Pd-Induced Double CâH Bond Activation in Annulative Syntheses of

Article Cite This: J. Org. Chem. 2018, 83, 5199−5209

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Pd-Induced Double C−H Bond Activation in Annulative Syntheses of Bipyrrole Boomerangs: Mechanistic Insights from NMR Spectroscopy and Computation Marika Ż yła-Karwowska, Liliia Moshniaha, Halina Zhylitskaya, and Marcin Stępień* Wydział Chemii, Uniwersytet Wrocławski, ul. F. Joliot-Curie 14, 50-383 Wrocław, Poland S Supporting Information *

ABSTRACT: 1,n-Dipyrrolylalkanes can be efficiently converted into extensively π-conjugated bipyrroles by PdIImediated annulative double C−H activation, and this approach might be further developed into tandem processes involving further cyclization of substituents or oxygenation of pyrrolic αpositions. Herein, the mechanism of these transformations is explored using NMR spectroscopy and DFT calculations. The kinetics of the annulation are found to depend on the conjugation extent and donor−acceptor character of the pyrroles, as well as on substitution and the linker length. Combined experimental and theoretical evidence indicates that a change of the rate-determining step occurs for the most electron-deficient substrates. The unprecedented double α-oxygenation of bipyrroles is found to be a stepwise process, involving α-acetoxylated intermediates.

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a new class of bright donor−acceptor fluorophores (Scheme 1).45 These systems were obtained in an efficient one-step synthesis from the corresponding 1,n-dipyrrolylalkanes with the general structure RnX (X = EE = COOEt) containing fused electron-deficient naphthalenediamide and napthalenemonoimide subunits (R = NDA and NMI, respectively). The double C−H bond activation used palladium(II) acetate in acetic acid46−52 as the coupling system, which was optimized for catalytic use with silver(I) carbonate as the stoichiometric oxidant. The scope of the synthesis was further expanded to include two new tandem processes: a bis-annulative assembly of a cyclooctatetraene derivative dcTT1EE and the formation of unprecedented lactams cNDA1O and cNMI1O from the corresponding α-unsubstituted precursors NDA1 H and NMI1H. The latter process combines the annulation step with double oxygenation of the terminal pyrrole α positions. Direct activation of C−H bonds with transition metals offers an appealing mechanistic alternative to oxidative annulations commonly used in nanographene chemistry, as it obviates the formation of highly oxidized arene intermediates, usually radical cations, and can potentially offer a more selective route to intramolecular C−C bond formation. In the present case, annulative double C−H bond activation was found to be compatible with both electron-rich and electron-poor heterocyclic subunits, as well as with various ring sizes. The closure of five-membered rings (for n = 1) is of particular interest because oxidative pentannulations involving, e.g., FeCl3 are only rarely reported,53−55 and in fact, our attempts to cyclize NDA1EE with FeCl3 resulted only in the recovery of the starting material.45

INTRODUCTION Coupling of aromatic subunits, the key transformation utilized in the synthesis of nanographenes and other polycyclic aromatics,1,2 is typically achieved using oxidative approaches, epitomized by the FeCl3-mediated coupling of oligoaryls.3 Oxidative couplings are, however, plagued by low yields, unpredictable selectivity, and occasional failures in seemingly straightforward cases.4 Furthermore, these methods are often unsuitable for synthesizing strained aromatics5,6 and may fail with electron-poor precursors.7 Some of these limitations can be overcome with the aid of reductive Ullmann-type chemistry,8,9 dehydrohalogenative couplings,7,10−13 and nucleophilic oxidative arylations,14,15 at the added expense of selective prefunctionalization of at least one reactant. The latter requirement is obviated by transition metal-mediated double C−H bond activation, a powerful synthetic strategy with a rapidly growing scope of use.16,17 In particular, palladium-catalyzed oxidative carbocyclizations have been studied as an annulation method,18 with recent examples of five-19−32 and six-membered26,33−39 ring closures achieved in moderately sized aromatic systems. While many of the reactions reported to date suffer from a limited scope and moderate yields, the double C−H bond activation method offers a promising synthetic approach toward highly elaborate πconjugated targets. This strategy has so far remained relatively unexplored, even though it might provide access to new classes of organic materials, to be used as semiconductors and functional chromophores. In the course of our ongoing research on extensively fused oligopyrroles,40−44 we have recently employed Pd-induced double C−H bond activation for the synthesis of electrondeficient N,N′-bridged α,α′-bipyrroles cNDAnEE and cNMInEE, © 2018 American Chemical Society

