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

Summary 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 a-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 a-radical or a-cation upon a-C-H bond scission (Campos, 2007;Chen, W. J. et al., 2018;Nakajima et al., 2016;Shi et al., 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 et al., 2015;Rommelspacher et al., 1985;Shamma, 2012). As a result, numerous oxidative cross-dehydrogenative couplings (CDC) have been developed for functionalization of tertiary amines via a-C-H bond dissociation (Chi et al., 2019;Girard et al., 2014;Szatmá ri et al., 2016;Yoo et al., 2010) (Scheme 1).
In these CDC processes, the tertiary amine is first oxidized, via different modes of a-C-H bond rupture (Scheme 1), to a-amino radical or iminium ion either by transition metals (Cheng et al., 2017;Murahashi et al., 2003;Shao et al., 2015), organic oxidants (Allen et al., 2011;Damico et al., 1966;Sundberg et al., 1991), or by electro- (Basle et al., 2010;Fu et al., 2017;Yoshida et al., 2002) or photo-oxidants (Condie et al., 2010;McNally et al., 2011;Ravelli et al., 2016;Thullen et al., 2017). The a-amino intermediate is then intercepted by an appropriate reagent to furnish a new a-C-R bond (Scheme 1). It may need to mention that among the two primary modes of a-C-H bond rupture via CDC, the iminium route, rather than the radical route (McNally et al., 2011;Thullen et al., 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 CuCl 2 /O 2 pair, whereas a hydrogen-electron transfer (HT-ET) is favored with a CuBr/tBuOOH pair. Although the relevance of a-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.
As generally known, there are basically three mechanisms for amine oxidation (Scheme 3). Actually, direct hydride transfer (H À T, pathway a) is quite frequently seen when organic cations (e.g., Ph 3 C + ) are used as the acceptors (Richter and GarcíaMancheñ o, 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 a-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 (Hariand Kö nig, 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.
Although syntheses via oxidative cleavage of the a-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., , 2016Ratnikovand 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 a-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 pK a 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 a-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 DH H -D (hydridereleasing ability) of tertiary amines (where D denotes donor), (2) the a-C-H bond homolytic energy DH HD , (3) the deprotonation energy of amine radical cations DH PD (HD ,+ ), and (4) the hydrogen-atom-donating ability of radical cations DH HD (HD ,+ ). Direct measurement or derivation of these energetic parameters was described in the following section. This energetic scale (with 4 3 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 Scheme 1. CDC Process of Tertiary Amines in Organic Synthesis 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 a-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 pK a (Bordwell et al., 1988), to measure the hydride-releasing ability instead, i.e., hydricity DH H -D of this a-C-H bond. As mentioned above, this is because the a-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 a-C-H hydride with 4acetamido-2,2,6,6-tetramethyloxopiperidinium perchlorate (AcNH-TEMPO + ClO 4 À ) (Equation 1) whose hydride affinity DH H -A (where A denotes acceptor) in acetonitrile was well established (Table S1 in Supplemental Information). Thus, determination of the THIQ hydricity DH H -D becomes a matter of measuring the heat DH rxn of the hydride exchange reaction (by isothermal titration calorimetry, see Supplemental Information for details). The hydricity DH H -D (HD) can then be evaluated from Equation 2 using the known DH H -A (AcNH-TEMPO + ) of À105.6 kcal mol À1 (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 (DH H -D (PyH 2 ) = 48.0 kcal mol À1 ) and DH rxn (Equation 4).

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 DH H -D (HD) (Scheme 4). As shown, the hydrogen-atom donability of tertiary amines, i.e. the homolytic a-C-H bond dissociation energy DH HD (HD), can be obtained from the experimentally measurable hydricity DH H -D (HD) and the reduction potential of its corresponding iminium ion, E red (D + ) (Equation 5). The respective cycles for evaluating the a-C-H homolytic (DH HD (HD ,+ )) and heterolytic energies (DH PD (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 E ox (HD) (see Supplemental Information for details). These bond parameters, together with the relevant redox potentials determined in this work, are summarized in Table 1.

