Catalytic cross-coupling of diazo compounds with coinage metal-based catalysts: An experimental and theoretical study

PAPER Ca aly ic c oss-coupling o diazo compounds wi h coinage me al-based ca alys s: an expe imen al and heo e ical s udy† I an Ri illa, a W. M. C. Samee a, b Eleu e io Al a ez, c M. Ma Díaz-Requejo,* a Feliu Mase as* b,d and Ped o J. Pé ez* a We examined he abili y o Tp x M (Tp x = hyd o is(py azolyl)bo a e ligand; M = Cu and Ag) and IP MCl (IP = 1,3-bis(diisop opylphenyl)imidazol-2-ylidene; M = Cu, Ag, Au) complexes as ca alys p ecu so s o he c oss-coupling o diazo compounds. Expe imen al da a showed ha he me al cen e can be uned wi h he app op ia e selec ion o he ligand o yield ei he he homo- o he e o-coupling (c oss-coupling) p oduc s. A compu a ional s udy o he eac ion mechanism allowed he a ionaliza ion o he expe i- men al eac i i y pa e ns, and he iden ifica ion o he key eac ion s ep con olling he selec i i y: he ini ial eac ion be ween he me alloca bene in e media e and one o he diazo compounds. In oduc ion The me al-ca alyzed ca bene ans e eac ion o diazo com- pounds has cons i u ed a use ul me hodology in o ganic syn- hesis, bo h in in e - and in amolecula ashions. 1 Du ing his eac ion, unsa u a ed agmen s can be modi ied upon addi ion o a CR 1 R 2 agmen o yield h ee membe ings (Scheme 1). Also, sa u a ed X–Y bonds can be unc ionalized, affo ding he co esponding inse ion p oduc s. The main d awback o all hese eac ions consis s o he non-desi ed side- eac ion ha o igina es om he coupling o he me alloca bene in e media e wi h a second molecule o he diazo eagen (Scheme 1). Fu he , his homocoupling eac ion is a ou ed o e he addi ion/inse ion p ocesses, al hough he use o a low diazo concen a ion usually p e- cludes such coupling. Se e al g oups ha e explo ed his e- ac ion as an al e na i e syn he ic ou e o ole in syn hesis, whe e he coupling o wo agmen s always de i es om he same diazo eagen . The u henium-based sys ems we e he commonly used ca alys s o his ans o ma ion, 2 and he ansi ion me als om g oups 4–6 3 and 9–11 ha e also been employed. 4 Hodgson and co-wo ke s desc ibed 5 he c oss- coupling o wo diazoace a es o o mulae N 2 C(H)CO 2 R wi h diffe en R g oups. Bu i was no un il e y ecen ly ha Da ies and co-wo ke s ha e desc ibed a hodium-based ca a- ly ic sys em o p omo e he efficien c oss-coupling o wo dis- inc diazo compounds 6 wi h a e y high egioselec i i y owa d he Eisome [eqn (1)]. ð1Þ Scheme 1 Me al-ca alyzed ca bene ans e eac ions. †Elec onic supplemen a y in o ma ion (ESI) a ailable: C ys allog aphic da a o compound 4(CIF). Con o ma ional analysis o selec ed s uc u es. E alua ion o s e ic/elec onic effec s h ough ONIOM calcula ions. To al ene gies and Ca e- sian coo dina es o all epo ed s uc u es. CCDC 905569. Fo ESI and c ys allo- g aphic da a in CIF o o he elec onic o ma see DOI: 10.1039/c2d 32439c a Labo a o io de Ca álisis Homogénea, Depa amen o de Química y Ciencias de los Ma e iales, Unidad Asociada al CSIC, Cen o de In es igación en Química Sos enible (CIQSO), Uni e sidad de Huel a, Campus de El Ca men s/n, 21007 Huel a, Spain. E-mail: [email p o ec ed], [email p o ec ed]; Fax: +34-959219942 b Ins i u e o Chemical Resea ch o Ca alonia (ICIQ), 43007 Ta agona, Ca alonia, Spain. E-mail: [email p o ec ed]; Fax: (+34) 977 920 231 c Ins i u o de In es igaciones Químicas, Cen o de In es igaciones Isla de La Ca uja, A da Ame ico Vespucio 49, 41092 Se illa, Spain d Depa amen de Química, Uni e si a Au ònoma de Ba celona, 08193 Bella e a, Ca alonia, Spain :15. View A icle Online View Jou nal | View Issue We ha e desc ibed se e al ca aly ic sys ems based on he g oup 11 me al complexes o he addi ion 7 o inse ion 8 o CHCO 2 E (de i ed e hyl diazoace a e, EDA) o o ganic sub- s a es. In iew o he in e es on he abo e c oss-coupling e- ac ion, we ha e s udied he po en ial o ou ca alys s (Tp x Mand IP MCl; Tp x = hyd o is(py azolyl)bo a e ligand; IP = N-he e o- cyclic ca bene ligand) in his ans o ma ion, whe e we ha e ound ha bo h he coppe and sil e can be uned wi h ligands o affo d he o ma ion o desi ed ole ins. Theo e ical calcu- la ions we e ca ied ou o a ionalize he mechanis ic de ails. Resul s and discussion Ca alys sc eening o he c oss-coupling eac ion o diazo compounds P e ious wo k ca ied ou in ou labo a o y has shown ha wo amilies o g oup 11 me al-based ca alys s con aining hyd o is(py azolyl)bo a e (Tp x )o N-he e ocyclic ca bene (NHC) ligands (Scheme 2) eadily ans e ed ca bene uni s : CHCO 2 E om e hyl diazoace a e (EDA, N 2 CHCO 2 E ) o se e al sa u a ed o unsa u a ed subs a es. 7–9 The ca aly ic coupling o wo ca bene g oups was obse ed as a side eac ion, and his p ocess could be a oided by slow addi ion o EDA. The a o emen ioned wo k by Da ies and co-wo ke s 6 guided us o explo e he ca aly ic po en ial o hese compounds owa d he coupling o wo diffe en diazo compounds wi h he aim o inducing he syn hesis o he ole in de i ed om he c oss- coupling o bo h ca benes. In he i s se ies o expe imen s, we es ed he ca aly ic ac i i y o se e al Tp x -con aining complexes in he c oss- coupling eac ion o wo diffe en diazo compounds, EDA [A in eqn (2)] and e hyl 2-phenyldiazoace a e [B in eqn (2)]. ð2Þ We could expec he o ma ion o h ee ole ins: hose ha a e coming om he homocoupling (1,2) and he a ge ed he e ocoupling ole in (3) wi h bo h Zand Eisome s. As shown in Table 1, he coppe -based ca alys s exclusi ely affo ded a mix u e o die hyl uma a e and malea e (i.e., he homo- coupling p oduc s om EDA). Nei he o he o he homo- coupling ole in 2no he he e ocoupling 3we e de ec ed a he end o he eac ion, and diazo compound Bwas eco e ed. In con as , he analogous sil e -based complexes ga e 90% o he a ge ed c oss-coupling p oduc 3, whe eas he homo- coupling de i a i es 1and 2we e no o med. Diffe en E:Z egioselec i i ies we e induced by bo h sil e ca alys s (Table 1, en ies 4, 5). In e es ingly, a mino p oduc was also o med in his case, and was iden i ied as an azine (4) ha o mally de i ed om he coupling o wo molecules o diazo com- pound Ba e he loss o a molecule o N 2 . Ye desc ibed, 10 we ha e unambiguously cha ac e ized compound 4by compa - ing he li e a u e da a as well as by X- ay diff ac ion s udies (see ESI†). A e hese