Article pubs.acs.org/Organometallics
Reactivity Comparison of Primary Aromatic Amines and Thiols in E− H Insertion Reactions with Diazoacetates Catalyzed by Iridium(III) Tetratolylporphyrin Bernie J. Anding, Taiwo O. Dairo, and L. Keith Woo* Department of Chemistry, Iowa State University, 1605 Gilman Hall, 2415 Osborn Drive, Ames, Iowa 50011-1021, United States S Supporting Information *
ABSTRACT: A detailed kinetic study is described for the insertion of carbenes from methyl diazoacetate into the N−H bond of aniline, using Ir(TTP)CH3 (TTP = tetratolylporphyrinato) as a catalyst. Aniline strongly coordinates to the Ir center with a binding constant of K = (2.5 ± 0.5) × 104 at 296 K, forming an inactive hexacoordinate complex, (aniline)Ir(TTP)CH3. The rate of N−H insertion is first order in both diazo ester and catalyst. When the true amount of active, five-coordinate Ir(TTP)CH3 is taken into account, the insertion rate is found to be independent of the aniline concentration. This indicates that the rate-limiting step in the catalytic cycle occurs prior to the nucleophilic attack of aniline on an Ir carbene complex to generate a coordinated ylide. Thus, with N−H insertion catalyzed by Ir(TTP)CH3, aniline is both a strong ligand and a potent nucleophile. This is in contrast to the analogous catalytic insertion of carbenes into S−H bonds. p-Toluenethiol is a more weakly binding ligand toward Ir(TTP)CH3 (K = 680 ± 20 at 296 K). Moreover, the rate of S−H insertion is first order in diazo reagent, catalyst, and thiol concentrations. In this case, the slow step is nucleophilic attack of the thiol on the Ir carbene complex to form a coordinated sulfonium ylide intermediate. In comparison to aniline, p-toluenethiol is a weaker ligand and a poorer nucleophile. The consequence of these differences is that the rate of aniline attack on the carbene intermediate is much faster than the rate of formation of the intermediate carbene complex; whereas the rate of nucleophilic addition of the thiol is slower that the rate of carbene complex formation.
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INTRODUCTION Catalytic carbene transfer reactions based on diazo compounds provide versatile, atom-economical approaches for organic synthesis.1 In addition to C−C bond formation, diazo reagents provide an important approach in the construction of heteroatom−carbon bonds.2−19 In particular, the insertion of carbenes from diazo esters into the N−H bonds of amines, using transition-metal catalysts, provides an effective and direct synthesis of amino acid derivatives and biologically important heterocycles.20−24 A variety of catalysts have been developed for N−H insertion, including copper bronze,25 Rh2(OAc)4,26 Fe(III)6,27 and Ru(II) porphyrin complexes,28,29 and Fe(III) corroles.27 Theoretical and experimental approaches have been employed to examine the mechanism of N−H insertion with diazo esters. Results of these investigations with iron porphyrin complexes reveal that the molecular steps depend on the ligation of the metal, the formal oxidation state, and the d electron count. For example, DFT studies indicate that N−H insertions catalyzed by Fe(II) porphyrin thiolates proceed through an open-shell singlet Fe(II) carbene complex.30 The d6 configuration of Fe(II) leads to displacement of N2 from a coordinated diazo ester and allows significant Fe−C bonding that favors formation of an intermediate carbene complex (Scheme 1). In contrast, N−H insertion catalysis with Fe(III) porphyrins and corroles reportedly involves ylide formation through a noncarbene pathway.27 Presumably, the lower © XXXX American Chemical Society
Scheme 1. N−H Insertion Mechanism with Fe(II) Thiolate Catalyst Involving a Carbene Intermediate
electron density of Fe(III) disfavors formation of a carbene complex from the diazo reagent. Instead, two pathways with multicentered transition states were proposed (Scheme 2) that produce a free nitrogen ylide.27 Received: March 9, 2017
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DOI: 10.1021/acs.organomet.7b00185 Organometallics XXXX, XXX, XXX−XXX
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Organometallics Scheme 2. Carbene-Free Ylide Pathways for Fe(III)a
aniline and contrast this to the related insertion with the S−H bond of p-toluenethiol.
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PREVIOUS N−H INSERTION RESULTS We recently described the catalytic utility of iridium(III) porphyrinato complexes in carbene transfer reactions.15,62−64 In reactions with amines and ethyl diazoacetate (EDA), the formation of amino acid esters was efficiently catalyzed by Ir(TTP)CH3 (1). Under optimized conditions with a singlealiquot addition of EDA, aniline afforded a 92% yield of ethyl phenylglycinate (eq 1). Carbene dimerization was a minor side
a
Adapted from ref 27.
