A Switchable Gold Catalyst by Encapsulation in a Self‐Assembled Cage

Abstract Dinuclear gold complexes have the ability to interact with one or more substrates in a dual‐activation mode, leading to different reactivity and selectivity than their mononuclear relatives. In this contribution, this difference was used to control the catalytic properties of a gold‐based catalytic system by site‐isolation of mononuclear gold complexes by selective encapsulation. The typical dual‐activation mode is prohibited by this catalyst encapsulation, leading to typical behavior as a result of mononuclear activation. This strategy can be used as a switch (on/off) for a catalytic reaction and also permits reversible control over the product distribution during the course of a reaction.

There is ag rowing interest in transition-metal catalysis in confined spacesa st he approach provides an additional tool to control selectivitya nd activity in catalysis. [1] For example,i th as been demonstratedt hat the encapsulation of rhodiumc omplexes in ah emispherical porphyrin assembly results in catalysts with increased activity and unprecedented branched selectivity in the hydroformylationo ft erminal and internal alkenes. [2] In addition, the encapsulation of transition-metal complexes in preformed cavities through weak interactions can lead to unexpected reactivity:M 4 L 6 anionic tetrahedral capsules, for instance, can host cationic organometallic catalysts in their hydrophobic cavities, [3] thereby inducing substrate selectivity. [4] Moreover,r eaction rates [5] and productd istribution [6] can be greatlya ffected by catalyst encapsulation. Interestingly, many catalytic reactions operate through ad inuclear mechanism [7] or deactivate via ad inuclearp athway; [8,9] by encapsulation of at ransition metal complex, such decomposition pathways can be suppressed, leading to higher catalytic turnover numbers. [10] In principle, an encapsulatione ventc ould also change the catalyticp athway of ar eaction, and as such can be used as as witch for ac atalytict ransformation. Switchable catalysis is an interesting upcoming field of research as it provides new tools to control the reaction process with externals timuli such as light, pH, or metalc oordination, ac onceptt hat is important to control reactions in nature. [11] In ar ecents tudy,e ncapsulation of ap hotoredoxc atalystw as shown to be af easible stimulus to steer reactivity. [12] In ap revious paperw er eported the encapsulation of an N-heterocyclic carbene( NHC)m ononuclear gold(I) complex inside aself-assembled hexamericresorcin [4]arene cage 1 6 and showed that the encapsulated catalyst gives ad ifferent product distribution than the free complex. [13] This supramolecular complexi sf ormedi na polar,w ater-saturated solvents (Scheme1). [14,15] In the currentc ontribution,w e reporth ow we changet he active gold complex from dinuclear to mononuclear by reversible encapsulation andd emonstrate that this can be used for both switching on/off ar eaction, as well as for controlling its selectivity during the courseofareaction. Changing the reactivityo rs electivity of ag old catalyst has been shown before by changingt he ligands [16] or Brønsted acid/base effects [17] and even by guest bindingbyarotaxane, [18] but reversibly changing the active species of ag old-catalyzed reactiona saresult of encapsulationh as,t ot he best of our knowledge,not been shown before.
In this study we use ad inuclear hydroxyl-bridged gold complex [{Au(NHC)} 2 (m-OH)][X] instead of am ononuclear gold complex. [19] This complex reactst hrough different mechanisms than mononuclear gold complexes [20] and is ap rivileged catalyst for dual activation reactions. [21] It, however,i st oo large to fit inside the cage 1 6, [22] and should be split into mononuclear complexes upon encapsulation. The NHC-Au-X fragment displays the traditional Lewis acidic character of mononuclear cationic gold catalysts, activatingu nsaturated substrates such as alkynes through p-coordination, making themm ore electrophilic and susceptible towards nucleophilic attack. [23] Meanwhile, the NHC-Au-OH speciesb ehaves as aB rønsted base and is known to s-activate substrates such as terminal alkynes or phenols. [24] Together the two species, NHC-Au-X and NHC-Au-OH, can dually activate substrates through both p-a nd s-activation (Scheme 2). This dual-activation mode was originally proposed by To ste and Houk [25] and is well established andemployed nowadays. In addition, this dual activation has elegantly been explored by Hashmi [26] and Zhang [27] for the formation of gold acetylides, which can react as an ucleophile and attack the p-activated bond of the substrate, and as such represents ac ommon strategy in gold-mediated synthesis.
We envisioned that encapsulation of the two fragments of the dinuclearg old catalyst [{Au(NHC)} 2 (m-OH)][X] in separate cages would alter its typical reactivity as they undergot ransformations in as itei solated fashion.W ea nticipatedt hat by complexe ncapsulationw ec ould reversibly switch between the dinuclear and mononuclear catalyst and, therefore, have at ool to shiftf rom dual gold catalysis to am ononuclearr eaction mechanism. This forms the basis for an on/off switchable system,b ut can also alter the product distribution during ag old-catalyzed transformation.
