Toward Rational Understandings of α-C-H Functionalization: Energetic Studies of Representative Tertiary Amines.

Functionalization of α-C-H bonds of tertiary amines to build various α-C-X bonds has become a mainstream in synthetic chemistry nowadays. However, due to lack of fundamental knowledge on α-C-H bond strength as an energetic guideline, rational exploration of new synthetic methodologies remains a far-reaching anticipation. Herein, we report a unique hydricity-based approach to establish the first integrated energetic scale covering both the homolytic and heterolytic energies of α-C-H bonds for 45 representative tertiary amines and their radical cations. As showcased from the studies on tetrahydroisoquinolines (THIQs) by virtue of their thermodynamic criteria, the feasibility and mechanisms of THIQ oxidation were deduced, which, indeed, were found to correspond well with experimental observations. This integrated scale provides a good example to relate bond energetics with mechanisms and thermodynamic reactivity of amine α-C-H functionalization and hence, may be referenced for analyzing similar structure-property problems for various substrates.

Introduction

Because of a high efficiency and atom economy, direct C–H functionalization has become a prevalent strategy for converting readily accessible starting materials into potentially bioactive scaffolds (Blakemore et al., 2018, Qin et al., 2017, Saint-Denis et al., 2018). However, most C–H bonds are comparatively inactive, therefore substrates with a C–H bond at the α-position of some heteroatom-centered entities, such as an N-containing moiety, have attracted much attention, as a consequence of the latent stabilizing effect of the neighboring electron pair on the incipient α-radical or α-cation upon α-C-H bond scission (Campos, 2007, Chen et al., 2018, Nakajima et al., 2016, Shi and Xia, 2012, Zhang et al., 2019). Among this category of Y-C–H (Y = N, O, S, P, etc.) type compounds, tertiary amines are the most popular due especially to the widespread presence of their structural motif in many natural alkaloids and bioactive molecules (Beatty and Stephenson, 2015, Rommelspacher and Susilo, 1985, Shamma, 2012). As a result, numerous oxidative cross-dehydrogenative couplings (CDC) have been developed for functionalization of tertiary amines via α-C–H bond dissociation (Chi et al., 2019, Girard et al., 2014, Szatmári et al., 2016, Yoo and Li, 2010) (Scheme 1).

Scheme 1

CDC Process of Tertiary Amines in Organic Synthesis

In these CDC processes, the tertiary amine is first oxidized, via different modes of α-C–H bond rupture (Scheme 1), to α-amino radical or iminium ion either by transition metals (Cheng et al., 2017, Murahashi et al., 2003, Shao et al., 2015), organic oxidants (Allen and Lambert, 2011, Damico and Broaddus, 1966, Sundberg et al., 1991), or by electro- (Basle et al., 2010, Fu et al., 2017, Yoshida and Suga, 2002) or photo-oxidants (Condie et al., 2010, McNally et al., 2011, Ravelli et al., 2016, Thullen and Rovis, 2017). The α-amino intermediate is then intercepted by an appropriate reagent to furnish a new α-C–R bond (Scheme 1). It may need to mention that among the two primary modes of α-C-H bond rupture via CDC, the iminium route, rather than the radical route(McNally et al., 2011, Thullen and Rovis, 2017), would be more emphasized in the context, due mainly to a higher degree of complexity of the former (vide infra). Some typical reaction trends observed experimentally are represented in Scheme 2. As shown in 2a, substitution change at the N atom substantially varied the tetrahydroisoquinoline (THIQ) reaction yield from 0% to 100%. Similar impact on the coupling yields could also be dominated by the choice of oxidants (Scheme 2B) (Wan et al., 2014, Xie et al., 2014). Moreover, Scheme 2C shows an example of a varying mechanism for two similar Cu-catalyzed CDCs, that is, an electron-hydrogen transfer (ET-HT) is followed with the CuCl2/O2 pair, whereas a hydrogen-electron transfer (HT-ET) is favored with a CuBr/tBuOOH pair. Although the relevance of α-C–H bond cleavage in affecting the reaction pattern and outcomes was well demonstrated (Oss et al., 2018, Zhang et al., 2012), till now, no practical guideline could be found in literature for reasonably elucidating these puzzling observations exemplified. This actually points out a keen demand for a rational understanding of the diversified CDC reactivity and mechanisms.

Scheme 2

Representative Reactivity Trends for THIQ-Involved Processes in Organic Synthesis

(A) Substituent effects; (B) Effects of oxidants; (C) Mechanism diversities.

