Inorganica Chimica Acta 362 (2009) 1229–1233

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Inorganica Chimica Acta

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In situ dimanganese catalyst for fast screening of molecular recognition catalystsfor regioselective oxygenation of an sp3 C–H bond

Siddhartha Das, Gary W. Brudvig *, Robert H. Crabtree *

Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT, 06520-8107, United States

a r t i c l e i n f o a b s t r a c t

Article history:Received 28 May 2008Accepted 9 June 2008Available online 17 June 2008

Keyword:Hydrogen bond

0020-1693/$ - see front matter � 2008 Elsevier B.V. Adoi:10.1016/j.ica.2008.06.009

* Corresponding authors.E-mail addresses: gary.brudvig@yale.edu (G.W. B

le.edu (R.H. Crabtree).

We report a rapid method for assembling our di-l-oxo dimanganese catalyst, verified by ESI-MS and EPR,assessing its water oxidation activity by a Clark electrode O2-assay study and its regioselective C–H acti-vation activity by product analysis in catalytic runs.

� 2008 Elsevier B.V. All rights reserved.

1. Introduction

Synthesis and isolation of suitable high valent catalysts as wellas finding a suitable catalyst–substrate combination have pre-sented major challenges in research directed toward biomimeticregioselective C–H bond oxygenation [1–3]. In the absence ofmolecular recognition, a typical catalyst brings about oxygenationof a substrate at the most reactive site [4–9]. While this approach isof significance, it is of limited use for bringing about reaction at aless reactive site. Chelate control has been used in a number ofcases, but this causes activation only at a neighbouring site [10–12]. The use of a molecular recognition unit at a remote locationon a ligand to bind the substrate prior to reaction can provide highselectivity. When the target reaction is the oxygenation of a satu-rated C–H bond, this presents several complications in the designof ligand. As most of the bonds are more oxidation prone than sat-urated C–H bonds, all the groups in the ligand have to be highlyoxidation resistant. Moreover, once such a ligand has been de-signed and synthesized, the isolation of a high-valent metal cata-lyst bearing the ligand is time-consuming.

The di-l-oxo dimanganese [MnIII(l-O)2MnIV] core has beenproved to be an exceptionally active oxidation catalyst. But isola-tion of an intact [LMnIII(l-O)2MnIVL]X3 (X: anion) complex with aligand L has proved to be tedious and has only been achieved withlimited success. Other than the complex with the molecular recog-nition ligand, LMR, shown in Scheme 1, high valent di-l-oxo diman-ganese complexes, even those bearing much simpler ligands, wereonly isolated in low yield [13,14]. With change of ligand, the solu-

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rudvig), robert.crabtree@ya-

bility, stability, selectivity and activity of [LMn(l-O)2MnL]3+

change in an unpredictable fashion.Recent studies by our group indicate that [LMRMnIII(l-O)2

MnIVLMR]3+ can function as an efficient catalyst for oxygenationof saturated C–H bonds with high regio- (>98%) and stereoselectiv-ity (>99%) and with hundreds of turnovers (total turnover >700)[15]. Our molecular recognition ligand, LMR, can lead to selectiveoxygenation at a remote unactivated site. We found that for regio-selective catalysis, steric exclusion of unbound substrate by boundsubstrate is an important requirement [16]. This prevents theunselective reaction of unbound substrate molecules at the activesite and puts another constraint on the design.

These difficulties have led us to look for an easier method toscreen ligands. In the present study, we have used ligand substitu-tion to prepare the catalyst in situ (Scheme 1). This in situ catalysthas an activity comparable to the isolated catalyst with the molec-ular recognition ligand (LMR) suggesting that this strategy can beused as a fast screening method for catalysts that are otherwise dif-ficult to synthesize [15]. Once initial data have been obtained in ascreen of this type, the successful system can be isolated and fullycharacterized for definitive studies.

2. Experimental

2.1. Materials

Ibuprofen, tetrabutyl ammonium oxone (used as primaryoxidant), dipy, HPLC grade acetonitrile were bought from Sigma–Aldrich and were used without further purification. [(dipy)2M-n(O)2Mn(dipy)2] (ClO4)3 was synthesized according to literatureprocedure [24].