In a similar manner, the carbene insertion process into the S−H bonds of thiols with diazo reagents is an efficient method for the construction of C−S bonds,27−29 with significant potential for preparing compounds with useful biological activities.31,32 Comparisons of N−H and S−H insertion processes have been reported with a few catalysts, including heterogeneous Cu33 and engineered P450 heme enzymes.34−36 Such comparisons are infrequent due to the different reactivities of amines and thiols toward transition metals. For example, monodentate amines are well-known ligands for transition metals37 and are common nucleophiles for organic reactions. In contrast, monodentate thiols, in neutral form, are relatively rare as ligands.38,39 However, sulfur-containing substrates can bind strongly to transition metals and often poison catalysts.40−45 In addition, thiols as sources of ligands46−48 generally afford the thiolate complex.49−52 Nonetheless, thiol complexes have been prepared by ligand substitution,53,54 including a number of Ru porphyrin thiol complexes, Ru(por)(RSH)2.55 In several cases, binding of the thiol is reversible and the complexes are only characterized in situ. Reversible binding of thiols to five-coordinate RuCl2(P− N)(PPh3) (P−N = o-diphenylphosphino-N,N′-dimethylaniline) occurs to form octahedral products, RuCl2(P−N)(PPh3)(RSH), with equilibrium constants K = 296 ± 20 (for MeSH) and K = 154 ± 8 (for EtSH).39 Neutral thiols are also weakly nucleophilic, and the reactive form is generally the thiolate, produced by the presence of a base.56,57 Given the synthetic importance of heteroatom ylide chemistry in organic synthesis58−60 and the functional group tolerance of N−H and S−H insertion reactions with diazo reagents,2,61 an improved understanding of the mechanisms involved with the reactions of amines and thiols with diazoacetates should lead to further development and implementation. We have explored the use of metalloporphyrins as efficient catalysts for the insertion of carbenes, derived from alkyl diazoacetates, into the N−H and S−H bonds of amines and thiols, respectively. In particular, (tetratolylporphyrinato)methyliridium(III) (Ir(TTP)CH3) serves as a common catalyst that allows for a direct comparison of E−H insertion reactions of primary aromatic amines and neutral thiols.62,63 We report herein a new kinetic study for the insertion of carbenes from diazo esters into the N−H bond of
reaction, producing a 1% combined yield of diethyl maleates and fumarates. A 7% yield of the double-insertion product of aniline was also produced. Low catalyst loadings (0.07 mol %) were sufficient to effect the reaction with high yields. Titration experiments, monitored by UV−visible spectrophotometry, demonstrated that aniline bound reversibly to Ir(TTP)CH3 in benzene with the equilibrium constant K = (2.5 ± 0.5) × 104 at 23 °C (eq 2). The proposed catalytic cycle for N−H insertion is shown in Scheme 3. Reversible amine ligation to the iridium metal center forms a catalytically inactive hexacoordinated complex, (amine)Ir(TTP)CH3 (2-NH2R). Upon dissociation of amine, diazo acetate binding to the five-coordinate iridium center Scheme 3. Proposed Catalytic Cycle for the Ir(TTP)CH3Catalyzed Insertion of Carbenes from Diazo Esters into N− H Bonds
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DOI: 10.1021/acs.organomet.7b00185 Organometallics XXXX, XXX, XXX−XXX
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Organometallics
× 10−6 M, Figure 1), indicating that the rate is first order in [Ir(TTP)CH3].
generates an iridium carbene complex (3). Nucleophilic attack of the amine on the metal carbene complex produces a coordinated nitrogen ylide (4-NH2R), which rearranges to form the N−H insertion product and regenerates the Ir(TTP)CH3 catalyst (1). Ylide formation was established with diallylamine as a substrate. Treating diallylamine with an equimolar amount of EDA in the presence of catalytic Ir(TTP)CH3, at ambient temperature, generated primarily the N−H insertion product along with a small amount of a diester compound, presumably formed as a result of a tandem 2,3-sigmatropic rearrangement and N−H insertion (Scheme 4). Moreover, a free ylide is not Scheme 4. Internal Trapping of Coordinated Nitrogen Ylide with Diallylamine
Figure 1. Initial rates versus [Ir(TTP)CH3] in CD2Cl2 at 300 K. Conditions: [aniline]0 = 0.119 M and [MDA]0 = 0.117 M.
The reaction rate dependence on MDA concentration was explored with [Ir(TTP)CH3]0 = 8.92 × 10−6 M and [aniline]0 = 0.119 M. The plot of ln[MDA] vs time exhibited a linear behavior, consistent with a rate law that is first order in [MDA] (Figure 2).
produced, as revealed by reactions containing diethyl azodicarboxylate (DEAD).27 In N−H insertion catalyzed by Fe(TTP)Cl, a free ylide was trapped with DEAD (Scheme 5). However, no trapped ylide was observed for Ir(TTP)CH3catalyzed reactions of aniline and EDA in the presence of DEAD.