As generally known, there are basically three mechanisms for amine oxidation (Scheme 3). Actually, direct hydride transfer (H−T, pathway a) is quite frequently seen when organic cations (e.g., Ph3C+) are used as the acceptors (Richter and GarcíaMancheño, 2010, Xie et al., 2014). Alternatively, when a latent radical species [e.g., peroxides (Zhang et al., 2017) and azo compounds (Liu et al., 2017a)] is used as the initiator, the reaction may proceed through C–H bond homolysis to yield α-amino radicals (pathway b), which are then oxidized to iminium ions via fast electron transfer. On the other hand, if amine is to react with a single-electron oxidant [e.g., radical cations (Huo et al., 2014), transition metal (Brzozowski et al., 2015), photo-oxidant (Hari and König, 2011, McManus et al., 2018), or an anode (Franckeand Little, 2014)], formation of radical cation would be expected (pathway c), which can subsequently decompose through either hydrogen-atom transfer (HT) or stepwise proton-electron transfer (PT-ET). This rule of thumb provides a hint for one to assess which mechanism, a particular amine oxidation, is more likely to follow, but with no indication on reactivity issue in relation to the thermodynamic driving force of bond cleavage.

Scheme 3

Possible Pathways for Generation of Iminium Ions from Tertiary Amines

Although syntheses via oxidative cleavage of the α-C–H bonds of tertiary amines have advanced greatly, till present, investigations on the oxidation mechanisms are sparse, however (Liu et al., 2017b, Morgante et al., 2019), and, some are even subject to debates. For instance, Klussmann et al. and Doyle et al. both conducted serious investigations on Cu-catalyzed oxidative coupling mechanisms of THIQs with tBuO⋅, but ended up in different conclusions on mechanisms (HT vs. ET), based on each other's sound experimental evidences (Boess et al., 2012, Boess et al., 2016, Ratnikov and Doyle, 2013). The controversy has lasted several years and seems still not fully settled down. This, in our view, is due to the fact that only the conventional measures, such as kinetic study, intermediate and product analysis, etc., are often not sufficient to describe a reaction mechanism. In this regard, establishment of an integrated energetic scale embracing all the possible elementary steps in Scheme 3 should be helpful for mechanistic judgment because of the inherent relationship between bond energy and reactivity.

Despite the definite need of thermodynamic data related to the α-C–H bonds of tertiary amines (Xue et al., 2017, Yang et al., 2018), they have seldom been determined. In fact, almost all the currently known bond energies of organic molecules that cannot be directly measured by the gas-phase techniques were derived from measurement of corresponding pKa values in solution through the properly designed thermochemical cycles of Bordwell (Bordwell et al., 1988). However, this method would not be applicable to the present substrates, because the acidity of the C–H bond adjacent to nitrogen is too weak to allow a deprotonation by any strong base present in solution.

In the present work, we developed a unique hydride-transfer-based methodology to construct an integrated α-C–H bond energy scale of tertiary amines. The scale is composed of four fundamental quantities required for diagnosing the C–H functionalization mechanisms, including (1) the hydricity ΔHH-D (hydride-releasing ability) of tertiary amines (where D denotes donor), (2) the α-C–H bond homolytic energy ΔHHD, (3) the deprotonation energy of amine radical cations ΔHPD(HD⋅+), and (4) the hydrogen-atom-donating ability of radical cations ΔHHD(HD⋅+). Direct measurement or derivation of these energetic parameters was described in the following section. This energetic scale (with 4 × 45 new bond energies), together with the redox data of relevant species, was then used to analyze the possible mechanisms and their corresponding structure–property relationships. Particularly, in order to help synthetic chemists to get more acquainted with this bond-energy-based mechanistic analysis, the feasibility and mechanisms of the well-studied THIQ oxidations by various oxidants were investigated in more details, perhaps with a sacrifice of some synthetically more favored cases, to showcase the plausible applicability of bond-energetic diagnosis of reaction feasibility/mechanism issues. Experimental confirmations of this line of rational analyses were also exemplified and discussed. Although only representative tertiary amines were chosen in this first systematic study on the Y-C–H type bond energy scale and its application, we believe the insights derived herewith could provide useful hints for analyzing other Y-C–H systems as well.

