbythenearbyPygroupwhichactsasan in situ baseaccepting theproton fromMeOH (Figure4). Thisstep leads to the formation of a low-lying MMA coordinatedproduct7 (ΔG6!7 = -24.1 kcalmol

-1 andΔG‡6!7 =2.7 kcalmol-1).

TheeaseofthisstepwithitsverylowbarrierisremarkableifonerecallsthatonpathwayD,methanolysisoftheacylcomplex7aisthemostdifficultstep,withthehighestactivationenergy.

Figure 2. Carbonylation,MeOHuptake, and formationof keteneandMMA.Energies(ΔHandΔG) areinkcalmol-1relativeto1a.

Figure3.MMAdissociationandregenerationof1a.Energiesareinkcalmol-1relativeto1a.Thesolidlineindicatesfreeenergiescorrectedforbasis-setsuperpositionerror(BSSE),withtheBSSE-correctedΔHandΔGencircled.

In 7, MMA is strongly bound to the metal atom and fulldissociationishighlyendergonic,withacomputedΔGof11.0kcalmol-1 (for the reaction 7→ [Pd(PyPPh2)(HPyPPh2)]

+ (8) +MMA).WelocatedanumberofassociativeinterchangepathwayswhereMMAisreplacedwithfreshreactant,propyne,throughtransitionstateswithfourligandscoordinatedtoPd.However,thefullMMAdissociation indicated to be more favourable than all the otherpathways(withakineticbarrierofΔG‡7!8=16.8kcalmol

-1).Thepropyneuptaketo8 regeneratesthecomplex1a (ΔG8!1a= -16.5kcalmol-1).

Scheme4.CatalyticcycleofpathwaysD(right)andE(left)involvingP,NligandasaninSituBase,accordingtoDFT.

ThekeyintermediatesinpathwayEaretheacryloylcomplexes4-6. Such complexes are known (for selected examples seereferences 31-36), but their involvement in alkoxycarbonylationhas, to our knowledge, not been suggested before. From theoptimisedstructuresinFigure4andthebonddistancesinTable2itcanbeseenhow,uponadditionandreorientationofMeOH,themetal atom isdisplaced fromaposition closer to the carbonylCatomtotheterminalmethylenegroup.Inisomer6theligandhassignificant ketene character, apparent from the short C2-C3distanceandanincreasedC2-C3-Oabondangleapproaching180°.The trends in bond distances are reflected in the computedWibergbondindices(WBIs),ameasureforthecovalentcharacterof a bond37 (which tends to adopt values close to 1 and 2 forcovalent single and double bonds, respectively, affording lowervaluesforbondswithhighioniccharactersuchasthePd-CbondsinTable2).

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Figure4.Optimisedstructuresofintermediates4-6

Scheme5.Labellingschemeforcomplexes4-6.

Table2:Selectedbonddistances(inÅ)withWibergbondindices[insquarebrackets]ofcomplexes4-6,aswellasselectedbondangles (in degrees, for atom labelling see Scheme 5), B3PW91-D3/ECP2/PCMlevel.Parameter 4 5 6

d(Pd-C1) 2.213[0.38] 2.295[0.31] 2.063[0.53]d(Pd-C2) 2.236[0.20] 2.263[0.18] 2.265[0.20]d(Pd-C3) 2.104[0.48] 2.054[0.54] 2.757[0.15]d(C1-C2) 1.398[1.46] 1.382[1.56] 1.446[1.20]d(C2-C3) 1.435[1.18] 1.457[1.11] 1.361[1.40]d(C3-Oa) 1.183[1.95] 1.187[1.93] 1.159[2.08]d(C3-Ob) n.a. 3.481[0.00] 2.966[0.02]a(C1-C2-C3) 114.8 114.8 120.3a(C2-C3-Oa) 146.1 140.8 170.8