Figure 2. First-order plot of ln[MDA] vs time in CD2Cl2 at 300 K. Conditions: [Ir(TTP)CH3]0 = 8.92 × 10−6 M, [MDA]0 = 0.117 M, and [aniline]0 = 0.119 M.
The rate dependence on the aniline concentration was also measured at 300 K for [Ir(TTP)CH3]0 = 8.92 × 10−6 M and [MDA]0 = 0.117 M, with [aniline]0 varied from 0.0595 to 0.209 M. Table 1 gives the initial rates with increasing aniline
Scheme 5. Free Nitrogen Ylide Trapping Results with DEAD
Table 1. Initial Rates for N−H Insertion in CD2Cl2 at 300 Ka [aniline] (M) 0.0595 0.0883 0.119 0.146 0.178 0.209
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NEW KINETIC INVESTIGATIONS Additional detailed kinetic studies were undertaken to gain further mechanistic insights into the N−H insertion reaction. For ease of monitoring by 1H NMR, methyl diazoacetate (MDA) was used as the carbene source. The initial reaction rates (∼10% of reaction or less) were determined at 300 K for each kinetic run from plots of the concentrations of MDA and product versus time. When the catalyst concentration was varied with the same initial concentrations of the aniline (0.119 M) and MDA (0.117 M), the initial reaction rate increased linearly with the rise in the catalyst concentration ((5.56−16.6)
rate (10−5 M/s)
log[aniline]
log(rate)
± ± ± ± ± ±
−1.23 −1.05 −0.92 −0.84 −0.75 −0.68
−4.20 −4.39 −4.52 −4.59 −4.66 −4.79
6.2 4.0 3.0 2.6 2.1 1.8
0.2 0.1 0.1 0.1 0.1 0.2
Conditions: [Ir(TTP)CH3]0 = 8.92 × 10−6 M and [MDA]0 = 0.117 M.
a
concentration. As shown in Figure 3, the slope of the log(initial rate) vs log[aniline] plot is −0.95 ± 0.03, indicating the strongly inhibiting nature of the amine binding to Ir(TTP)CH3. The catalytic process shown in Scheme 3 involves dual roles for the amineinhibitory binding to Ir(TTP)CH3 and nucleophilic attack on the carbene complex 3, to form ylide intermediate 4−NH2R. Although the strong binding of aniline C
DOI: 10.1021/acs.organomet.7b00185 Organometallics XXXX, XXX, XXX−XXX
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Organometallics [Ir(TTP)CH3] =
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(6)
k[Ir(TTP)CH3]0 [MDA][RNH 2]n 1 + K[RNH 2]
(7)
CONCLUSIONS The results of this work provide a new kinetic analysis of the molecular steps involved with (tetratolylporphyrinato)methyliridium(III) in the catalytic insertion of carbenes, derived from diazo esters, into the N−H bond of aromatic amines (Scheme 3). In this system, aniline is a strongly binding ligand, as reflected in a binding constant to Ir(TTP)CH3 of K = 2.5 × 104. Moreover, aniline is also a potent nucleophile, as its attack on the intermediate carbene complex 3 is fast relative to the prior steps in the catalytic cycle, since the rate is independent of the amine concentration. In comparison to aniline, ptoluenethiol is a weaker ligand and a poorer nucleophile. Presumably, the rate of formation of the carbene complex 3 from Ir(TTP)CH3 is the same, whether the catalyst substrate is amine or thiol. Thus, the outcome of these findings is that the rate of aniline attack on the carbene species 3 (Scheme 3) is faster than the rate of formation of the carbene intermediate, whereas the rate of attack of the thiol is so sluggish that the nucleophilic addition step is slower than the rate of carbene formation. These reactivity differences have potentially important implications for heteroatom ylide formation in carbene reactions for organic synthesis.
order (n = 0). The resulting rate law (eq 6, n = 0) indicates that the transition state contains only the components of Ir(TTP)CH3 and MDA, and resembles the carbene complex 3. Consequently, attack of aniline on the carbene complex, 3, and formation of ylide complex 4−NH2R are fast relative to the prior steps.