Structural Effects and Energetic Criteria of Amine a-C-H Bond Scission
As shown in Scheme 3, generation of iminium ion is the key step in a-C-H functionalization of tertiary amines, which could be initiated by either hydride (H À T), hydrogen (HT), or electron transfer (ET), corresponding respectively to the energetic terms of DH H -D , DH HD , or E ox (HD). The effects of amine structural variations on the corresponding energies as well as on understanding of amine a-transformations are addressed below, jointly with experimental verification, wherever applicable.

On Hydride Removal
As known from the hydricity data (DH H -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 = CH 3 : 72.7) <7e (CH 2 Ph: 75.1) <7f (CHPh 2 : 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 DH H -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 (DH H -D ) of amines derived in this work are depicted in Figure 1, along with the known hydride affinity (DH H -A ) data of common hydride acceptors for comparison. The combined scale reveals that amines (colored bars, ranging 60-92 kcal mol À1 ) are generally weaker hydride donors than biomimetic donors such as 1,3-dimethyl-2,3-dihydro-1H-benzimidazole (DMBI, 54.1 kcal mol À1 ), 1-benzyl-1,4-dihydropyridine-3-carboxamide (BNAH, 64.2 kcal mol À1 ), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (HEH, 69.3 kcal mol À1 ). Indeed, strong oxidants with -DH H -A values greater than 100 kcal mol À1 (e.g., DDQ, Ph 3 C + , Scheme 3. Possible Pathways for Generation of Iminium Ions from Tertiary Amines AcNH-TEMPO + ) were experimentally observed to be capable of splitting the a-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 + ,-DH H -A = 85 kcal mol À1 ) (Oss et al., 2018). It was also found that only the more reactive N-alkyl-THIQs (DH H -D : 72-76 kcal mol À1 ) 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(C 6 F 5 ) 3 (Heiden et al., 2015) with a ÀDH H -A close to the DH H -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 À T between tertiary amines and B(C 6 F 5 ) 3 was indeed observed in a double-acid catalyzed amine a-C-H functionalization (Shang et al., 2018).

On Hydrogen Removal
The amine a-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 (DH HD , i.e., BDE) is the key factor governing amines' reactivity. As seen in Table 1, the DH HD (88.1 kcal mol À1 ) of tribenzylamine 1 obtained here agrees well with the gas-phase value 89.1 kcal mol À1 in literature (Dombrowski et al., 1999). On the other hand, the newly derived DH HD of 79.4 kcal mol À1 for 2e may suggest a need for reexamining the previously reported value of 88.6 kcal mol À1 (Denisov et al., 2005), because it is well known that replacing a hydrogen from trimethylamine (DH HD = 87 kcal mol À1 ) (Grela et al., 1984) with a phenyl group could not be expected to largely increase DH HD due to a better delocalization of spin (Cheng et al., 2016). Generally, the DH HD values of the amine a-C-H bonds in the absence of a strong EWG or steric disturbance are found to be around 80 kcal mol À1 or below, which are significantly lower than the regular C(sp 3 )-H bonds (Cheng et al., 2016) without a so-called ''two-center-three-electron'' (3 in 2) radical stabilization (Griller et al., 1981;Lalevé e et al., 2002;Wayner et al., 1997). As realized, the effect of structural variations on the DH HD (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 et al., 2010;Johnny et al., 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.  ). a In units of kcal mol À1 , obtained from Scheme 4 within experimental error of G0.5 kcal mol À1 , taking E(H 0/+ ) = À2.31 V and E(H À/0 ) = À1.14 V (Parker, 1992). b In units of V vs Fc 0/+ , obtained from CV experiments within experimental error of G30 mV. c Measured by Ph 3 C + ClO 4 with DH H -A (Ph 3 C + ) = À104.3 kcal mol À1 . Figure 2 shows the DH HD range for amines (blue bar), together with hydrogen affinities (DH HA ) 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 -DH HA > 90 kcal mol À1 (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 a-C-H bonds via HT (i.e., HAT). This anticipation has actually been experimentally confirmed, as will be exemplified below. In the oxidative a-C-H functionalization of tertiary amines, both the Cl 3 C , (ÀDH HA = 93.8 kcal mol À1 ) and Br , (ÀDH HA = 88 kcal mol À1 ) 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 (-DH HA = 107 kcal mol À1 ) was found to be feasible in hydrogen atom abstraction to selectively functionalize a-CÀH 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 (-DH HA : 80-90 kcal mol À1 ) 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 Ph 3 Si-S , (-DH HA z 90 kcal mol À1 ) was found to be a good catalyst for homolysis of a-CÀH bonds of N-Acyl-THIQ (Yan et al., 2016). For some commercially available oxidants with -DH HA values of 50-80 kcal mol À1 [e.g., O 2 , 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).