indings, we wonde i he complexes IP MCl (IP = 1,3-bis(diisop opylphenyl)imidazol-2-ylidene; M = Cu, Ag and Au) could be also ac i e o he eac ion shown in eqn (2), gi en hei al eady commen ed capabili ies o ca bene ans- e om EDA. 8a,b,11 Table 2 summa izes he esul s ha we ha e ob ained. F om which, he ollowing in o ma ion can be ex ac ed: (i) a halide sca enge (NaBA ′ 4 (A ′= 3,5-bis( i luo o- me hyl) phenyl)) is equi ed o he eac ion o occu wi h he Cu- and Ag-based ca alys s; (ii) he gold complex emained ca aly ically inac i e wi h and wi hou such a sca enge . Wi h coppe (Table 2, en y 2), homocoupling o EDA was obse ed as he mino p oduc , while he c oss-coupling p oduc , 3,was ob ained as he main p oduc (89%). A simila esul was obse ed wi h he sil e analogue, bu wi h he lack o 1. Scheme 2 Ligands employed in his wo k. Table 1 C oss-coupling o diazo compounds Aand Bca alysed by Tp x M(M= Cu, Ag) a En y Ca alys 1:2:3:4(%) E:Z(3) 1 b Tp B 3 Cu 100:0:0:0 — 2 b Tp Ph Cu 100:0:0:0 — 3 b CuI 100 : 0 : 0 : 0 — 4Tp *,B Ag 0 : 0 : 90 : 10 78 : 22 5Tp B 3 Ag 0 : 0 : 90 : 10 58 : 42 a Reac ion condi ions: 0.0125 mmol ca alys ; 5 mL CH 2 Cl 2 ; 0.25 mmol o each diazo compound a 5 °C. b The diazo compound B emained un eac ed in he eac ion mix u e. Table 2 C oss-coupling o diazo compounds Aand Busing IP MCl (M = Cu, Ag and Au) as a p eca alys a En y Ca alys 1:2:3:4(%) E:Z(3) 1 IP CuCl —— 2 IP CuCl + NaBA ′ 4 5 : 0 : 89 : 6 76 : 24 3 IP AgCl —— 4 IP AgCl + NaBA ′ 4 0 : 0 : 91 : 9 80 : 20 5 b IP AuCl + NaBA ′ 4 —— a Reac ion condi ions: 0.0125 mmol ca alys ; 5 mL CH 2 Cl 2 ; NaBA ′ 4 (1 equi .); 0.25 mmol diazo compounds a 5 °C. b Bo h diazo compounds emain un eac ed in he eac ion mix u e. Again, homocoupling o he diazo compound B(i.e., ole in 2) was no de ec ed. The E:Z a io o 3was simila wi h bo h me als (en ies 2 and 4), indica ing a simila ca aly ic pocke . The azine, 4, was also o med o a simila ex en o ha in he Tp x M sys em. I is wo h men ioning ha he expe imen s we e ca ied ou upon addi ion o he diazo compounds in one po ion a he beginning o he eac ion. The op imized esul s shown in Tables 1 and 2 we e ob ained a 5 °C, and no signi ican eac ion ou come was obse ed below his empe a u e. When he eac ions we e ca ied ou a oom empe a u e (23 °C) wi h Tp *,B Ag and IP AgCl as ca alys p ecu so s, he 1:2:3:4 a io o p oduc s ound a he end o he eac ion was 0 : 0 : 57 : 43 and 0 : 0 : 47 : 53, espec i ely. Fu he , bo h ca alys s p o ide a sig- ni ican inc ease o he azine, 4. The E/Zselec i i y did no change wi h he empe a u e. The abo e expe imen al da a ha e shown ha Tp x Ag and IP MCl (M = Cu and Ag) complexes a e ac i e ca alys s o he c oss-coupling eac ion o N 2 C(H)CO 2 E and N 2 C(Ph)CO 2 E o affo d he desi ed he e ocoupling-de i ed ole ins 3. Fu he , his is he i s example o g oup 11 me al-based ca alys s o his eac ion a hose le els o efficiency. A mino p oduc was iden i ied as he azine (4). On he o he hand, he Tp x Cu sys em exclusi ely led o he homocoupling p oduc s, 1. The e- o e, he e is a clea effec o he ligand (Tp x s. IP ) in he coppe case as well as an effec o he me al, Cu