Inthepathwaysdiscussedsofar,wehaveassumedthatonlyoneof the PyPPh2 ligands is protonated. Under the strongly acidicconditions, however, it may well be possible that a significantfraction of the catalyst has both ligands protonated. We havetherefore recalculated the crucial steps on pathways E fordiprotonated, dicationic intermediates (see Figure S3 in the SI).Introduction of the second proton decreases the MMAdissociation barrier to 13.2 kcal mol-1, but the overall barrierremainscomparabletothatofmonocationicpathway,asnowtheoverallbarrierhasbeenshiftedtotheprotontransferstepratherthan the product dissociation step (7+ + Propyne → TS1–2i+ +

MMA, ΔG‡ = 16.8 kcal mol-1). The concomitant quantitativechanges to the energetics along with the selectivity andsubstituenteffectsarediscussedbelow.

Figure 5 Intermediates for product release on the dicationic version of pathwayE.ThesolidlineindicatesBSSE-correctedfreeenergies,withBSSE-correctedΔHandΔGencircled.

2.2Selectivityandsubstituenteffects.Thepathwaysdiscussedsofar produce branched MMA, the main product observedexperimentally. The linear/branched selectivity is determinedearlyonthepath,uponintramolecularprotonationofcoordinatedpropynein1.ThisstepinournewpathwayEisthesameasintheoriginal pathway D (where observed selectivities are wellreproduced). The minor changes in conformational preferencesfound in thepresentwork lead tonegligible changes in the finalenergetics: Intermediate 1 (leading to a branched product) ismore stable by ΔG = 2.5 kcal mol-1 (ΔH = 3.4 kcal mol-1) thanintermediate1L(leadingtothelinearproduct).Theappearanceofthe new intermediate 1a and its equivalent 1aL (leading to thelinearproduct)slightlyaffectsthecomputedselectivities,becausethe highest point on the branched pathway is TS1a-1 (i.e.formation of1),whereas on the linear pathway it isTS1-2L (i.e.the protonation of the alkyne, see Figure 6). The two kineticbarriersleadingtotheisomericproductsdifferbyΔΔG‡=3.7kcalmol-1, corresponding to a high selectivity towards the branchedproduct at 45 °C (Table 3), which is consistent with theexperimental results. On the dicationic pathway, no isomercorresponding to 1a exists, and the selectivity is determined bythe difference between TS1-2i+ and TS1L-2L+ (see Figure S4),affordingaslightlyreducedΔΔG‡=2.9kcalmol-1.

SubstitutingthePymoietywitha6-Me-Pygroupfurtherenhancesthe selectivity toward the branched product. This is fully borneout inourcalculations,where thegreater stericeffectsongoingfrom PyPPh2 to by (6-Me-Py)PPh2 increases ΔΔG

‡ from 3.7 kcalmol-1to6.3kcalmol-1.Thelattervaluecorrespondstoaselectivityof99.99%,ingoodagreementwiththeexperimentalobservationstowardsselectivity.

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Figure6.Pathwaysforformationofbranched(right)andlinear(left)products;energies(ΔHandΔG)areinkcalmol-1relativeto1a.SelectivityisgovernedbythedifferencebetweenTS1a-1andTS1-2L.

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Inthecontextoftheoverallactivitiesdiscussedinthenextsection,wealsoevaluatedtheselectivity-determiningdifferenceinthefreeenergybarrierfortwootherligandswithNMe2andClsubstituentsin 4- and 6-positions of the 2-pyridyl moiety, respectively. In allthese cases, the high branched selectivity is predicted to bemaintainedorslightlyenhanced(ΔΔG‡valuesinupperhalfofTable3). Only for the dicationic mechanism with PyPPh2 and (4-Me2N-Py)PPh2ligands,aslightreductioninselectivitywouldbepredicted(lowerhalfofTable3).

Table3:Effectsofdifferent2-pyridylphosphineligandsystemson branched to linear products selectivitiesa and the overallenergybarriers (energyspan,ΔG‡MARI!HETS).All thevaluesaregiveninkcalmol-1.