Received: March 9, 2018 Published: April 9, 2018 5199

DOI: 10.1021/acs.joc.8b00630 J. Org. Chem. 2018, 83, 5199−5209

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The Journal of Organic Chemistry

an elevated temperature in the spectrometer, and 1H NMR spectra were recorded periodically. Cyclization kinetics were initially explored for the NDAnEE series under uncatalyzed coupling conditions (Scheme 1). Clean conversion to the respective cNDAnEE product was observed for n = 1 and 2, when each of the starting materials (ca. 7 mM in AcOH-d4) was heated at 360 K in the presence of 30 mM Pd(OAc)2 (Figures S3−S4 and S7−S8). Under such conditions, the cyclization was virtually complete in approximately 2 h. Initial reaction rates determined for NDA1EE showed a linear dependence on the starting concentration of Pd(OAc)2, indicating that, at least at the beginning of the reaction, the process is effectively first-order in the metal salt (Figure S6). With the approximation of the initial coupling kinetics as first-order with respect to both NDA1EE and Pd(OAc)2, effective rate constants of 3.00(11)·10−2 M−1 s−1 and 3.04(6)·10−2 M−1 s−1 were obtained for NDA1EE and NDA2EE, respectively, and calculated relative to monomeric Pd(OAc)2. Departures from the above idealized kinetics were, however, observed for reaction times longer than ca. 25 min. In contrast to the latter two systems, which show comparable reactivity, NDA3EE cyclized far more slowly, and kinetic experiments had to be performed at a higher temperature. Indeed, even after 7 h of incubation at 390 K, only partial conversion to cNDA3EE was observed (Figures S5 and S9). Because of these harsh reaction conditions, partial cleavage of the amide groups in cNDA3EE was observed as a follow-up process, apparently yielding cyclic anhydride functionalities. In DMSO-d6, the cyclization of NDA1EE (360 K, 6 mM concentration, ca. 1.33 equiv of Pd, 8.3% conversion after 88 min, Figure S1) was much less efficient than in AcOH-d4 under analogous conditions (ca. 0.8 equiv of Pd, 81% conversion after 88 min). In the former solvent, the consumption of Pd(OAc)2, accompanied by the release of AcOH, was observably faster than the formation of the product, cNDA1EE, indicating that an unspecified side reaction competed with the coupling process. Cyclization of NDA1EE performed under catalytic conditions (5 equiv of Ag2CO3, AcOH-d4, 360 K) demonstrated a strong effect of catalyst loading on the reaction rates and conversions. At 40 mol % loading of Pd(OAc)2, a near complete conversion to cNDA1EE was observed after 75 min of heating. When the amount of PdII was reduced to 10 and 1 mol %, the annulation became significantly slower and conversions of 51% and 5%, respectively, were attained after 5.5 h at 360 K. These results indicate that deactivation of the PdII catalyst was more significant in the in situ NMR experiments than under preparative conditions. Attempts to quantify the kinetics for the NMInEE series were only partly successful because of the limited solubility of reactants in acetic acid. The spectroscopic picture was further complicated by self-aggregation (and occasionally precipitation) of the products. It was nevertheless found that the NMI systems cyclize at rates comparable to their NDA counterparts. In particular, NMI3EE was also the slowest reacting species in the series. However, in contrast to cNDA3EE, the imide product cNMI3EE was completely stable when formed at 390 K in AcOH-d4, and no formation of anhydride byproducts was observed. In situ monitoring of annulation reactions for the ester-free substrates, NDA1H and NMI1H, provided an unexpectedly detailed insight into the course of events leading to the formation of dilactam products. Specifically, when NDA1H (6 mM in AcOH-d4) was incubated with 5 equiv of Pd(OAc)2 at

Scheme 1. Scope of Reactivity Explored in This Worka

a

Reagents and conditions:45 (a) Pd(OAc)2 (10 mol %), Ag2CO3 (1 equiv), AcOH, 120 °C; (b) Pd(OAc)2 (3 equiv), AcOH, 120 °C; (c) Pd(OAc)2 (3 equiv), AcOK (3 equiv), AcOH, 150 °C.

Here we present a mechanistic analysis of the above Pdinduced chemistry, which provides insight into the structural and electronic factors that govern the C−C coupling reaction and into the selectivity of observed tandem processes. We achieve these goals by means of 1H NMR spectroscopy, which is used to investigate relative coupling kinetics for various bipyrrolyl precursors and to search for observable reaction intermediates. The resulting spectroscopic picture is rationalized by extensive DFT calculations, which provide a mechanistic description not only for the C−C coupling but also for the α-oxygenation reaction.

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RESULTS AND DISCUSSION NMR Experiments. The simplicity of the reactant systems enables direct monitoring of the coupling reaction in situ by means of 1H NMR spectroscopy. This approach was facilitated by convenient reaction times (minutes to hours), limited reactivity at room temperature, and by the absence of paramagnetic intermediates. In a typical experiment, a bipyrrolylalkane was dissolved in a deuterated solvent, usually acetic acid-d4, along with a given amount of the Pd(OAc)2 trimer and, in the case of catalytic reactions, an Ag salt. Such samples, containing mM concentrations of reactants, were prepared in an inert-atmosphere chamber to exclude participation of dioxygen. The sample was then incubated at 5200


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The Journal of Organic Chemistry Scheme 2. Mechanistic Outline of Pd-Induced Processes Observed for Dipyrrolylalkanes RnX a

a

For clarity, ancillary ligands on Pd are not indicated. Corresponding structures shown in Figures 2 and 4 are listed in the table.