s. Ag, in he Tp x case. In o de o asce ain he na u e o he mechanism ha go e ns his ans o ma ion, a comple e heo e ical s udy has been ca ied ou wi h bo h he Tp B 3 M (M = Cu, Ag) and IP MCl sys ems (M = Cu, Ag, Au), which is he subjec o he nex sec ion. Compu a ional s udies The p oposed mechanism o he eac ion o N 2 C(Ph)CO 2 E (6a) and N 2 C(H)CO 2 E (6b) ca alyzed by Tp x M(5) is shown in Scheme 3. The i s s ep o his mechanism is he coo di- na ion o 6a and 6b o he ca alys (5). S a ing om he esul - ing complexes (7a and 7b), N 2 dissocia ion leads o he ac i e me alloca bene in e media es 8a and 8b ia TS1a and TS1b, espec i ely. These me alloca benes can eac wi h N 2 C(Ph)- CO 2 E (6a)o N 2 C(H)CO 2 E (6b) o o m he c oss-coupling (CC) p oduc (3), homocoupling (HC) p oduc s (1and 2), and azine (AZ, 4) (see Fig. S1a, ESI†). The c oss-coupling and homocoupling p ocesses unde go h ough TS2. I is well- known om he li e a u e 12 ha TS2 should ha e an an ipe i- plana a angemen o he M–C and C–N bonds, bu his lea es s ill some con o ma ional lexibili y associa ed wi h he app oach o he wo agmen s. We epo he e only he mos s able con o ma ion o TS2, in o ma ion on he con o ma ion- al sea ch can be ound in he ESI†sec ion. Tp B 3 M sys ems Fi s , we compu ed he ee ene gy p o iles o he eac ion o N 2 C(Ph)CO 2 E (6a) and N 2 C(H)CO 2 E (6b) ca alyzed by Tp B 3 Ag. Resul s a e summa ized in Scheme 4A. Coo dina ion o 6a and 6b on Tp B 3 Ag is ende gonic by +9.5 (7a) and +5.0 (7b) kcal mol −1 , espec i ely. The key s ep happens o be he subsequen N 2 elimina ion om 7a, leading o he me allo- ca bene 8a h ough ansi ion s a e TS1a wi h a ela i e ene gy o 19.8 kcal mol −1 . In a simila ein, he second me allo- ca bene, 8b, can be o med h ough TS1b wi h a ela i e ene gy o 22.0 kcal mol −1 . This s ep is c i ical because i cons i u es he highes ene gy poin in pa hways leading o he p oduc s. The ela i e ene gies o TS1a and TS1b indica e ha in he case o Tp B 3 Ag, N 2 C(Ph)CO 2 E will eac be o e ha N 2 C(H)CO 2 E . We analyze he o igin o he disc imina ion on he eac ion o he i s diazo molecule wi h he me al complex h ough ONIOM- (B3LYP : MM3) calcula ions wi h a mechanical embedding scheme (see Fig. S2, ESI†). This p o ed ha he eason is pu ely elec onic, when using an MM desc ip ion o phenyl he dis- c imina ion disappea ed. S a ing om he a ou ed me alloca bene (8a), wo close ene gy compe ing pa hways lead o c oss-coupling p oduc (3) and azine (4), h ough ansi ion s a es wi h ela i e ee ene - gies o 11.8 kcal mol −1 (TS2 CC ) and 12.3 kcal mol −1 (TS AZ ), espec i ely. Fu he , hese wo ansi ion s a es yield he 3:4 a io o 70 : 30, which is in easonable ag eemen wi h he expe imen al alue (90 : 10). The mos s able ansi ion s a es leading o he Eand Z o ms o he c oss-coupling p oduc s hold he ba ie heigh s o 11.8 and 11.9 kcal mol −1 , gi ing ise o he compu ed E:Z a io o 54 : 46, which is in ag ee- men wi h he expe imen ally obse ed alue (58 : 42). In bo h ansi ion s a es, Ag–C and C–N bonds a e in he an ipe i- plana con o ma ion (Scheme 3). The a ou able c oss-coupling p oduc , 3(E), is −81.1 kcal mol −1 