Ligand ΔΔG‡ %Branched(at45°C)EnergySpan

MechanismEPyPPh2 3.7 99.71 16.8(6-Me-Py)PPh2 6.3 99.99 16.8(4-Me2N)PyPPh2 4.4 99.91 18.2(6-Cl-Py)PPh2 5.9 99.99 15.9(4-Cl-Py)PPh2 4.8 99.95 17.9MechanismE(Dicationic)PyPPh2 2.9 98.99 16.8(6-Me-Py)PPh2 4.7 99.94 18.2(4-Me2N-Py)PPh2 2.5 98.12 19.6(6-Cl-Py)PPh2 5.7 99.99 16.4(4-Cl-Py)PPh2 3.8 99.78 16.7

aFor mechanism E, ΔΔG‡ = ΔG‡1L!2L – ΔG‡1!1a (cf. Table S6), for mechanism E

(dicationic),ΔΔG‡=ΔG‡1L!2L+–ΔG‡1!2i

+(cf.FigureS4)2.3 Catalytic activity and substituent effects. The overall kineticefficiency and, in particular, substituent effects on it, can beevaluatedusingKozuchandShaik’s38-40energeticspanmodel.Thismodel identifies the rate-limiting states (as opposed to a singlerate-limiting step) as those that maximise the energy differencebetween the lowest intermediate and the highest transition stateon a continuous (free-)energy profile of a catalytic cycle. On themonocationicreactionpathwayE,wehave identified intermediate7asthemostabundantreactionintermediate(MARI)andTS7–8ashighestenergytransitionstate(HETS).TheresultingoverallbarrierbetweenMARI andHETS is 16.8 kcalmol-1, consistentwithahighTOF at 45 °C. For pathway D, the overall barrier was originallyreported to be 22.9 kcal mol-1, however this value is erroneousbecause one of the important intermediates, namely 7 in thecurrent investigation (which is the MARI for pathway E) wasoverlookedandmissingfromthereactionprofile.TheMARIonthereaction profile of pathway E ismore stable by 19.3 kcalmol-1 infree energy (21.6 kcal mol-1 in enthalpy) than the MARI on thereactionprofileofpathwayD.Thus,theoriginalpathwayDwithits

HETS for methanolyis of the acyl complex should have an actualoverall free energy barrier of more than 40 kcal mol-1, much toohightobeovercomeundertheexperimentalconditions.

For the original pathwayD, introduction of an NMe2 group in 4-position of the 2-Py moiety was predicted to lower the overallbarrier notably (by 3.6 kcal mol-1).29, 30 In contrast, in our newmechanismE,thesamesubstitutionraisestheoverallbarrierfrom16.8kcalmol-1 to18.2kcalmol-1 (seeenergyspanvalues inupperhalfofTable3).ThisincreaseintheoverallbarriershoulddecreasetheTOFrelative to thatof theoriginalsystem, ingoodagreementwiththeexperimentalresultsdiscussedinSection1.Thereasonforthisdifferent substituenteffect inpathwaysD andE is that in theformer,thehighesttransitionstate(HETS)isthatformethanolysis,which is significantly reduced as the basicity of the Py group isincreased, whereas in the latter (pathway E), the HETS is forproduct release,which isonly littleaffectedby thebasicityof theligand.