Results

In a CDC process, the tertiary amine actually acts as a reductant to transfer its α-C–H to a suitable acceptor. In order to assess the trend of this bond to deliver its hydrogen, we explored an alternative approach, rather than by using the method of Bordwell that requires the knowledge of pKa (Bordwell et al., 1988), to measure the hydride-releasing ability instead, i.e., hydricity ΔHH-D of this α-C–H bond. As mentioned above, this is because the α-C–H bond of amines is too weak to allow deprotonation, but it is feasible to deliver a hydride. As expected, THIQ analogs could quantitatively exchange their α-C–H hydride with 4-acetamido-2,2,6,6-tetramethyloxopiperidinium perchlorate (AcNH-TEMPO+ClO4−) (Equation 1) whose hydride affinity ΔHH-A (where A denotes acceptor) in acetonitrile was well established (Table S1 in Supplemental Information). Thus, determination of the THIQ hydricity ΔHH-D becomes a matter of measuring the heat ΔHrxn of the hydride exchange reaction (by isothermal titration calorimetry, see Supplemental Information for details). The hydricity ΔHH-D(HD) can then be evaluated from Equation 2 using the known ΔHH-A(AcNH-TEMPO+) of −105.6 kcal mol−1 (Zhu et al., 2011). For acyclic amines, another reduction process (Equation 3) was employed to avoid the possible coupling of amines with hydride acceptors. Their hydricity was derived from the known hydricity of the dihydropyridine (ΔHH-D(PyH2) = 48.0 kcal mol−1) and ΔHrxn (Equation 4).

Next, a thermochemical cycle was established according to the Hess's Law to derive other thermodynamic quantities on the basis of the available ΔHH-D(HD) (Scheme 4). As shown, the hydrogen-atom donability of tertiary amines, i.e. the homolytic α-C–H bond dissociation energy ΔHHD(HD), can be obtained from the experimentally measurable hydricity ΔHH-D(HD) and the reduction potential of its corresponding iminium ion, Ered(D+) (Equation 5). The respective cycles for evaluating the α-C–H homolytic (ΔHHD(HD⋅+)) and heterolytic energies (ΔHPD(HD⋅+)) of amine radical cations were also designed (Equations 6 and 7), where the energy required for converting amines (HD) to its radical cations (HD⋅+) is described by their oxidation potentials Eox(HD) (see Supplemental Information for details). These bond parameters, together with the relevant redox potentials determined in this work, are summarized in Table 1.

Scheme 4

Thermodynamic Cycles for Derivation of ΔHHD(H), ΔHHD(HD•+), and ΔHPD(HD•+)

Table 1

Integrated α-C−H Bond Homolytic Energy [ΔHHD(HD)] and Hydricity [ΔHH-D(HD)] Scale of Tertiary Amines, Homolytic/Heterolytic Energy Scales of Amine Radical Cations [ΔHHD(HD•+)/ΔHPD(HD•+)], and the Relevant Redox Data in Acetonitrile at 298 K

Substrates	R		ΔHH-D(HD)a	ΔHHD(HD)a	ΔHHD(HD•+)a	ΔHPD(HD•+)a	Eox(HD)b	Ered(D+)b
	1		76.6	88.1	34.9	19.4	0.67	−1.64
	2a	p-CN	81.4	79.3	40.1	12.9	0.65	−1.05
	2b	p-Br	77.0	80.0	37.3	15.2	0.58	−1.27
	2c	p-Cl	75.7	79.2	36.3	14.6	0.57	−1.29
	2d	p-F	76.0	81.3	36.6	16.7	0.57	−1.37
	2e	H	73.9	79.4	35.2	15.5	0.54	−1.38
	2f	p-Me	70.2	76.7	31.7	13.0	0.53	−1.42
	2g	p-OMe	63.1	71.4	24.8	8.0	0.52	−1.50
	2h	p-NMe2	60.9	73.4	27.5	14.8	0.31	−1.68
	2i	o,o’-Me2	62.9	72.1	24.2	8.2	0.54	−1.54
	3a	1-Naph	76.2	79.7	37.5	15.8	0.54	−1.29
	3b	2-Naph	75.2	78.4	36.7	14.8	0.53	−1.28
	4		69.8	71.0	31.8	7.7	0.51	−1.19
	5		61.9	70.0	18.5	1.5	0.74	−1.49
	6a	p-NO2	82.1c	74.7	36.7	2.3	0.83	−0.82
	6b	p-CN	80.7	74.5	36.9	3.7	0.76	−0.87
	6c	p-CF3	79.7	75.0	37.2	5.6	0.70	−0.94
	6d	p-Cl	78.9	75.7	41.3	11.1	0.49	−1.00
	6e	H	77.9	76.5	41.7	13.4	0.43	−1.08
	6f	p-Me	77.6	76.3	42.9	15.0	0.35	−1.10
	6g	p-OMe	75.4	74.9	43.8	16.4	0.23	−1.12
	6h	o-OMe	77.6	78.7	42.3	16.4	0.39	−1.19
	6i	m-OMe	79.0	77.6	43.5	15.1	0.40	−1.08
	7a	Me	72.7	78.0	34.9	13.2	0.50	−1.37
	7b	Et	72.2	77.7	35.5	14.1	0.45	−1.38
	7c	CH2CO2Et	79.4	81.2	37.6	12.5	0.67	−1.22
	7d	CH2CHCH2	73.1	77.5	33.4	10.8	0.58	−1.33
	7e	CH2Ph	75.1	79.0	35.2	12.1	0.59	−1.31
	7f	CHPh2	76.6	79.8	34.8	11.1	0.67	−1.28
	7g	Cbz	92.5c	80.5	32.5	−6.4	1.46	−0.62
	7h	1-Naph	82.2	83.5	47.5	21.8	0.43	−1.13
	7i	2-Naph	76.1	73.5	42.2	12.7	0.33	−1.03
	8a	Me	75.8	84.1	39.8	21.1	0.42	−1.50
	8b	Ph	74.3	80.5	36.2	15.4	0.51	−1.41
	9a	7-NO2	81.4	75.4	43.6	10.6	0.50	−0.88
	9b	6-CN	82.0	74.1	44.4	9.5	0.49	−0.80
	9c	6-Br	80.3	77.1	43.4	13.2	0.46	−1.00
	9d	6-OMe	76.9	79.2	41.3	16.7	0.40	−1.24
	10a	Cl	77.5	77.5	40.6	13.6	0.46	−1.14
	10b	H	75.7	77.3	40.2	14.8	0.40	−1.21
	10c	OMe	72.0	75.2	41.1	17.3	0.20	−1.28
	11		80.0c	78.1	44.0	15.2	0.42	−1.06
	12		71.1	70.2	34.4	6.5	0.45	−1.10
	13		77.9	77.4	41.0	13.5	0.46	−1.12
	14		66.7	74.5	42.0	22.8	−0.07	−1.48