below he en y channel Scheme 3 P oposed ca aly ic cycle o he eac ion o N 2 C(Ph)CO 2 E (6a) and N 2 C(H)CO 2 E (6b) ca alyzed by Tp x M (M = Ag, Cu). (no shown in he ee ene gy p o ile). The al e na i e pa hway leading o he homocoupling p oduc (2) om8a mus be dis- ca ded because o he high ba ie o he ansi ion s a e (22.9 kcal mol −1 o TS2 HC , mo e han 10 kcal mol −1 han he compe ing pa hways). The e o e, he e is a s ong p e e ence o N 2 C(H)CO 2 E o be he second subs a e o eac wi h he sys em. We a ibu e his p e e ence o s e ic effec s, as he sys em becomes oo c owded o accep a second subs a e con- aining a phenyl g oup. Fo he sake o comple ion, we also checked he ba ie s o he homocoupling and c oss-coupling s a ing om he less a ou able me alloca bene, 8b, ed lines in Scheme 4A. The ee ene gies o he co esponding ansi ion s a es a e p ohi- bi i ely high 21.5 kcal mol −1 (TS HC′ ) and 23.2 kcal mol −1 (TS CC′ ) o compe e wi h he pa hways h ough 8a.I ishowe e wo h ema king ha he en y o 6a as a second subs a e molecule, leading in his case o homocoupling, is also a ou ed. Calcula ed ee ene gy p o iles o he analogous Tp B 3 Cu sys em a e shown in Scheme 4B. The mos s iking diffe ence is ha now he o ma ion o 8b has a lowe ee ene gy ba ie (19.5 kcal mol −1 ) han ha o 8a (22.6 kcal mol −1 ). This is due o he ac ha he coo dina ion o N 2 C(Ph)CO 2 E o he Tp B 3 Cu is difficul , as he Cu-coo dina ion sphe e (i.e.,Cu– ligand bond dis ances) is ela i ely smalle han he Ag-based sys em (Fig. 1). As a esul , compu ed ee ene gies o 7a and he subsequen ansi ion s a e o he N 2 dissocia ion a e ela- i ely highe in ene gy. The e o e, 8b is he ac i e me allo- ca bene in e media e in solu ion. S a ing om 8b, binding o N 2 C(H)CO 2 E as he second diazo molecule is a o ed due o s e ic easons, analogously o he sil e sys em. Howe e , in his case binding o a second uni o 6b leads o he homo- coupling p oduc . IP MCl sys ems Acco ding o he expe imen al obse a ions, IP CuCl and IP AgCl sys ems canno pe o m c oss-coupling o N 2 C(Ph)- CO 2 E and N 2 C(H)CO 2 E , and hey only become ac i e in he p esence o a base, NaBA ′ 4. This obse a ion and p e ious epo s in he li e a u e 11 sugges ed ha NaBA ′ 4 could abs ac Cl − om IP MCl, leading he ac i e p ecu so s, IP M + ha may ini ia e he ca aly ic cycle. Howe e , he Au-based sys em is no ac i e o c oss-coupling o homocoupling. We ca ied ou DFT calcula ions o unde s and hese puzzling obse a ions. Ou calcula ions (summa ized in Scheme 5) indica ed ha i is mo e difficul o o m he IP M + ac i e species om he s a ing IP MCl + NaBPh 4 in he case o gold. The ela i e ene - gies a e 19.5 kcal mol −l o he coppe sys em, 21.9 kcal mol −l o he sil e sys em, and 28.0 kcal mol −l o he gold sys em. As a esul , he a ailabili y o IP Au + will be lowe han ha o IP Cu + and IP Ag + , which explains he in e io eac i i y o he gold sys em. This is no in con adic ion wi h he efficiency o he IP AuCl + EDA sys em o o he p ocesses such as C–H Scheme 4 F ee ene gy p ofiles (kcal mol −1 ) o he eac ion o N 2 C(Ph)CO 2 E (6a) and N 2 C(H)CO 2 E (6b) ca alyzed by (A) Tp B 3 Ag and (B) Tp B 3 Cu. Fig. 1 Op imised s uc u es o 7a: (A) Ag-based sys em and (B) Cu-based sys em. ac i a ion, 11 because he eac i i y depends bo h on concen- a ion and ene gy ba ie . 