Fig. 1. ESI-MS of [(LMR)MnIII(O)2MnIV(dipy)(ClO4)2]+ (solid green line) (m/z = 1042).Simulated spectrum is shown in broken black line. (For interpretation of thereferences to colour in figure legends, the reader is referred to the web version ofthis article.)

Fig. 2. EPR spectrum of [(LMR)MnIII(O)2MnIV(dipy)(ClO4)2]+.

Scheme 1. Synthesis of Cin situ.

Fig. 3. Oxygen assay with Clark electrode in H2O:CH3CN = 1:1 with Cinact

(100 mM) + Dipy (400 mM) (black line) and Cin situ [Cinact (100 mM) + LMR

(200 mM)] (red line). Primary oxidant: oxone (5 mM). Temperature: 25 �C.

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2.2. Physical measurements

1H and 13C NMR spectra were recorded in deuterated solvents(Cambridge Isotope Laboratories) at 25 �C on a Bruker 400 or Bru-ker 500 spectrometer at the Yale Department of Chemistry Instru-ment Center. Electrospray ionization–mass spectroscopy (ESI-MS)was done on a Waters ZQ LC–MS instrument. Gas chromatogra-phy–mass spectroscopy (GC–MS) was done on an Agilent 5973GC–MS instrument.

2.3. Syntheses

Ligand LMR and catalyst Cinact were synthesized following liter-ature procedure [15,24].

2.4. Catalytic conditions

To a solution of 7 mM (1 equiv.) of S1 in 20 ml acetonitrile,0.03 equiv. of Cinact and 0.06 equiv. of LMR or terpy were added.The solution was cooled in an ice bath and 5 ml CH3CN solutionof tetrabutyl ammonium Oxone�, TBAO (5 mmol) was added andthe solution was stirred at room temperature, 0 �C and �20 �C. Atroom temperature, after 6 h the reaction was quenched by additionof excess aqueous NaHSO3, acidified with 0.1 N HCl solution andthe products and unreacted substrate were extracted in ether.The ether extract was evaporated under vacuum and the residuewas dried in vacuo in the presence of P2O5. The products were ana-lyzed by 1H NMR and GC–MS.

3. Results and discussion

3.1. Synthesis and characterization of active in situ dimanganesecatalyst (Cin situ)

[(dipy)2Mn(O)2Mn(dipy)2](ClO4)3 (Cinact) (dipy = 2,20-dipyridyl)has a high valent di-l-oxo dimanganese site. This complex hasbeen found to be almost inactive catalytically because it lacksexchangeable terminal water ligands, so we do not expect a back-ground oxidation from it. However, the Mn-dipy bonds in theMn(III/IV) dimer are quite labile, allowing the bidentate dipy tobe easily replaced by the tridentate LMR to form the desired activecatalyst (Cin situ) in situ.

To an acetonitrile solution of Cinact, LMR is added Cinact:LMR in1:2 molar ratio. After 5 min, the ESI-MS spectra of this solutiongave a peak at m/z = 1042 with isotopic peaks closely matchingthe simulated isotopic distribution of [(LMR)MnIIIMnIV(O)2(dipy)(ClO4)2]+ showing the formation of the desired high valent diman-ganese complex with LMR as a ligand (Fig. 1). An EPR spectrum ofthe same solution gives the 16 line spectrum characteristic of theMnIII(l-O)2MnIV core (Fig. 2). To demonstrate successful formationof an active catalyst, we used oxygen evolution from water oxida-

Fig. 4. Molecular model (Chem 3D) of ibuprofen (S1) docked to one side of Cin situ

via –COOH� � �HOOC– H-bonding. The other side of dimanganese complex mighthave LMR as the ligand or might have one or two dipy. Due to the �32� anglebetween the KTA –COOH group and the plane containing the imide group, thesubstrate needs a bent sp3 carbon group after the –COOH group for the rest of thesubstrate to come into proximity with the active site (ideally 4–5 Å between targetC atom and Mn) [16].

Scheme 2. Possible products from oxidation of ibuprofen (S1). Bold arrows indicatealternate sites of attack.