For thedicationic route,whichwewouldexpect tobecomemorerelevant with decreasing pH, an overall barrier of 16.8 kcal mol-1between MARI and HETS is computed, i.e. same as that on themonocationic pathway E. The MARI on both pathways(monocationicanddicationic)are7and7+,thoughdifferentspecieswere identified controlling the overall turnover frequency (XTOF).Details of XTOF for the dicationic pathway are given in Table S4.Going from the PyPPh2 to the (4-Me2N-Py)PPh2 ligand on thedicationicpathway slightly increases theoverall barrier, from18.2kcalmol-1 to19.6kcalmol-1 (which shoulddecrease thepredictedTOF).41

Since an increase of ligand basicity causes the overall activity todecrease slightly, a reduction of basicity might actually have theoppositeeffect,i.e.increasetheoverallactivity.Inordertotestthispossibility computationally, we considered two chlorinatedderivatives. When a Cl atom is placed on the 4-position of thepyridyl moiety, an increase in the overall free energy span ispredictedon themonocationicpathway;however theoverall freeenergyspanslightlydecreasedforthedicationicpathway(Table3).When theCl atom is placedon the6-position (thereby combiningelectronicandstericeffects),aslightdecreaseintheoverallbarrierispredictedforbothmonocationicanddicationicpathways(by0.9kcalmol-1and0.5kcalmol-1,compareentriesforPyPPh2and(6-Cl-Py)PPh2 inTable3).

41At lowpH,our calculations suggest that thisligandwouldthusimpartanincreaseinactivity.Encouragingly,thisprediction is supported by the results obtained at Shell42 whichshowasignificantincreaseinactivitywiththe(6-Cl-Py)PPh2ligand,in the methoxycarbonylation of propyne albeit under slightlydifferent reaction conditions [reaction temperature30°Cand45°CforPyPPh2and(6-Cl-Py)PPh2,respectively].Wehavealsotestedtheactivity of the catalyst derived from (6-Cl-Py)PPh2 in themethoxycarbonylationofphenylacetyleneandfoundthatthe(6-Cl-

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Py)PPh2 ligand does indeed produce amore active catalyst underthesameconditions(Table1,Entries4and5)aspredicted.

ConclusionsInsummary,wehavetestedpredictionsbasedonDFTabouthowtoincrease the activity of palladium catalysts with P,N hemilabileligands in alkyne alkoxycarbonylation. The simple ligandsubstitutionfrominsilicodesign,namelygoingfromPyPPh2tothe(4-Me2-N)PyPPh2 ligand,was realised experimentally, but failed toproduce the predicted rate enhancement.We have thus revisitedandrevisedtheoriginallyproposedmechanism(D)computationallyat the B3PW91-D3/PCM level of density functional theory. Onreaction profiles of the revised mechanism (E), highly reactiveacryloyl and ketene-type intermediates are identified,which havevery low barriers for the alcoholysis step and an overall kineticbarrierofΔG‡=16.8kcalmol-1.

Barriers controlling branched/linear selectivity are comparable inboth pathways D and E, which are improved on going from 2-PyPPh2to(6-Me-Py)PPh2and(6-Cl-Py)PPh2ligandsystemstowardsthebranched-formingroute.Both(6-Me-Py)PPh2and(6-Cl-Py)PPh2ligand systems are analogous to each other on controlling theselectivities,andthelatteralsodecreasestheoverallbarrierto15.9kcalmol-1.

Underhigheracidconcentrations,modeledbytwoprotonatedP,N-ligands, alkyne alkoxycarbonylation may follow the dicationicversionof insitubasemechanism,againwithanoverallbarrierof16.8kcalmol-1

UnliketheresultsobtainedfortheoriginalpathwayD,onthenewpathwayE the (4-Me2N-Py)PPh2 ligand system isnow indicated todecreasethecatalyticactivity.Ontheotherhand,aslightdecreaseintheoverallbarrierispredictedforthe(6-Cl-Py)PPh2ligandsystemat higher acid concentrations. This prediction was testedexperimentally and the results show that the (6-Cl-Py)PPh2 doesindeed produce a more active catalyst for the carbonylation ofphenylacetylene.

Wehope that our detailed computational insightswill help in thedesignoffurtherimprovedcatalystsforcarbonylationbytuningthestereoelectronicpropertiesoftheligand.