13 Ou expe imen al esul s showed ha bo h he IP Cu + and IP Ag + sys ems p e e c oss-coupling a he han homo- coupling. Acco ding o he ee ene gy p o iles (Scheme 6), N 2 dissocia ion om N 2 C(Ph)CO 2 E bound complex (7a) is easie han he N 2 C(H)CO 2 E bound species (7b) in bo h sys ems. The e o e, he eac ion passes h ough he me alloca bene 8a, leading o he desi ed c oss-coupling p oduc , 3. In he case o IP Ag + ,Eand Z o ms o 3a e o med wi h ba ie s o 15.5 and 18.2 kcal mol −1 , espec i ely. Fu he , he calcula ed E:Z a io o 99 : 1 ep oduced he expe imen al end (E:Z= 80 : 20). Simila ea u es can be seen o he analogous Cu-based sys em, whe e he calcula ed ba ie s o he E(17.8 kcal mol −1 ) and Z(20.4 kcal mol −1 ) p oduc s yield he E:Z a io o 99 : 1, which also suppo s he expe imen al obse a ions (76 : 24). We obse ed azine as a side p oduc wi h bo h he ca alys s, and ou calcula ed 3:4 a io o 99 : 1 o he Ag- based sys em and 100 : 0 o he Cu-based sys em suppo he expe imen al ends. I is impo an o no e ha he IP Cu + sys em p o ides homocoupling p oduc (2)asa mino p oduc due o he ac ha he ene gy sepa a ion be ween TS1a and TS1b is only 2.6 kcal mol −1 , and he e o e he me alloca bene 8b can be o med. Howe e , we did no obse e homocoupling p oduc (1) in he case o IP Ag + , because he ene gy gap be ween TS1a and TS1b is 5.5 kcal mol −1 . Ou calcula ions ep oduce all expe imen al obse a ions, and p o ides a simple a ionaliza ion o hem. Compu a ional chemis y is hus a p omising ool o he e alua ion o he po en ial efficiency o new ligands o his chemical p ocess p io o hei expe imen al es ing. Conclusions We ha e shown ha Tp x Ag and IP MCl + NaBA ′ 4 (M = Cu and Ag) complexes a e ac i e ca alys s o he c oss-coupling eac- ion o N 2 CHCO 2 E and N 2 C(Ph)CO 2 E o affo d he e ocoupled ole ins E O 2 C(H)C C(Ph)CO 2 E , which cons i u e he i s example o g oup 11 me al-based ca alys s a his le el o efficiency. The ela ed Tp x Cu complexes exclusi ely lead o he Scheme 5 F ee ene gy p ofiles (kcal mol −1 ) o he o ma ion o IP M + om IP MCl. Scheme 6 F ee ene gy p ofiles (kcal mol −1 ) o he eac ion o N 2 C(Ph)CO 2 E and N 2 C(H)CO 2 E ca alyzed by (A) IP Ag + and (B) IP Cu + . homocoupling p oduc s, E O 2 C(H)C C(H)CO 2 E . IP AuCl does no eac unde simila condi ions. This di e se eac i i y could be explained by a compu- a ional s udy on he eac ion mechanism. The eac ion akes place in a mononuclea complex, wi h one diazo compound eac ing sequen ially a e he o he . In all eac ing sys ems excep Tp x Cu, he ini ial eac ion wi h N 2 C(Ph)CO 2 E is a o ed because o elec onic easons. The second diazo compound o eac is always N 2 C(H)- CO 2 E due o s e ic easons. As a esul , he he e o- coupling p oduc is ob ained om Tp x Ag and IP MCl (M = Cu and Ag), and he homocoupling p oduc om Tp x Cu. The lack o eac i i y o IP AuCl is sa is ac o ily explained by he highe ene gy cos o displacemen o he Cl − g oup o p oduce he ac i e ca alys . Expe imen al sec ion Gene al manipula ions All expe imen s we e pe o med using con en ional acuum line and Schlenk echniques o in a d ybox. The complexes Tp x M 14 and IP MCl 15 we e p epa ed acco ding o li e a u e p ocedu es as well as he diazo compounds e hyl-2-diazo- ace a e-2-phenylace a e 16 and NaBA ′ 4 (A ′= e akis(3,5-bis- ( i luo ome hyl)phenyl)bo a e). 