360 K, the direct annulation product, cNDA1H, was rapidly formed (Scheme 2, Figure 1). This species, however, underwent immediate further reactions leading ultimately to the formation of the dilactam product cNDA1O. This reaction was, however, not selective, and a competing formation of oligomeric byproducts was observed (see below). It was found that the conversion of cNDA1H into cNDA1O proceeds with the intermediacy of two species, cNDA1H,OAc and cNDA1OAc, containing, respectively, one and two acetoxy groups at the pyrrolic α positions. These two forms were additionally trapped in an independent experiment performed in nondeuterated

acetic acid, which enabled unequivocal identification of the OAc groups by means of 1H−13C correlation spectroscopy (Figure 1). In the entire reaction sequence, resonance line widths remained narrow for all species taking part in the α-oxygenation process (i.e., NDA1H, cNDA1H, cNDA1H,OAc, cNDA1OAc, and cNDA1O), indicating that the transformation does not involve significant concentrations of paramagnetic intermediates. In comparison with NDA1H, NMI1H would slowly cyclize to cNMI1H even at 300 K, and a complete conversion could be observed at 360 K after ca. 1 h. However, at that temperature, subsequent α-acetoxylations were slower than in the case of cNDA1H, and in consequence, more oligomeric products were formed, thus compromising the final yield of cNMI1O. Importantly, in the above in situ experiments, no αacetoxylation was detected for either NDA1H or NMI1H prior to the annulation step, implying a lower reactivity of monopyrrolic units in comparison with the corresponding bipyrroles. In the above kinetic experiment, the final yield of cNDA1O, determined from 1H NMR integral intensities, was 22%. Analysis of the NMR data confirmed that the reaction was limited by the low overall selectivity of the α-oxygenation process. It was presumed that competing intermolecular selfcoupling the initially formed cNDA1H may produce oligomers of the general structure (cNDA1)mX (represented as (cR1)mX in Scheme 2). Their formation could be inferred from the emergence of extremely broadened signals in the aromatic region of the 1H NMR spectrum, accompanied by somewhat better resolved resonances of NMe2 groups. Partial summation of molar fractions for consecutive intermediates in the αoxygenation process (Figure 2, Table S4) indicated that the loss of material due to oligomerization occurs at all stages of the reaction except for the final transformation of cNDA1OAc into cNDA1O . The latter observation might be tentatively rationalized by the absence of free α positions in cNDA1OAc. Each of the four reaction steps leading from NDA1H to cNDA1O can be considered a two-electron oxidation. and consequently, 4 equiv of PdII are formally needed to complete the entire sequence. In fact, in the presence of only ca. 1.3 equiv

Figure 1. Identification of intermediates in the stepwise formation of cNDA1O from NDA1H using NMR spectroscopy. The mixture was obtained by heating NDA1H with 1 equiv of Pd(OAc)2 (AcOH, 120 °C, 5 min). 2D panels (bottom) show HSQC and HMBC correlations (blue and red, respectively). Selected integral intensities are given in red. 5201


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to produce a high-valent PdIII or PdIV intermediate.66,56,67−70 Herein the absence of a strong oxidant in the reactant system may implicate the sole involvement of PdII and Pd0 species in the acetoxylation step. The conversion of diacetoxy intermediates cR1 OAc (cNDA1OAc and cNMI1OAc) into the corresponding dilactams cR1O is reminiscent of oxidative syntheses of p-benzoquinones from hydroquinone diacetates. The latter transformations are, however, typically performed in two steps, i.e., using acidic or basic ester cleavage followed by oxidation with, e.g., FeCl3,71,72 AgIIO,73 DDQ,74 O2/NO2,75 or air.76 Similarly, the 4,4′diphenoquinone unit of the natural product purpurone was generated via basic hydrolysis and subsequent aerial oxidation.77 While the mechanism of oxidative cleavage of cR1OAc is not known, it can be noted that the resulting lactams, cR1O, are not preceded by any long-lived intermediates, such as partial solvolysis products, which could be observed by 1H NMR. Coupling experiments performed in AcOH-d4 revealed Pdcatalyzed selective deuteration of pyrrolic α positions in the majority of the investigated dipyrrolylalkanes. This effect could be deduced from the behavior of the corresponding 1H NMR signal, which disappeared faster than other signals of the starting material in the course of the coupling reaction. For systems devoid of the α-ester group, namely, NDA1H and NMI1H, α-deuteration was rapid even at room temperature and could be brought to completion before observable amounts of coupling products were formed. α-Deuteration was significantly slower in the diester systems NDAnEE and NMInEE. In particular, when a 5.6 mM solution of NMI3EE in AcOH-d4 was heated at 360 K, a virtually complete α-deuteration was observed after ca. 5 h, with only trace amounts of cNMI3EE being formed. Under analogous conditions, NDA3EE behaved similarly. In the more rapidly cyclizing NDA2EE and NMI2EE, deuteration was still observable at 360 K, whereas in the case of NDA1EE and NMI1EE, the relative rate of cyclization was sufficiently high to conceal any effect of H/D exchange. Apart from α-deuteration, isotopic exchange at other positions was not observed in either NDA or NMI series. For TT1EE, the reaction with excess Pd(OAc)2 performed at 350 K in AcOH-d4 provided clear evidence for a two-step bisannulation process with well resolved kinetics (Scheme 3, Figure 3). The observed reactivity was not measurably affected by the presence of dioxygen in the sample. After the initial buildup of the bipyrrole intermediate cTT1EE (Scheme 3), the