ExperimentalSection

LigandSynthesisandCatalysisAllreactionswerecarriedoutunderanatmosphereofdrynitrogen,unlessotherwisestated,usingstandardSchlenklinetechniquesandoven dried (200 °C) glassware. CH2Cl2, Et2O, THF, toluene andhexane were collected from a Grubbs type solvent purificationsystem,43 and deoxygenated by bubbling with N2 for 30 minutes.CD2Cl2wasdriedoveractivated4Åmolecular sieves for72hoursand deoxygenated by successive freeze-pump-thaw cycles.MeOHwaspurchasedasanhydrous,storedover3ÅmolecularsievesanddeoxygenatedbybubblingwithN2 for30minutes.

1H, 13Cand 31Pand NMR spectra were recorded at ambient temperature unlessotherwise statedon Jeol ECP (Eclipse) 300, Jeol ECS 300, Jeol ECS400, Varian 400-MR, Varian VNMRS 500 spectrometers and aBrukerAvanceIIIHD500spectrometerequippedwitha13C-observe

(DCH) cryogenic probe. Chemical shifts δ are given in parts permillion (ppm) and coupling constants J are in Hz. 1H and 13Cchemical shifts were referenced to residual solvent peaks. 31Pchemicalshiftswerereferencedto85%H3PO4.MassSpectrawererecordedbytheUniversityofBristolMassSpectrometryServiceona VG Analytical Autospec (EI) or VG Analytical Quattro (ESI)spectrometer. Elemental Analysis was carried out by theMicroanalyticalLaboratoryoftheSchoolofChemistry,UniversityofBristol. Thin Layer Chromatography (TLC) was performed usingMerck Kieselgel 60 F254 (Merck) aluminium backed plates (0.25mm layer of silica). Flash column chromatographywas performedusing a Biotage Isolera Spektra One Chromatographic Isolationsystem and the solvent system stated. DMAE (dried over 4 Åmolecular sieves) was purchased from commercial suppliers andpurified before use. Other commercial reagents were used assuppliedunlessotherwisestated.PyPPh2,

44(4-Me2N-Py)PPh245were

madebyliteratureprocedures.Synthesisof(4-OMe-Py)PPh22-Bromo-4-methoxypyridine(0.500g,2.66mmol)wasdissolvedinEt2O(10cm3).Thiswascooledto-78°Candn-BuLi(1.70cm3,2.72mmol,1.6Minhexanes)wasaddeddropwise,givingabrightorangesolution.Afterstirringfor30minutesatthistemperature,ClPPh2(0.40cm3,2.22mmol)wasaddeddropwiseandthereactionallowedtowarmtoambienttemperatureandwasstirredfor2hours,afterwhichdeoxygenatedH2O(10cm

3)wasaddedtoquenchthereaction.TheEt2OlayerwasextractedandtheaqueouslayerwashedwithEt2O(2x10cm

3).Theorganicportionswerecollected,driedoverNa2SO4,filteredandthesolventremovedinvacuotoyieldthecrudemixtureasapinkoil.Recrystallisationfromhexane(ca.5cm3)at-20°Cgavetheproductasanoffwhitesolid(0.527g,81%).1HNMR(400MHz,CD2Cl2):δH8.50-8.49(m,1H,pyH(H-6)),7.42-7.33(m,10H,phH),6.73-6.71(m,1H,pyH(H-5)),6.66-6.65(m,1H,pyH(H-3)),3.72(s,3H,OCH3).

13C{1H}NMR(126MHz,CD2Cl2):δC166.1(d,

1JC,P=4.5Hz,pyC(C-2)),165.6(d,3JC,P=4.2Hz,

pyC(C-4)),152.0(d,3JC,P=13.5Hz,pyC(C-6)),137.0(d,1JC,P=10.8

Hz,phC(C-1)),134.7(d,2JC,P=19.9Hz,phC(C-2andC-6)),129.6(s,phC(C-4)),129.1(d,3JC,P=7.2Hz,phC(C-3andC-5)),115.3(d,

2JC,P=20.1Hz,pyC(C-3)),108.4(s,pyC(C-5)),55.6(s,OCH3).