Note: The hydricity [ΔHH-D(HD)] of 6e (77.9 kcal mol−1) is consistent well with the values of 77.0 and 78.6 kcal mol−1 derived independently from other acceptors (phenothiazinium perchlorate and Ph3C+ClO4-).

In units of kcal mol−1, obtained from Scheme 4 within experimental error of ±0.5 kcal mol−1, taking E(H0/+) = −2.31 V and E(H−/0) = −1.14 V (Parker, 1992).

In units of V vs Fc0/+, obtained from CV experiments within experimental error of ±30 mV.

Measured by Ph3C+ClO4- with ΔHH-A(Ph3C+) = −104.3 kcal mol−1.

Discussion

Structural Effects and Energetic Criteria of Amine α-C–H Bond Scission

As shown in Scheme 3, generation of iminium ion is the key step in α-C–H functionalization of tertiary amines, which could be initiated by either hydride (H−T), hydrogen (HT), or electron transfer (ET), corresponding respectively to the energetic terms of ΔHH-D, ΔHHD, or Eox(HD). The effects of amine structural variations on the corresponding energies as well as on understanding of amine α-transformations are addressed below, jointly with experimental verification, wherever applicable.

On Hydride Removal

As known from the hydricity data (ΔHH-D) of amines in Table 1, series 2, 6, and 9 mimic the general trend as seen in other hydridic systems (e.g. NADH models (Zhu and Wang, 2010)), that is, remote electron-donating groups (EDGs) at N atom facilitate C–H bond scission by stabilizing the nascent iminium ion, whereas electron-withdrawing groups (EWGs) do the opposite. Although such trend basically remains also for series 7 with adjacent substitution at N atom, the structural effect is notably more pronounced and likely also complicated by factors other than the electronic effect. For example, steric effect should at least be partially responsible for the derived hydricity order of 7a (R = CH3: 72.7) <7e (CH2Ph: 75.1) <7f (CHPh2: 76.6) and 7i (2-Naph: 76.1) <6e (Ph: 77.9) <7h (1-Naph: 82.2). Also, it is worth noting that the effects of changing the ring size (6e vs. 11 and 12) or aromaticity (7a vs. 14) are quite significant. One can find that the hydricity of serial 6 determined here correlates well with the previously observed kinetic trend of THIQ oxidation by DDQ (Tsang et al., 2017). Besides, the gradual increase of ΔHH-D for N-Ph (6e), N-(1-Naph) (7h), and N-Cbz (7g) is also found to agree with the descending reaction rates of their oxidation by DDQ (Tsang et al., 2017).