S. Das et al. / Inorganica Chimica Acta 362 (2009) 1229–1233 1231

tion with oxone as primary oxidant as an assay. While Cinact doesnot evolve O2 from H2O with oxone�, the Cinact + LMR combinationdoes indeed do so according to oxygen assay studies with Clarkelectrode (Fig. 3). We therefore propose that the Cinact + LMR com-

Fig. 5. 1H NMR (CDCl3) of the product mixture after oxidation of ibuprofen by (a) Cin

bination generates an active catalyst, Cin situ, in which two dipy li-gands have been replaced by LMR.

3.2. Design of substrate

Molecular models of a Mn(l-O)2Mn complex with LMR as the li-gand were constructed by importing crystal structure parametersof ligand LMR and the Mn(l-O)2Mn core followed by energy mini-mization (MM2, CAChe 5) [15]. The crystal structure of LMR showsa�32� angle between the –COOH and the plane of the imide group.Thus, an sp3 carbon center is required a to the –COOH group tobring the remote C–H bond within�4–5 Å distance from the metal,a distance necessary for successful attack to take place by the high-valent metal site (Fig. 4) [2,15,16].

situ and (b) ‘Cinact + terpy’ (only the aromatic region has been shown for clarity).

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4. Regioselective oxygenation of ibuprofen (S1)

4.1. Prediction from molecular modeling

Ibuprofen [2-(4-isobutyl-phenyl)-propionic acid] (S1) was se-lected as the most suitable substrate. Ibuprofen is a rigid substratewith at least two alternate sites of attack: the benzylic C–H bondsremote from the –COOH group and the –COOH group itself. But,with molecular recognition, we expected selective oxidation atthe remote benzylic C–H bond with Cin situ as the catalyst, asshown in Fig. 4, giving P1 as the major product, any initial –CH(OH)intermediate being rapidly oxidized to the ketone. Oxidation at the–COOH site is expected to give P01 via oxidative decarboxylationunder reaction and workup conditions (Scheme 2) [17–21]. With-out the molecular recognition both P1 and P01 are expected to formin comparable amount.

4.2. Catalytic conditions

With –COOH� � �HOOC– H-bonding as the source of the recogni-tion, it was necessary to use a non-protic solvent. Acetonitrile isnot only non-protic but also relatively oxidation resistant. For atypical run, the ratio of substrate:Cinact:LMR:TBAO was set at100:3:6:500 and the reaction was carried out at room temperature,0 �C and �20 �C (see Section 2).

4.3. Control experiments

Three control experiments were run under identical conditions(i) with added terpy (instead of LMR) to solutions of Cinact (terpy:[2,20;60,200]terpyridine), (ii) with Cinact alone and (iii) with the man-ganese catalyst omitted.

Fig. 6. 1H NMR (CDCl3) of P1

4.4. Product analysis

Products of ibuprofen oxidation were analyzed by 1H NMR(CDCl3) (Fig. 5) and ESI-MS. As the carboxylic acids were found tobe inappropriate for GC–MS, their methyl esters were preparedby addition of trimethylsilyldiazomethane in a methanol–benzene(2:7) solution of the residue [22]. Product P1 was isolated as a purecompound by reversed phase HPLC using a C8 column. 1H NMR(Fig. 6) and ESI-MS (Fig. 7) were used to identify the productsunequivocally by comparison with the 1H NMR of P01 and GC–MSof both P1 and P01, which are available in the literature [15,17,23].

4.5. Catalytic results

We found that in the absence of manganese catalyst no oxida-tion takes place. With Cin situ, P1 is always formed in a higher per-centage than in any of the control experiments. This is consistentwith our molecular model with ibuprofen H-bonded to the pro-posed active complex (Fig. 4). On lowering of temperature, theselectivity was enhanced, presumably due to the entropic factorwith �96.5% selectivity for P1 at �20 �C (Table 1). Turnovers of20–27 were recorded with Cin situ catalyst combination indicatingthe reversibility in substrate–catalyst binding. In our controlexperiments with ‘Cinact + terpy’, where the ligand –COOH groupis absent, P01 was always obtained in appreciable amounts andthe P1:P01 ratio remained practically unchanged at alltemperatures.