Indeed,w hen complex [{Au(IPr)} 2 (m-OH)][BF 4 ] 2 (Scheme 3) and the capsule were mixed together,e ncapsulation of am ononuclear gold complex was confirmed by 1 HNMR and 1 H2DDOSY NMR (see the Supporting Information). To demonstrate the principle of switching catalyst activity by selective encapsulation, the dual gold-catalyzed hydrophenoxylation reaction was studied. [21,28] This reaction requires s-activation of ap henol by the NHC-Au-OH moiety and p-activation of an alkyne by the cationic NHC-Au-Xf ragment (Scheme 4). Indeed, it was observed that the standard reaction between phenol (4) and diphenylacetylene (5)r eadily takes place when using 2 as catalysti nt he absence of the cage (full conversion within 60 min). However, in the presence of the cage, the dinuclear complex 2 is broken and encapsulated as mononuclear spe-cies. As the dual reactionp athway is no longer available, no conversion to vinyl ether 6 is obtained, even after 24 h. [29] We wondered if the reactionc ould be switched on again by adding ac ompeting guest that would bind more strongly to the cage than the goldc atalyst. For this purpose we selected tetraalkylammonium salts, as they are known to bind very strongly inside the hexamer. [15] Gratifyingly,u pon addition of Et 4 N + BF 4 À (7)t oe xpel the gold catalystf rom the cage, the catalytic activity was restored and product 6 was obtained in 89 %y ield after one hour.
Next we explored the cage effect on changing the product distribution of ar eaction. For this purpose we exploredt he conversion of 4-phenyl-1-butyne (8). Depending on the available reactionp athways, the transformation can yield up to four products (Table 1). In the absence of the cage, 2 can activate two substrates in a s-a nd p-activation mode and, therefore, dimerization of 8 takesp lace through ad ual-activation mechanism, yieldingt he branched and linear products, 11 and 12 respectively (Table1,e ntry 1; Scheme 5). [26b, 30] As anticipated, this dual-activationr eactionp athway is completely blocked upon encapsulation of the catalyst and the production of 11 and 12 stopped. Instead, when in the cage, the catalyst produced the intramolecularly cyclized product 10,w hich is known to form via am ononuclear pathway inside the cage (Table 1, entry 2). [13] In the presence of the cage and the competingg uest 7,p roduct 10 was not formed and dimerization products 11 and 12 were obtained (Table 1, entry 3), indicating that under these conditions the catalysis proceeds via ad ualgold mechanism and thus takes place outside the cage.
Due to the presence of water molecules to facilitate the selfassemblyo ft he capsule, the well-documented hydration product 9 was formed in all cases through p-activation of the triple bond, [31,32] but only in minor amounts. We observed an in- creasedr ate of formation of this product in the presence of both cage and competingg uest 7,w hich is interesting but difficult to explain.T he addition of only the competing guest 7, in the absence of cage but with the same amount of water present,d oes not lead to increased formationo fp roduct 9 (Table 1, entry 4).
Next we investigated whether it would be possible to switch the product selectivity duringt he course of the reaction (Figure 1). The reactionw as initiated using only the dinuclear gold catalyst 2.U nder these reaction conditions, the branched dimer 11 was the main product formed, indicating that the dual activation pathway is dominating. After 3h,a ne xcess of cage 1 6 was added, thereby removing the dinuclear gold complex from the reaction mixture by encapsulationoft he cationic mononuclear gold fragment. The formation of 11 immediately stopped, while productiono fc ompound 10 started. After another 3h,c ompound 7 was added as ac ompeting guest for 1 6 ,r eleasing the catalystf rom the cage. As compound 10 can only be formed while the cationic gold species is encapsulated in 1 6 ,i ts production stopped, whereas formation of 11 started again.T he formationo fp roduct 12 followed the same trend as 11,b ut it was lessc lear as this compound was formed in much smallera mounts. As ketone 9 can be formed both inside and outside the cage (Table1), the formation of this product could not be switched;t he faster formation of this product after addition of both cage and Et 4 N + BF 4 À (7)c orresponds with the observations in Ta ble1.
In conclusion, we have demonstrated that it is possible to control the pathway by which gold complexes convert substrate molecules by complex encapsulation events. In the presence of as elf-assembled hexameric resorcin [4]arene cage the dinuclearc omplex [{Au(NHC)} 2 (m-OH)][X] breaks into mononuclear units that are encapsulated as the dinuclearg old complex 2 is too large to fit inside the cage. By doing so, the dual activation reactivity typical for complex 2 is switched into (re)activity that is typical for mononuclearc omplexes. By using this strategy on ar eactiont hat can only proceed through ad ual-activation pathway, we have demonstrated on/off switching of agold-catalyzed reaction. Moreover,this approach also provides tools to change the product distribution during the course of ar eaction, which is demonstrated in the activation of 4-phenyl-1-butyne. In summary,t his strategy of switching the active specieso fagold-catalyzed reactionb ym eanso f host-guesti nteractions provides an ew approach to controlling catalytic transformations, even during the course of the reaction.

Experimental Section
Hydrophenoxylation experiments:T he catalyst 2 (0.025 mol %) was added to as olution of 4 (550 mm)a nd 5 (500 mm)a nd in selected experiments cage 1 6 (50 mm)a nd/or competing guest 7 (50 mm)i n[ D 8 ]toluene. The mixture was heated to 80 8Ca nd yields were monitored using GC and 1 HNMR of the crude mixture.
Catalytic experiments with substrate 8:T he catalyst 2 (2.5 mol %), H 2 O( 44 mm), substrate 8 (66 mm), and, in selected experiments, cage 1 6 (33 mm)a nd/or competing guest 7 (33 mm) were mixed in [D 6 ]benzene and heated to 70 8Cf or 48 h. Yields were monitored using GC and 1 HNMR of the crude mixture and were determined as the average of two experiments. Scheme5.Dimerization of terminal alkynes through s-and p-activation.