To help people to more easily apply these energetic data in analyzing/predicting the trend of hydride exchange reactions, the hydricity (ΔHH-D) of amines derived in this work are depicted in Figure 1, along with the known hydride affinity (ΔHH-A) data of common hydride acceptors for comparison. The combined scale reveals that amines (colored bars, ranging 60–92 kcal mol−1) are generally weaker hydride donors than biomimetic donors such as 1,3-dimethyl-2,3-dihydro-1H-benzimidazole (DMBI, 54.1 kcal mol−1), 1-benzyl-1,4-dihydropyridine-3-carboxamide (BNAH, 64.2 kcal mol−1), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (HEH, 69.3 kcal mol−1). Indeed, strong oxidants with –ΔHH-A values greater than 100 kcal mol−1 (e.g., DDQ, Ph3C+, AcNH-TEMPO+) were experimentally observed to be capable of splitting the α-C–H bonds of all N-alkyl/aryl-THIQs in a few minutes at room temperature (de Costa et al., 1992, Tsang et al., 2017). This also explains the need of a longer reaction time (2h) reported for N-Cbz-THIQ (Yan et al., 2015) and the loss of its reactivity with a weaker oxidant, tropylium (T+,–ΔHH-A = 85 kcal mol−1) (Oss et al., 2018). It was also found that only the more reactive N-alkyl-THIQs (ΔHH-D: 72–76 kcal mol−1) could be oxidized by T+ (Oss et al., 2018). These examples demonstrated that the energetic data here derived can actually well rationalize the previously observed reactivity trend in the oxidation of various THIQs by different oxidants as represented in Scheme 2A and 2B. Based on energetic criteria, if a weak oxidant such as AcrH+, p-BQ, or B(C6F5)3 (Heiden et al., 2015) with a −ΔHH-A close to the ΔHH-D of the amines is employed, no complete reaction would be expected. Under this circumstance, only an equilibrium may be realized. Recently, such reversible H−T between tertiary amines and B(C6F5)3 was indeed observed in a double-acid catalyzed amine α-C–H functionalization (Shang et al., 2018).

Figure 1

Hydricity Scale (ΔHH-D) of Amines (Colored Bars) and Hydride Affinity (ΔHH-A) for Common Hydride Acceptors in Acetonitrile (Data on Top)

Note: p-BQ: p-benzoquinone; AcrH+: acridinium; T+: tropylium; PhXn+: 9-phenylxanthylium, also see Table S1 (Zhu et al., 2008a, Zhu et al., 2008b, Zhu et al., 2007).

On Hydrogen Removal

The amine α-C–H bond may also be cleaved through HT (i.e., HAT) when there exist radical initiators. In such cases, hydrogen-donating ability of the C–H bond (ΔHHD, i.e., BDE) is the key factor governing amines' reactivity. As seen in Table 1, the ΔHHD (88.1 kcal mol−1) of tribenzylamine 1 obtained here agrees well with the gas-phase value 89.1 kcal mol−1 in literature (Dombrowski et al., 1999). On the other hand, the newly derived ΔHHD of 79.4 kcal mol−1 for 2e may suggest a need for reexamining the previously reported value of 88.6 kcal mol−1 (Denisov et al., 2005), because it is well known that replacing a hydrogen from trimethylamine (ΔHHD = 87 kcal mol−1) (Grela et al., 1984) with a phenyl group could not be expected to largely increase ΔHHD due to a better delocalization of spin (Cheng et al., 2016). Generally, the ΔHHD values of the amine α-C–H bonds in the absence of a strong EWG or steric disturbance are found to be around 80 kcal mol−1 or below, which are significantly lower than the regular C(sp3)–H bonds (Cheng et al., 2016) without a so-called “two-center-three-electron” (3 in 2) radical stabilization (Griller and Lossing, 1981, Lalevée et al., 2002, Wayner et al., 1997). As realized, the effect of structural variations on the ΔHHD (i.e., BDE) of amines is more complicated than on hydricities; this situation was also commonly observed in other studies on radical stability in the literature (Hioe and Zipse, 2010, Johnny and Hendrik, 2012, Zipse, 2006). Nevertheless, the effect of structural variation in these radicals still could be reasonably understood by considering the interplays between the electronic and steric factors, with special attention paid on the differences between the remote and adjacent substitution and on their electron density between the “3 in 2” radicals and the normal carbon radicals.