Figure 2. Stepwise formation of cNDA1O from NDA1H observed by 1 H NMR spectroscopy (6 mM in AcOH-d4, 360 K, ∼5 equiv of Pd(OAc)2). Dashed lines represent partial sums of molar fractions. (Summation ranges are indicated with dashed brackets in the legend.) Structures of intermediates are provided in Scheme 2 (gray box, R = NDA).

of Pd(OAc)2, a considerable fraction of the starting material was left unreacted and oligomeric products were predominantly formed. Small amounts of cNDA1H,OAc and cNDA1OAc were also produced. The latter intermediates remained stable toward further conversion to cNDA1O, apparently because palladium(II) was no longer available for subsequent oxidation. Similarly, cyclizations performed for NDA1H under catalytic conditions were found to yield exclusively oligomeric materials. The oligomeric oxidation products (cNDA1)mX (labeled (cR1)mX in Scheme 2) are characterized by broadened 1H NMR spectra, which are not useful for detailed spectroscopic work. Consequently, neither the identity of the end groups X nor the oxidation level of the oligopyrrole backbone could be determined experimentally. The oligomeric nature of these products could nevertheless be verified by means of 1H DOSY experiments (Figure S10), which showed decreased diffusion coefficients of the oligomeric fractions relative to those of the corresponding dilactam cNDA1O. While the broadening of 1H NMR signals of the polymer may indicate structural inhomogeneity, the oligomers can be proposed to contain a significant proportion of annulated subunits, which are α−αlinked into longer strands, in line with the proposed formula (cNDA1)mX. This view finds support in the earlier observation that, in the ester-containing NDAnEE and NMInEE series, intermolecular α−α-coupling is too slow to compete with annulation. Despite the noncatalytic character of the α-acetoxylation described above and its presently limited scope, the reaction is of fundamental interest because of its positional selectivity and applicability to electron-poor aromatics. Efficient transition metal-mediated C−H acetoxylations have recently received considerable attention,56 but the majority of synthetically useful reactions reported to date are assisted by metal coordination57−61 or are limited to electron-rich substrates, such as indoles.62−64 In particular, some of the most successful Pdbased approaches to aromatic acetoxylation57,59,60,65 involve the use of a strong oxidant, such as PhI(OAc)2, which is necessary

Scheme 3. Double Annulative Coupling of the TT1EE

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more rapid than annulation. Interestingly, when the experiment was performed at an even higher temperature of 380 K, nearly complete deuteration of all thiophene positions was additionally observed in the ultimate cyclization product, dcTT1EE. These relative deuteration rates suggest that, in TT1EE, palladation of thiophenes is significantly slower than at pyrrolic α positions. The above results indicate that the initial α-palladation of the pyrrole is a reversible process in those cases for which H−D exchange is observed prior to cyclization. The equilibrium is apparently strongly shifted toward the substrates, because no αpalladated intermediates could be observed by 1H NMR for any of the systems studied. α-Palladation is slowed down by the presence of the α-ester substituent and, to a lesser extent, by the electron-withdrawing groups bound to the β positions (i.e., NDA and NMI units vs TT substituents). Most importantly, observation of H−D exchange indicates that the first C−H bond activation is not the rate-determining step (RDS) of the annulation reaction. Thus, the observed drastic deactivation of NDA3EE and NMI3EE can be proposed to result from altered energetics of subsequent mechanistic steps. The lack of observable α-deuteration in NDA1EE and NMI1EE is not a conclusive evidence for the rate-determining character of the first palladation in the cyclization reaction, but it nevertheless implies that a change in the RDS may be possible in rapidly cyclizing electron-poor systems. Similarly, the formation of the eight-membered ring in dcTT1EE is faster than H−D exchange

Figure 3. Kinetics of Pd-induced bis-annulation monitored for TT1EE using 1H NMR spectroscopy (350 K, 6 mM, 5 equiv of Pd(OAc)2).