31P{1H}NMR(162MHz,CD2Cl2):δP-2.8(s,Ph2PR).HR-MS(EI):m/zcalc.forC18H16NOP[M]

+=293.0970;obs.=293.0980.Elem.Anal.found(calc.forC18H16NOP):C,73.26(73.61);H,5.30(5.50);N,4.76(4.73).Synthesisof(6-Cl-Py)PPh2Thisligandwasmadebyamodificationofaliteraturemethod.46Ph2PH(2.52g,13.5mmol)inTHF(15cm

3)wascooledto-78°Candn-BuLi(8.45cm3,13.5mmol,1.6Minhexanes)wasaddeddropwise,givingabrightorangesolution.Afterstirringthereactionmixturefor30minat-78°C,thereactionallowedtowarmtoambienttemperatureandwasstirredfor1hour.Thereactionmixturewasthenaddeddropwisetoasolutionof2,6-Dichloropyridine(2.00g,13.5mmol)inTHF(20cm3)at-78°C.Thereactionallowedtowarmtoambienttemperatureandwasstirredfor18hours.Volatileswereremovedinvacuoandthereactionwasdissolvedintoluene(20cm3).DeoxygenatedH2O(20cm

3)wasthenadded.Thetoluenelayerwasextractedandtheaqueouslayerwashedwithtoluene(3x10cm3).Theorganicportionswerecollected,driedoverMgSO4,filteredandthesolventremovedinvacuotoyieldthecrudemixtureasapaleorangesolid.RecrystallisationfromMeOHgavetheproductasawhitesolid(2.44g).TheMeOHsupernatantwasthenplacedina-20°Cfreezerwhereprecipitationoccurred.Thesupernatantwasremovedand

JournalName ARTICLE




anyremainingsolventremovedinvacuotoyieldadditionalproductasawhitesolid(combinedyield=2.97g,74%).31P,13Cand1HNMRdataallagreedwiththeliteraturevalues.47CatalyticmethoxycarbonylationofphenylacetyleneAdapted from previously reported procedure.48 Catalysis wasperformedusingaBaskerville“Multi-Cell”autoclave.Method A: The ligand (0.110 mmol) was added to the autoclaveand the system put under an atmosphere of N2. Solutions ofPd(OAc)2 (5.50 x 10

-3 mmol) in MeOH (0.5 cm3) and TsOH.H2O(0.220 mmol) in MeOH (0.5 cm3) were added, followed byphenylacetylene(5.50mmol).ThiswasthenwashedinusingMeOH(0.5cm3)andtheautoclaveflushedwiththreecyclesofCO(ca.10bar).Theautoclavewasthenpressuredto45barandheatedto60°C.Aftereither1houror4.5hours,theautoclavetransferredtoanicebathandoncecooled,thesystemwasvented.Method B: The ligand (0.55 x 10-3 mmol) was added to theautoclave and the system was put under an atmosphere of N2.Solutions of Pd(OAc)2 (2.75 x 10

-3 mmol) in MeOH (0.5 cm3) andTsOH.H2O(0.10mmol)inMeOH(0.5cm

3)wereadded,followedbyphenylacetylene(5.50mmol).ThiswasthenwashedinusingMeOH(0.5cm3)andtheautoclavewasflushedwiththreecyclesofCO(ca.10bar).Theautoclavewasthenpressurisedto45barandheatedto60 °C. After 15 minutes, the autoclave was transferred to an icebathandoncecooled,thesystemwasvented.For both methods A and B, a small sample of the product wasdissolved in CDCl3 and analysed by