Figure 2 shows the ΔHHD range for amines (blue bar), together with hydrogen affinities (ΔHHA) of some common hydrogen acceptors (Cheng et al., 2016; Pedley, 2012, Ruscic et al., 2013) for the convenience of energetic comparison that would benefit rational selection of reaction partners in synthesis. As implied in Figure 2, very reactive radicals with –ΔHHA> 90 kcal mol−1 (e.g., triethylenediamine radical cation, phenyl, alkoxy, and hydroxyl radicals), which can only be generated in situ from precursors, would be able to cleave the amine α-C–H bonds via HT (i.e., HAT). This anticipation has actually been experimentally confirmed, as will be exemplified below. In the oxidative α-C–H functionalization of tertiary amines, both the Cl3C⋅ (−ΔHHA = 93.8 kcal mol−1) and Br⋅ (−ΔHHA = 88 kcal mol−1) radicals were observed to be able to abstract the hydrogen atom from amines (Yan et al., 2015). And, the in-situ-generated triethylenediamine radical cation (–ΔHHA = 107 kcal mol−1) was found to be feasible in hydrogen atom abstraction to selectively functionalize α-C−H bonds of trialkylamines (Barham et al., 2016). Moreover, hydrogen transfers from THIQs to various oxygen-centered radicals (e.g., HO⋅, tBuO⋅, tBuOO⋅, isobutyronitrile-derived alkoxyl radical) (Chu and Qing, 2010, Ghobrial et al., 2010, Tang et al., 2011) were also reported as the initiated step to trigger CDCs. By the same line, moderate oxidants (–ΔHHA: 80–90 kcal mol−1) would be expected to react with amines reversibly, and they may possibly be used as catalysts to deliver hydrogen atom between amines and other substrates. Indeed, thiyl radical Ph3Si-S⋅ (–ΔHHA≈ 90 kcal mol−1) was found to be a good catalyst for homolysis of α-C−H bonds of N-Acyl-THIQ (Yan et al., 2016). For some commercially available oxidants with –ΔHHA values of 50–80 kcal mol−1[e.g., O2, 1,1-diphenyl-2-picrylhydrazyl (DPPH), tert-Butyl hydroperoxide (TBHP), butylatedhydroxytoluene (BHT), and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)], their relatively low hydrogen-accepting capacities should actually be the cause to prevent them from triggering homolysis of amine C–H bonds. However, if an amine radical cation is generated in advance, they should be able to easily abstract a hydrogen atom from this radical intermediate (vide infra).

Figure 2

Hydrogen-Atom-Donating Abilities (ΔHHD) of Amines (Blue Bar) and Hydrogen Atom Affinities (ΔHHA) of Common Acceptors

Also see Table S1 (Cheng et al., 2016).

On Electron-Coupled C–H Bond Cleavage of Amine Radical Cations

Removal of an electron from organic molecules is a very efficient way to activate inert C–H bond for inducing C–H functionalization (McManus et al., 2018, Ueda et al., 2014). Understanding of the mechanisms of degradation paths for radical cations generated by ET would require the energetic knowledge of their bond homolysis and heterolysis (cf. Scheme 3, path c). As presented herewith, the ΔHHD(HD⋅+) (releasing an H⋅) covers a range of 29–46 kcal mol−1, which is roughly 40 kcal mol−1 lower than the ΔHHD values of the parent amines, indicating a tremendous C-H bond activation. On the other hand, the ΔHPD(HD⋅+) (donating a proton) shows an energy range from −6.4 to 21.8 kcal mol−1 (Table 1). Here an even greater activation effect is demonstrated, although the pKa values of the parent amine α-C–H bonds are too high to measure in any solution.

Applications of Energetic Scale for Understanding THIQ Oxidation Mechanisms

Considering the inherent relationship between the bond energy and reactivity, further exploration of its predictive value would be beneficial for understanding amine chemistry, especially for those who are not too much familiar with the ways to use the available bond energy data in their synthetic methodology investigation. In the following subsections, we present examples to demonstrate the good potential of the bond energetic data in elucidating amine oxidation mechanisms. To make this line of energetic analysis easier to follow, here we have intended to choose some better-studied cases (rather than synthetically maybe more “useful” ones) to show the effectiveness of the energy data in mechanistic analysis. This is because the well-studied cases would allow the predictive value of the derived bond energy data to be directly backed up with existing experimental observations.

Generally, there are two types of oxidants used in the CDCs of amines: single-component hydride acceptors and dual-component oxidants (electron and hydrogen acceptors). We will start with the former, which were more extensively developed.