latter species was gradually consumed to yield dcTT1EE as the only observable product. Deuterium exchange at the α positions of TT1EE was insignificant at 300 K, as in other diester systems. However, in experiments performed at 350 and 360 K (Figures 3 and S2, respectively), the rate of disappearance was faster for the α resonances than for other 1 H NMR signals of TT1EE, indicating that α-deuteration is

Figure 4. Free energy profile for Pd(OAc)2-induced coupling of H1H. ΔG298 values (kcal/mol) correspond to the ωB97XD (red) and M06 (gray) potential energy surfaces. 3D representations are provided for structures represented with blue bars. Green lines indicate intrinsic reaction coordinate connectivities. Dashed lines indicate steps for which transition states were not determined. Selected transition state geometries are shown for NMI3EE in the gray box. 5203


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interaction instead of a Pd−O bond. Interestingly, the release of cH1H from π3 is predicted to be endergonic for a number of simple mononuclear byproducts, such as Pd0(AcOH)2 (35 kcal/mol, ωB97XD), PdII(H)(OAc)(AcOH) (22 kcal/mol), or PdII(H)(OAc)(AcOH)2 (13 kcal/mol). These results point toward thermodynamic instability of mononuclear Pd0 species and PdII hydrides in acetic acid. Related palladium hydrides, of the general formula Pd(H)(OOCR)L2, were postulated as intermediates in palladium oxidation catalysis.99,100 The absence of aerobic oxidation in our experiments is consistent with the presumed instability of Pd hydride species. Similarly, in the cyclization of H1H, a hypothetical release of dihydrogen, accompanied by the recovery of Pd3(OAc)6, would be endergonic with a ΔG298 of 10 kcal/mol. It can thus be inferred that the thermodynamic driving force for the stoichiometric coupling reaction is provided by the formation of palladium metal from the transient mononuclear palladium(0) species. In its catalytic variants, the reaction is driven by the consumption of the oxidant; for instance, the overall ΔG298 value for the coupling is −28.6 kcal/mol relative to the DDQ−DDQH2 redox couple. Subsequent extensive calculations showed that the mechanistic route established for H1H can also be identified for more complex dipyrrolylalkanes containing NDA and NMI subunits linked via bridges of variable length (Tables 1 and 2). In this

on thiophenes. The process also shows complete positional selectivity (e.g., no benzannulation is observed, cf. Scheme 3), indicating that once the first C−H bond activation occurs at the correct position, subsequent cyclization is rapid and nonreversible. DFT Calculations. The mechanism of Pd(OAc)2-induced cyclization was first probed computationally for the substituentfree di(pyrrol-1-yl)methane H1H (Figure 4). The potential energy surface of the reaction was explored at the PCM(AcOH)/ωB97XD/6-31G(d,p),Lanl2DZ level of theory,78 taking into account solvation effects and dispersion interactions.79 Similar levels of theory have recently been applied to various problems in Pd-based C−H bond activation.80−86 Energies of the resulting stationary points were additionally evaluated using SMD(AcOH)/M06/6-311++G(d,p),SDD,87 for comparison with other recent computational work on Pdinduced reactivity.88,89 The potential energy surface is made more complex by the conformational flexibility of the intermediates, which involves torsional degrees of freedom within the dipyrrolylmethane and around the Pd center. Intrinsic reaction coordinate (IRC) analyses performed for the bond-forming transition states and restricted conformational searches performed for local energy minima showed that the entire reaction path likely involves conformational rearrangement of intermediates at several stages. Because such conformational steps generally have low barriers and are unlikely to be rate-determining, they are not discussed below. The mononuclear activation pathway, involving the monomeric Pd(κ2-OAc)2 species was investigated for H1H, assuming initial dissociation of the Pd3(OAc)6 trimer89,90 (Figure 4). The process begins with the formation of a van der Waals adduct of H1H and Pd(κ2-OAc)2 (vdW), which rearranges into a π complex (π1) with a η2 bond between Pd and one of the pyrrole rings. C−H bond activation then occurs via a concerted metalation−deprotonation step (CMD, TS-σ1),89,91−97 yielding the α-palladated intermediate σ1. The relatively low barrier and moderately endergonic character of the latter step are in line with the reversibility of palladation observed in our experiments, particularly for electron-rich pyrroles. The second CMD step, leading to the palladacycle intermediate σ2, is again preceded by the formation of a π complex (π2), this time characterized by η1 bonding to Pd. The formation of π1 and π2 intermediates may be attributed to the relatively electron-rich character of the dipyrrolyl substrates, although it can be noted that side-on binding of this type was recently predicted between certain chromone derivatives and Pd(TFA)2.83 A similar π complex was recently found computationally in β-palladation of indole, but it was nearly isergonic with the free Pd(κ2-OAc)2.98 In the present case, both π1 and π2 are stabilized by several kcal/mol relative to the unbound state of Pd(κ2-OAc)2. Reductive elimination (TS-RE) of palladium from σ2 is predicted to be the overall energy maximum along the reaction coordinate, thus corresponding to the rate-determining step of the H1H annulation. M06-based ΔG298 energies obtained for stationary points along the annulation coordinate are in semiquantitative agreement with the corresponding ωB97XD values. The former method predicts a greater stabilization of the π-bound intermediates and a noticeably lower, though still rate-limiting, barrier to reductive elimination. After the RE step, Pd0 is predicted to remain π-bonded to the coupled product, cH1H, in the form of the π3 intermediate. At this stage, coordination of acetic acid to Pd is very weak, with one AcOH molecule actually forming a weak Pd···HO