1H NMR spectroscopy.Conversion and selectivity was determined by integration of thephenylacetylene alkynyl proton (δH 3.10 ppm) and the methylatropate(δH6.38and5.90ppm)andmethylcinnamate(δH7.71and6.42ppm)alkenylprotons(seeSIforthespectra).DFTComputationsWe have used B3PW9149-51 hybrid functional, which has beensuccessfully validated to study related (2-pyridyl)thiourea Pd(II)complexes52andforarangeofreactionsthatrelyuponmetals.53-56WhencoupledwithGrimme’sDFT-D3,57-59includingBecke-Johnsondamping,60, 61 this functional benchmarks well against explicitlycorrelated CCSD(T).62 DFT-D3BJ correction has been computed fortheminimisedgeometries.Geometries of all complexes were fully optimized at theB3PW91/ECP1 level, where ECP1 corresponds with the 6-31G**basissetonallnonmetalatoms, inconjunctionwiththeSDDbasison Pd, denoting the small-core Stuttgart-Dresden relativisticeffective core potential (ECP) together with its valence basis set.The nature of all the possible minima and transition states wasverified by frequency calculations within the harmonicapproximation. Harmonic frequencies were computed analyticallyand were used to obtain enthalpic corrections from standardthermodynamic expressions at 298.15 K. ThermochemicalcorrectiontermsδEGwerecarriedoutasdifferenceofthereactionfree energy of a given step (ΔEB3PW91/ECP1 ) and the correspondingfreeenergy(ΔGB3PW91/ECP1):

𝛿𝐸! = ∆𝐺!!!"!"/!"#! − ∆𝐸!!!"!"/!"#! (1)To obtain starting structures for the transition states, connectingthe intermediates, potential energy profile calculations wereperformed at the same level, B3PW91/ECP1. All potential energyprofilecalculationswerecomputedby increasing themetal−liganddistance by 0.1 Å and optimizing the remaining geometricparameters using loose convergence criteria. Taking the highestpoints of these paths, full transition state optimisations wereperformed using QST3 algorithm63 and were confirmed to link to

the respective reactants and products using intrinsic reactioncoordinate(IRC)calculations.64,65

The energies of the pre-optimised complexes were refined usingthesamefunctionalandanECP2level.AtthislevelPdwastreatedwith the same SDD pseudopotential and valence basis as in ECP1whereas6-311+G**basissetwasusedforallotheratoms.Solventeffectswereincludedbyapolarisablecontinuum(PCM)66-68modelwith methanol as a solvent. DFT-D3BJ corrections were added toaccuratelyaccountforthemissingdispersion.Thefinal∆Gand∆Hvaluesarecalculatedas:

∆G=∆E+δESolv+δEDFTD3BJ+δEG (2)

∆H=∆E+δESolv+δEDFTD3BJ+δEH (3)

where∆E,andδESolvarecomputedattheB3PW91/ECP2level,δEGand δEH are computed at the RI- B3PW91/ECP1 level.WBIs werecomputed during natural population analysis.69 The energy spansandfreeenergies fortheproductdissociationwereobtainedaftercounterpoise corrections, which were calculated by performingsingle-pointcalculationsattheB3PW91/ECP2level(seeTablesS5a– S5p on the SI). All calculations were performed using Gaussian09.70

ConflictsofinterestTherearenoconflictstodeclare.

AcknowledgementsWe thank EaStCHEM and the School of Chemistry for support.Computations were carried out on a local Opteron PC clustermaintainedbyDr.H.Früchtl.WealsothankMrLukeCrawford fortechnical assistance with some calculations. The Bristol ChemicalSynthesis Centre for Doctoral Training (BCS CDT) funded by theEngineering and Physical Sciences Research Council (EPSRC)(EP/G036764/1)andtheUniversityofBristolarethankedforaPhDstudentship(toT.A.S.).

Keywords:alkoxycarbonylation•alkynes•carbonylation•densityfunctionalcalculations•homogeneouscatalysis•methylmethacrylate•palladium•reactionmechanisms

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