Oxidation by Hydride Acceptors

When a hydride acceptor serves as the oxidant, it was found that cleavage of the amine α-C–H bond could possibly be initiated either by hydride, hydrogen, or by electron transfer. Among them, the intrinsic barrier of electron transfer is known to be much lower than those of atom/group transfers (Brinkley and Roth, 2005, Fukuzumi, 2003, Gust et al., 1993, Li and Zhu, 2018). Therefore, even an uphill ET can be expected to occur if the energetic barrier is not much greater than 0.5 eV (1 eV = 23.1 kcal mol−1), because the deficiency of driving forces could be easily compensated by exothermic follow-up processes (Cheng et al., 1998, Eberson, 1982). This energetic feature makes ET the preferential pathway for initiating C–H bond cleavage.

As known, DDQ, Ph3C+, and TEMPO+ are popular oxidants used in CDC of amines (Richter and GarcíaMancheño, 2011, Song et al., 2018, Wendlandt and Stahl, 2015, Zhang and Li, 2006). Their Ered, ΔHH-A, and ΔHHA values in acetonitrile were reported (Table S1) (Heiden and Lathem, 2015, Zhu et al., 2007, Zhu et al., 2010, Zhu and Wang, 2010). This allowed the thermodynamics of the elementary steps of their reactions with THIQs to be evaluated by jointly using the corresponding data in Table 1. The so-derived energetic data are presented in Table 2. Taking the oxidation of N-Ph-THIQ with DDQ as an example, all its elementary steps are illustrated in Scheme 5.

Table 2

Thermodynamics for Each Elementary Step in the Oxidation of THIQs by Hydride Acceptors in Acetonitrile at 298 K (kcal Mol−1)

THIQ	Oxidant	Step aΔHH-T	Step bΔHHT	Step cΔGET	Step dΔHHT	Step eΔHPT	Step fΔGET	Mechanism
N-Cbz	DDQ	−11.5	20.5	30.5	−41.0	−10.0	−32.0	H−T
N-Ph	DDQ	−26.1	16.5	6.8	−31.8	9.7	−42.6	ET–HT
N-(1-Naph)	DDQ	−21.8	23.5	6.8	−26.0	16.7	−45.3	ET–HT
N-Cbz	Ph3C+	−11.8	37.1	37.6	−51.0	−0.5	−48.9	H−T
N-(4-MeO-Ar)	Ph3C+	−28.9	31.5	9.2	−39.7	22.3	−60.4	ET–HT

Also see Table S1.

Scheme 5

Thermodynamic Analysis of Possible Pathways in the Oxidation of N-Ph-THIQ by DDQ (kcal mol−1)

Also see Table S1.

Based on thermodynamic criteria, a comparison of the energies of paths a, b, and c in Scheme 5 immediately excludes the HT path, because it is 16.5 kcal mol−1 uphill. At first, one may guess that the H−T (path b:−26.1 kcal mol−1) must be a favorable process because of the exothermicity of the overall H−T. However, many previous studies indicated that this is most likely not the case especially when competing with an ET (path c: 6.8 kcal mol−1) in the reaction system, due to the extremely higher intrinsic barrier for H−T (Brinkley and Roth, 2005, Eberson, 1982, Gust et al., 1993, Li and Zhu, 2018). The energy requirement for ET to occur in N-Ph-THIQ oxidation by DDQ (ΔGET = 6.8 kcal mol−1) can be well filled up by the highly exothermic follow-up hydrogen release from its radical cation (step d, ΔHHT = −31.8 kcal mol−1). Therefore, the ET-HT process would be most favorable. On the other side, the PT-ET path for N-Ph-THIQ⋅+ decay should be unlikely to follow, because the PT (step e) is endothermic (ΔHPT = 9.7 kcal mol−1). This bond-energy-based analysis of oxidation mechanism can, indeed, be backed up by experiments and calculations (Chen et al., 2015). The oxidation mechanisms of other THIQ analogs by DDQ may be identified as well by similar thermodynamic analysis. For example, one could expect that the oxidation of N-(1-Naph)-THIQ may also go through an ET-HT path mechanism, because its ΔGET of 6.8 kcal mol−1 satisfies the empirical ET criterion (<0.5 eV, see above), whereas for oxidation of N-Cbz-THIQ, a direct H−T pathway would be preferred (Chen et al., 2015), because its ET is well above Eberson's maximum energetic criterion of 1 eV for electron transfer to take place (Cheng et al., 1998, Eberson, 1982). These energetic diagnoses exemplified, despite yet only on a thermodynamic basis, have already showed their good potential in accounting for the diversified observations of the CDCs of THIQs. This is most likely because, for this type of chemical transformation, the reaction can be largely driven by the inherent energetic factor featuring an enhanced reactivity of the C-H bond adjacent to an electron pair at nitrogen.