Table 1. Potential Energies,a,b Gibbs Free Energies,a,b,c and Key Structural Parametersb,d for the Two Initial Transition States of Pd-Induced Annulations RnX

TS-π1 ΔE

H1H H2H H3H NMIH1H H1ME H2ME H3ME NDA1ME NMIH1ME

23.0 25.5 25.0 19.8 24.0 24.0 25.5 21.1 22.5

ΔG

298

26.7 27.1 27.2 24.5 27.8 30.5 28.2 26.3 26.9

TS-σ1 Pd···Cα

ΔE

2.645 2.654 2.662 2.710 2.556 2.616 2.657 2.557 2.519

23.7 23.5 22.3 20.7 28.0 28.1 24.3 22.3 23.9

ΔG

298

24.5 25.7 25.0 21.7 31.5 30.0 27.1 25.8 28.5

Cα···H

O···H

1.340 1.324 1.335 1.311 1.297 1.290 1.304 1.282 1.267

1.252 1.275 1.260 1.280 1.300 1.320 1.298 1.317 1.337

a

In kcal/mol. bPCM(AcOH)/ωB97XD/6-31G(d,p),Lanl2DZ geometries and energies. cEnergies corresponding to rate-determining steps are printed in bold. dDistances in Å.

part of the analysis, the effect of the α-ester group was probed for methoxycarbonyl derivatives (ME), to simplify the conformational space of the reactants, whereas the possible steric influence of dipp substituents in NMI units was investigated by comparison with N-unsubstituted imide moieties (denoted NMIH). Because of the known difficulty of accurately estimating free energies in large molecular systems, in particular entropic contributions to ΔG,101,102 the primary goal of this study was not to qualitatively reproduce experimental reaction kinetics but to verify the persistence of the mechanistic pathway established above and to check the influence of structural changes on relative energetics of the coupling process. First, the initial palladation of relevant dipyrrolylmethane structures (n = 1, Table 1) was confirmed to involve discrete πcoordination and CMD steps, as evidenced by the successful location of the corresponding TS-π1 and TS-σ1 transition states. For H1ME, an increase of the TS-σ1 energy by 7 kcal/ 5204


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Table 2. Potential Energies,a,b Gibbs Free Energies,a,b,c and Key Structural Parametersb,d for the Three Final Transition States of Pd-Induced Annulations substrate RnX HnH

NMIHnH

NMInH

HnME

NDAnME NMIHnME

NMInME

TS-π2

TS-σ2

TS-RE

n

ΔE

ΔG298

Pd···Cα

ΔE

ΔG298

Cα···H

O···H

ΔE

ΔG298

Cα···Cα

1 2 3 1 2 3 1 2 3 1 2 3 1 1 2 3 1 2 3

22.4 18.7 19.1 18.6 10.5 3.9 18.3 5.8 2.7 26.1 19.5 18.6 21.2 22.1 8.4 5.3 21.9 3.6 0.8

25.1 23.9 25.4 22.6 18.9 14.5 23.0 15.8 14.9 28.3 25.4 25.7 24.1 25.8 19.2 15.6 25.0 14.5 13.5

2.565 2.683 2.860 2.378 2.773 2.734 2.383 2.776 2.880 2.543 2.735 2.836 2.342 2.363 2.759 2.875 2.340 2.744 2.866

22.9 21.0 20.8 17.2 8.3 5.1 17.1 11.1 9.7 29.3 26.6 26.5 21.8 22.8 9.7 8.2 22.6 14.9 12.8

24.4 24.0 24.3 20.5 12.3 11.6 19.6 17.4 17.0 29.4 29.6 29.3 22.5 24.2 16.4 14.8 25.8 19.2 20.1

1.307 1.356 1.377 1.282 1.362 1.381 1.280 1.343 1.319 1.284 1.376 1.399 1.273 1.269 1.333 1.309 1.266 1.343 1.316

1.330 1.256 1.228 1.360 1.236 1.215 1.362 1.262 1.281 1.361 1.225 1.202 1.371 1.379 1.268 1.291 1.384 1.256 1.283

33.3 25.2 25.0 23.0 15.2 16.7 22.9 14.7 16.3 32.1 25.4 26.0 23.5 23.6 17.8 22.3 23.4 17.4 21.0