4.6. Oxygenation of S1 in presence of acetic acid

We attribute the high regioselectivity in oxidation of ibuprofenby Cin situ to molecular recognition via H-bonding to the –COOHgroup in LMR, the ligand in Cin situ. To test the effect of H-bonding,

(Inset: aromatic region).

Fig. 7. ESI-mass spectrum of isolated P1 (m/z = 221 corresponds to P1H+; m/z = 242corresponds to tetrabutyl ammonium cation of TBAO, which was used as primaryoxidant and was in excess).

Table 1Product analysis of ibuprofen (S1) oxidation

Temperatures(�C)

Catalysts Total conversionsvs. substrate (%)

Totalconversions vs.product (%)

Turnovernumbers

P1 P01

20 Cin situ 72 85 13 24‘Cinact + terpy’ 70 69 23 23.3Cinact <1 �0

0 Cin situ 65 91 6 21.7‘Cinact + terpy’ 60 73 19 20Cinact 35 41.5 54.5 11.7

�20 Cin situ 82 96.5 2.2 27.3‘Cinact + terpy’ 81 73 15 27Cinact 48 41.5 42 16

20 Cin situa 73 73 18 24.3

‘Cinact + terpy’a 72 72 21 24

Turnovers: mol. products per mol. catalysts.a Catalytic solutions contained excess acetic acid.

S. Das et al. / Inorganica Chimica Acta 362 (2009) 1229–1233 1233

experiments were performed by adding acetic acid to the catalyticsolutions to disrupt the potential H-bonding leading to molecularrecognition. With 4 equiv. acetic acid in the medium for eachequiv. of substrate in the Cin situ system, the P1:P01 ratio fell from�7:1 to �3:1 on adding acetic acid. Control experiments with‘Cinact + terpy’ catalytic system gave the same 3:1 product mixtureunder identical conditions (Table 1). This is consistent with theproposed role of COOH� � �HOOC– H-bonding for high regioselectiv-ity in the oxygenation of ibuprofen.

4.7. Time dependent study in the oxygenation of S1

We were concerned about the potential degradation of P01 lead-ing to an apparent lower yield of P01 versus P1, with the Cin situ cat-alytic system. A time course study was carried out to test thispoint. The Cin situ catalytic system at 0 �C takes 24 h to reach com-pletion. We, therefore, began our product analyses at 0.5 h fol-

lowed by a series of measurements over 10 h. The P1:P01 ratioremained essentially constant throughout. A similar study withthe control in situ catalyst (‘Cinact + terpy’) also showed a constantP1:P01 ratio throughout. This suggests that the high P1:P01 ratio withthe Cin situ catalytic system is, indeed, due to molecular recognition.

5. Conclusions

We report a rapid screening method for testing ligands with adi-l-oxo dimanganese catalyst. The activity of the catalysts formedby displacement of dipy by terpy or LMR was confirmed by a Clarkelectrode O2-assay study (water oxidation activity) and the liganddisplacement reaction itself was detected by an ESI-MS study. Thisindicated the formation of a new complex, Cin situ, by replacementof dipy by LMR. With Cin situ, oxidation of ibuprofen (S1) occurs withhigh selectivity (�97% at �20 �C) at the benzylic C–H bond remotefrom the –COOH group, with 27 turnovers. This selectivity is attrib-uted to anchoring and orientation of the substrate (S1) via –COOH� � �HOOC– H-bonding between substrate –COOH group andthe –COOH group of LMR. Loss of selectivity after disruption ofthe H-bonding to the substrate with AcOH supports the proposedorigin of the selectivity. The isolated di-l-oxo dimanganese cata-lyst with LMR as the ligand gave higher selectivity (>98%) and muchhigher turnovers (>500) so it is necessary to isolate the complexesto gain maximal activity [15]. Nonetheless, displacement studiesmay be useful in comparing a range of ligands for catalysis.

Acknowledgement

This work was supported by National Science Foundation (CHE-0614403) and NIH (GM32715)

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