As for reactions with other oxidants, Ph3C+ and TEMPO+, there are some discussions in literature regarding their mechanisms (Richter et al., 2012, Xie et al., 2014), but further clarification is needed. By the same line of argument, we have also made predictions for them. The results are presented in Table 2 as examples, along with the relevant energetic data required for the mechanism elucidation. Additional experiments were also carried out for this purpose to further verify our thermodynamic prediction, and the results can be found in the Supplemental Information (see Figures S2 and S3 for details) to save space.

Oxidation by Dual-Component Oxidants

In the cases where dual-component oxidants [e.g., FeCl2/O2 (Brzozowski et al., 2015), I2/H2O2 (Nobuta et al., 2013), CuCl2/O2 (Boess et al., 2011), and CuBr/BuOOH (Li and Li, 2004)] are used cooperatively in CDCs, it is known that the amine oxidation can be initiated either by HT to radical scavengers such as I2 (Dhineshkumar et al., 2013) and TBHP (Li and Li, 2004) or by ET to single-electron oxidants, e.g., Cu2+ (Boess et al., 2011), Fe3+ (Brzozowski et al., 2015), I2 (Dhineshkumar et al., 2013), photo-oxidants (Condie et al., 2010), and anodes (Fu et al., 2017). The resulting amine radical or radical cation would then collapse to an iminium ion through ET or HT. As the above, these oxidation mechanisms can also be differentially elucidated based on the thermodynamics of amines and the particular oxidant pairs. A representative example is given below.

As briefly touched in the Introduction, Klussmann et al. (Boess et al., 2012) investigated the mechanistic differences between the CuCl2∙H2O/O2- and CuBr/TBHP-catalyzed CDCs of THIQs with nucleophiles. They found that the key intermediate with the aerobic method was an iminium ion formed via oxidation by Cu(II). However, in the CuBr/TBHP system, the precursor α-amino peroxide was formed from amine and TBHP via a radical pathway (Scheme 6). Now these two mechanisms can be reasonably differentiated using the thermodynamic data obtained here and elsewhere (see Table S2). The energetics for each possible step is shown in Scheme 6. For the CuCl2/O2 system (Scheme 6A), it is obvious that an ET from THIQ to Cu2+ is feasible, because its thermodynamic driving force is only 6.9 kcal mol−1; but an HT between THIQ and O2 would be unlikely to occur, because it is extremely endothermic (27.4 kcal mol−1). Consequently, the resulted THIQ⋅+ then rapidly degenerates to iminium ion by either HT (−7.6 kcal mol−1) to O2 or a PT-ET sequence to Cl−/Cu2+ (ca.−31 kcal mol−1). On the other hand, in the CuBr/TBHP system (Scheme 6B), HT should be the feasible initiating step for THIQ oxidation, because it is downhill by 29.6 kcal mol−1, whereas ET is, however, endothermic. As for the subsequent processes of HT, coupling of the THIQ⋅ radical with BuOO⋅ or BuO⋅ (ca.−60 kcal mol−1) is much more favorable than the ET path (0.5 kcal mol−1). This actually explains why α-amino peroxide was observed as the major intermediate.

Scheme 6

Thermodynamic Rationalization of Possible Pathways for Oxidization of N-Ph-THIQ by Dual-Component Oxidants

(A) the oxidatants are CuCl2/O2; (B) the oxidatants are CuBr/TBHP.

Also see Table S2.

Conclusion

Due to the inherent difficulties in measuring the pKa of α-C–H bond of tertiary amines, the Bordwell's method for solution BDEs is unfortunately not applicable for the target system of this work. For this reason, we have developed a new approach for the present bond energy study by taking advantage of our expertise in hydricity measurement. The first integrated α-C–H bond energy scale for representative tertiary amines were hereby established via a series of different cycles based on experimentally determined hydricities. Four major types of α-C–H bond energies including the hydricity [ΔHH-D(HD)] and BDE [ΔHHD(HD)] values for 45 parent tertiary amines and the BDEs [ΔHHD(HD⋅+)] and acidities [ΔHPD(HD⋅+)] for their radical cations in acetonitrile were determined. General utility of this integrated bond energetic scale for elucidating experimental observations were demonstrated, verifying its predictive value and reliability of the bond energetic analysis for understanding bond transformations via CDC process. The success of this type of rational analyses represented here would encourage more general practices along this line in the future and eventually promotes it to become a mainstream logic in reaction analysis and design.

Limitations of the Study

Present strategy is applicable for the tertiary amine with at least one benzyl substituent at the nitrogen atom. We are currently working on improving the methodology to accommodate broader range of substrates such as aliphatic cyclic amine, etc.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.