34.3 29.0 29.6 25.9 19.1 22.7 23.8 17.5 21.1 33.8 29.4 28.8 22.7 24.5 21.9 27.5 24.0 18.7 25.8

1.805 1.873 1.892 1.786 1.835 1.843 1.788 1.827 1.835 1.820 1.868 1.888 1.801 1.794 1.811 1.736 1.793 1.810 1.687

a

In kcal/mol. bPCM(AcOH)/ωB97XD/6-31G(d,p),Lanl2DZ geometries and energies. cEnergies corresponding to rate-determining steps are printed in bold. dDistances in Å.

mol relative to H1H results in a significantly higher palladation barrier. A similar difference is found between NMIH1H and NMIH1ME, in line with the experimentally observed difference in deuteration rates between the α-H and α-ester systems. Interestingly, the palladation barriers are predicted to be lower for NMIH1X and NDA1X than for the corresponding H1X (X = H, ME). This result shows that the formally electronwithdrawing NMI and NDA units can actually facilitate the C−H activation process, possibly because of their ability to delocalize partial charges in their π-conjugated ring system. While the accuracy of these calculations is likely insufficient to directly compare energies of TS-σ1 than for TS-π1, our calculated ΔE and ΔG values indicate that, in some extensively conjugated systems, the kinetics of the initial palladation may become limited by π-coordination rather than by the CMD step. Interestingly, in the HnX series, the energies of TS-σ1 than for TS-π1 show a fairly considerable, though rather irregular, dependence on the linker length, n. The effect is stronger when X = ME (e.g., the difference in ΔG298 of TS-σ1 = 4.4 kcal/mol between n = 1 and 3) and may be presumed to originate from a combination of electronic and steric contributions. Given their expected greater sensitivity to steric factors, the energetics of the ring-forming transition states, TS-π2, TS-σ2, and TS-RE, were explored more extensively, by additionally varying the linker length, n (Table 2). In analogy to the first C− H activation, the introduction of α-ester groups increases the potential energy barriers in the second palladation stage (TS-π2 and TS-σ2) by several kcal/mol, although this trend is not always retained in the corresponding Gibbs free energies. Similarly, these barriers are systematically lower in the πextended systems NMInX and NDAnX than in the corresponding HnX. For each series of dipyrrolylalkanes studied, the geometry of TS-π2 was considerably influenced by n. Specifically, the Pd···Cα distance increased with the increasing linker length and the position of the Pd center shifted somewhat toward the adjacent β carbon. In systems containing

NMI fragments, potential energies of the TS-π2 and TS-σ2 states decrease considerably when n is increased to 2 or 3. These changes are less pronounced in HnX systems, indicating that the observed stabilization is not a simple function of the ring strain, and originates, at least in part, from π-conjugative stabilization or dispersion interactions between subunits. The dispersive contributions in the second palladation step (TS-π2 and TS-σ2) may include both π-stacking between aromatic surfaces and interactions of remote groups, notably the bulky dipp substituents. The complexity of the latter effect is evident in the energy differences between corresponding NMIHnX and NMInX transition states (R″ = H and dipp, respectively). In NMI1X (X = H, ME), the dipp groups are sufficiently far apart in TS-π2 and TS-σ2, to make a little impact on the energies. In NMI2X and, especially, NMI3X, the aromatic units become aligned differently, leading to specific interactions between the dipp substituents, illustrated for NMI3ME in Figure 4 (gray box). In TS-π2 of that system, the dipp groups do not affect the alignment of the NMI fragments and contribute to the overall stabilization via dispersion interactions with the neighboring imide units. In contrast, in the TS-σ2 structure, one of the NMI units has to bend to accommodate the bulk of the dipp substituent, leading to a net destabilization of the transition state relative to the corresponding NMIH3ME structure (R″ = H, ΔΔG298 = 5.3 kcal/mol). The barrier to reductive elimination (TS-RE) is relatively insensitive to the presence of the α-ester substituents. A notable exception from this rule is provided by NMIH3ME and NMI3ME, in which TS-RE is apparently destabilized by steric repulsion between ester groups and the adjacent CH2 moieties of the bridge. In contrast, π-extension of pyrrole rings in NMI and NDA systems results in a notable stabilization of TS-RE, relative to the corresponding HnX dipyrrolylalkanes, occasionally exceeding −10 kcal/mol. Except for the sterically 5205


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Scheme 4. Mechanistic Proposal for the Pd-Induced Acetoxylation of Bridged Bipyrroles, cR1H, Investigated Computationally for cH1H, cNDA1H, and cNMI1H a

a

Transition state geometries were optimized at the PCM(AcOH)/ωB97XD/6-31G(d,p),Lanl2DZ level of theory. Energies are given relative to the trimer, Pd3(OAc)6. Geometry of the TS-OAc-c state optimized for cNMIH1H is shown in the box.