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EXPERIMENTAL SECTION
General Considerations. Unless noted otherwise, all manipulations were performed under a dry nitrogen atmosphere. Substrates were reagent grade and were used without purification for catalytic reactions. Aniline was stored in the dark under nitrogen prior to use. Ir(TTP)CH3 was prepared according to a previously reported method.65,66 CH2Cl2 was dried and deoxygenated by passage through columns of alumina and reduced copper. For kinetic studies, CD2Cl2 was dried over molecular sieves, deoxygenated by three freeze− pump−thaw cycles, and passed through a plug of activated alumina under a glovebox atmosphere. Kinetic measurements were done using
(3)
[Ir(TTP)CH3]0 = [Ir(TTP)CH3] + [Ir(TTP)CH3(RNH 2)]
(8)
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Figure 4. Plot of eq 8 where [Ir]0 = [Ir(TTP)CH3]0. The horizontal line is a visual guide.
[Ir(TTP)CH3(RNH 2)] [Ir(TTP)CH3][RNH 2]
(rate)K[RNH 2] = k[RNH 2]n [MDA][Ir(TTP)CH3]0
COMPARISON TO PREVIOUS S−H INSERTION RESULTS These findings are in stark contrast with our kinetic studies on the analogous S−H insertion reaction of p-toluenethiol and MDA catalyzed by Ir(TTP)CH3.63 Aromatic thiols are much weaker ligands for Ir, with binding constants to Ir(TTP)CH3 in the range of K = 400−800. The rate of S−H insertion was found to be first order for both [MDA] and [Ir(TTP)CH3]. In addition, p-toluenethiol is a poor nucleophile in this reaction on the basis of a similar kinetic analysis. Thus, plotting (rate)(1 + K[RSH])/([Ir(TTP)CH3]0[MDA]) vs [RSH] (eq 8 adapted for thiols, [RSH] = 0.0513−1.65 M), established the rate order of [RSH] to be first order (Figure S10 in the Supporting Information). Consequently, the rate-limiting step for S−H insertion is attack of the thiol on the Ir carbene complex, 3, to form the ylide complex 4−RSH.
inactivates the catalyst and overshadows the mechanistic details, it is possible to gain more information on subsequent steps. An insightful analysis of the mechanism is based on a kinetic strategy we employed for catalytic S−H insertion with MDA and p-toluenethiol.63 In this approach, the equilibrium binding constant of the amine to Ir(TTP)CH3 can be utilized to calculate the amount of active catalyst present in solution: that is, complex 1 that has a vacant coordination site. Combining the equilibrium binding expression (eq 3) with the sum of the amount of all iridium complexes (eq 4) yields the quantity of active catalyst 1 present in solution (eq 5). The simplified rate law is expressed by eq 6, where the rate orders for [Ir(TTP)CH3] and [MDA] have already been established as 1 and the order in [RNH2]n remains to be determined. Substitution of eq 5 into eq 6 gives the rate law (eq 7) expressed in known quantities. When K[RNH2] ≫ 1, the denominator of eq 7 simplifies to K[RNH2]. Rearranging eq 7 to eq 8 and plotting (rate)(K[RNH 2 ])/([Ir(TTP)CH3]0[MDA]) vs [RNH2] affords essentially a horizontal line (Figure 4), establishing the rate order of [RNH2] to be zero
K=
(5)
rate = k[Ir(TTP)CH3]1 [MDA]1 [RNH 2]n rate =
Figure 3. Plot of log(initial rate) vs log[aniline] to determine overall rate order for [aniline]. Conditions: [Ir(TTP)CH3]0 = 8.92 × 10−6 M and [MDA]0 = 0.117 M in CD2Cl2 at 300 K.
[Ir(TTP)CH3]0 1 + K[RNH 2]
(4) D
DOI: 10.1021/acs.organomet.7b00185 Organometallics XXXX, XXX, XXX−XXX
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Organometallics a Bruker DRX 400 MHz spectrometer. 1H NMR peak positions were referenced against residual proton resonances of deuterated solvents (δ, ppm: CDCl3, 7.26; CD2Cl2, 5.32). Kinetic Reactions. A portion of Ir(TTP)CH3 from a CH2Cl2 stock solution (6.57 × 10−5 M, (2.34−6.97) × 10−3 μmol) was collected in a medium-walled NMR tube and taken to dryness. Under a glovebox atmosphere, the tube was charged with aniline (from a CD2Cl2 stock solution, 25.0−87.8 μmol), mesitylene standard (40.0 μL from a 5.06 × 10−2 M CD2Cl2 stock solution, 2.02 μmol), and diluted to 4.20 × 102 μL with CD2Cl2. The tube was fitted with a septum and taken into the NMR instrument. After the instrument was tuned and the temperature equilibrated at 300.0 K, MDA (29.0 μL from a 1.70 M CD2Cl2 stock solution, 49.3 μmol) was added and the reaction was monitored by spectra acquired at 60 s intervals. Initial rates were determined at early reaction times (