17 E hyl diazoace a e was pu - chased om Sigma Ald ich. NMR spec a we e eco ded a 298 K using a Va ian Me cu y 400 ins umen . GC we e un in a Va ian 3900 model. Gene al ca aly ic eac ion In a ypical expe imen , he ca alys (0.0125 mmol) was dis- sol ed in 5 mL o he CH 2 Cl 2 . In he case o IP MCl complexes, 1 equi . o NaBA 4 ′was added o he abo e solu ion. Then, e hyl-2-diazoace a e (0.25 mmol) and e hyl-2-diazoace a e- 2-phenylace a e (0.25 mmol) we e added in one po ion. The eac ion mix u e was s i ed a 5 °C un il no diazo eagen s we e de ec ed by GC. The ola iles we e emo ed unde acuum, and he esidue was pu i ied by SiO 2 -column ch oma og aphy wi h AcOE –pe oleum e he (10 : 1). NMR s udies e ealed he o ma ion o h ee p oduc s (see eqn (2)). The compounds we e iden i ied by compa ing wi h he li e a- u e da a. 10,18 Compu a ional de ails All calcula ions we e pe o med using DFT wi h he B3LYP unc ional as implemen ed in he Gaussian09 p og am. 19 The LanL2DZ 20 basis se and associa ed effec i e co e po en ials wi h a single pola iza ion unc ion we e used o Ag (1.611), Cu (3.525), and a d pola iza ion was added o B (0.4280). 21 The 6-31G(d) basis se was used o he C, H, N, O, and B a oms. 22 The SMD app oach o T uhla and co-wo ke s was applied o sol a ion ea men s, 23 whe e dichlo ome hane (ε= 8.93) was used as he sol en . All s uc u e op imiza ions we e ull in he sol en phase wi h no es ic ions, and ib a ional equency calcula ions we e pe o med in o de o con i m ha he s a iona y poin s we e minima o ansi ion s a es. All ansi ion s a es had a single imagina y equency in he op imiza ion in sol en phase. F ee ene gy co ec ions a 298.15 K and 10 5 Pa p essu e we e used, including ze o poin ene gy co ec ions. Connec i i y o he ansi ion s a e s uc- u es was con i med by elaxing he ansi ion s a e geome y owa ds bo h he eac an and he p oduc . Single-poin es calcula ions wi h M06 and B97D p oduced sligh ly wo se ag eemen wi h expe imen han he B3LYP calcula ions, he e seems o be some p oblem wi h he in oduc ion o dispe sion co ec ions in hese sys ems. Hyb id quan um mechanics/molecula mechanics (QM : MM) 24 calcula ions we e pe o med wi h a new ONIOM- (DFT : MM3) implemen a ion de eloped by ou g oup, whe e we used he Gaussian09 s anda dized in e ace o un Tinke 6.0. 25 Acknowledgemen s We hank MINECO (CTQ2011-28942-CO2-01, CTQ2011-27033 and Consolide Ingenio 2010 CSD2006-0003), Jun a de Andalucía (P oyec o P10-FQM-06292), Gene ali a de Ca alunya (2009SGR-2059 and Xa xa de Re e ència en Química Teò ica i Compu acional) and he ICIQ Founda ion o inancial suppo . No es and e e ences 1(a) M. P. Doyle, R. Duffy, M. Ra niko and L. Zhou, Chem. Re ., 2010, 110, 704–724; (b) M. P. Doyle, M. A. 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