destabilized NMIH3ME and NMI3ME, the highest TS-RE energy within each series is observed for the shortest linker (n = 1). As shown in the above discussion, transition state energies for consecutive coupling steps show a relatively complex dependence on the reactant structure RnX, namely, the αsubstitution (X = H vs ME), linker length (n), and π-extension (R = NMI and NDA vs H). The rate-determining steps cannot be determined with certainty for specific RnX reactants on the basis of available DFT data because energy differences between consecutive transition states are generally comparable with the expected accuracy of the calculation. Nevertheless, the observed variation of TS energies suggests that the identity of the RDS will typically correlate with the identity of the X group. Specifically, TS-RE is the likely RDS for the more reactive substrates with X = H, whereas the initial C−H bond activation (TS-π1 and TS-σ1) is rate determining for the majority of deactivated systems with X = ME (EE). This conclusion is in line with the experimental observation of reversible C−H activation for X = H. α-Acetoxylation of cR1H was explored computationally with the initial assumption that the transfer of the OAc group occurs via ligand transposition in an α-palladated intermediate σ1 (Scheme 4). However, the energy barrier to such a transposition was found to be very high for three-coordinate PdII (TS-OAc-a, ΔG298 of ca. 40 kcal/mol). Because acetoxylation was only observed in acetic acid, we presumed that the process may be assisted by solvent coordination. Binding of an outersphere acetic acid molecule to the Pd center (TS-OAc-b) resulted in considerable lowering of potential energies, but this stabilization was completely outweighed by entropic effects. Finally, it was found that the coordination of an outer-sphere acetate81,103 leads to the most accessible transition states (TSOAc-c). Remarkably, the stabilization is particularly significant for π-extended systems cNDA1H and cNMI1H, indicating potential involvement of the polycyclic framework in charge delocalization. The TS-OAc-c mechanism was therefore considered the most viable option of those investigated, even though it is limited by the low availability of acetate anions in neat AcOH. As discussed in our previous report,45 the addition

of AcOK to reaction mixtures resulted in significantly improved yields of α-oxygenated products cNMI1O and cNMI1O, in line with the theoretical model presented above.

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CONCLUSIONS In this work, we demonstrated a mechanistic analysis of an annulative double C−H bond activation reaction and its tandem variants, as used for the synthesis of electron-deficient bipyrrole “boomerangs.” Our NMR experiments revealed that reaction kinetics of the NDAnEE series and their NMI counterparts were comparable for n = 1 and 2, whereas systems with n = 3 cyclized far more slowly. In the case of esterfree precursors, we proved that the course of events leading to dilactam products occurred through acetoxylation of α-pyrrolic positions and that this reactivity competed with oligomerization. This α-oxygenation process, which apparently does not involve high oxidation states of palladium, may become relevant as a preparatively useful transformation but is also of practical interest as a side reactivity to be avoided in Pd-mediated oxidative coupling chemistry. Moreover, the clear spectroscopic evidence of a two-step bis-annulation process was shown for the electron-rich thienyl-substituted TT1EE. Importantly, our Pd-induced approach works well for some electron-deficient and sterically encumbered targets that are not cyclized under oxidative coupling conditions. According to our computational analysis, these advantages appear to result from the stabilization of selected transition states by π conjugation, which occurs even in electron-poor frameworks, and from the involvement of palladacycle intermediates, which efficiently preorganize the substrate for annulation. Mechanistic understanding gained from this work will aid in further development of annulative double C−H bond activation and in designing tandem coupling reactions, e.g., ones combining multiple intra- and intermolecular steps.

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EXPERIMENTAL SECTION

General. Deuterated acetic acid was used as received. Dipyrrolylalkanes NDAnEE, NMInEE, (n = 1, 2, or 3), NDA1EE, NMI1EE, and TT1EE were prepared as previously reported.45 1H NMR spectra were 5206


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The Journal of Organic Chemistry recorded on high-field spectrometers (1H frequency 600.13 MHz), equipped with broad-band inverse or conventional gradient probe heads. Spectra were referenced to the residual solvent signal (acetic acid-d4, 3.02 ppm). Two-dimensional NMR spectra were recorded with 2048 data points in the t2 domain and up to 2048 points in the t1 domain, with a 1.5 s recovery delay. All 2D spectra were recorded with a gradient selection, with the exception of NOESY and ROESY. The NOESY mixing time and ROESY spinlock time were 500 and 300 ms, respectively. Details of computational work and kinetic analyses are given in the Supporting Information.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00630. Cartesian coordinates (ZIP) Computational methods, kinetic analysis, and additional NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Marcin Stępień: 0000-0002-4670-8093 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Science Center of Poland (2014/13/B/ST5/04394) is gratefully acknowledged. Quantum chemical calculations were performed in the Wrocław Center for Networking and Supercomputing.

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REFERENCES

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