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 DH HD (HD ,+ ) (releasing an H , ) covers a range of 29-46 kcal mol À1 , which is roughly 40 kcal mol À1 lower than the DH HD values of the parent amines, indicating a tremendous C-H bond activation. On the other hand, the DH PD (HD ,+ ) (donating a proton) shows an energy range from À6.4 to 21.8 kcal mol À1 (Table 1). Here an even greater activation effect is demonstrated, although the pK a values of the parent amine a-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. Note: p-BQ: p-benzoquinone; AcrH + : acridinium; T + : tropylium; PhXn + : 9-phenylxanthylium, also see Table S1 ( Zhu et al., 2008aZhu et al., , 2008bZhu et al., 2007).
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 a-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 et al., 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 À1 ), 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, Ph 3 C + , and TEMPO + are popular oxidants used in CDC of amines (Richter and GarcíaMancheñ o, 2011;Song et al., 2018;Wendlandtand Stahl, 2015;Zhang and Li, 2006). Their E red , DH H -A , and DH HA values in acetonitrile were reported (Table S1) (Heiden and Lathem 2015;Zhu et al., 2007, 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. 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 À1 uphill. At first, one may guess that the H À T (path b:À26.1 kcal mol À1 ) must be a favorable process because of the exothermicity of the overall H À 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 À1 ) in the reaction system, due to the extremely higher intrinsic barrier for H À 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 (DG ET = 6.8 kcal mol À1 ) can be well filled up by the highly exothermic follow-up hydrogen release from its radical cation (step d, DH HT = À31.8 kcal mol À1 ). 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 (DH PT = 9.7 kcal mol À1 ). 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 DG ET of 6.8 kcal mol À1 satisfies the empirical ET criterion (<0.5 eV, see above), whereas for oxidation of N-Cbz-THIQ, a direct H À 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, Ph 3 C + 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 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 CuCl 2 •H 2 O/O 2 -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 a-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 CuCl 2 /O 2 system (Scheme 6A), it is obvious that an ET from THIQ to Cu 2+ is

THIQ Oxidant
Step aDH H -T Step bDH HT Step cDG ET Step dDH HT Step eDH PT Step  Table S1.
Scheme 5. Thermodynamic Analysis of Possible Pathways in the Oxidation of N-Ph-THIQ by DDQ (kcal mol À1 ) Also see Table S1.
iScience 23, 100851, February 21, 2020 feasible, because its thermodynamic driving force is only 6.9 kcal mol À1 ; but an HT between THIQ and O 2 would be unlikely to occur, because it is extremely endothermic (27.4 kcal mol À1 ). Consequently, the resulted THIQ ,+ then rapidly degenerates to iminium ion by either HT (À7.6 kcal mol À1 ) to O 2 or a PT-ET sequence to Cl À /Cu 2+ (ca.À31 kcal mol À1 ). 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 À1 , whereas ET is, however, endothermic. As for the subsequent processes of HT, coupling of the THIQ , radical with t BuOO , or t BuO , (ca.À60 kcal mol À1 ) is much more favorable than the ET path (0.5 kcal mol À1 ). This actually explains why a-amino peroxide was observed as the major intermediate.

Conclusion
Due to the inherent difficulties in measuring the pK a of a-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 a-C-H bond energy scale for representative tertiary amines were hereby established via a series of different cycles based on experimentally determined hydricities.

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.

DATA AND CODE AVAILABILITY
The related figures and data in this article can be found at the database: https://data.mendeley.com/ datasets/r8ynb4s6s4/draft?a=16da539e-259c-45a1-9e05-7e4a2a79a6ae.
Reaction heat determination was conducted on MicroCal VP-ITC. 1 HNMR spectra were recorded in CD3CN on Bruker AVANCE III HD (400 MHz) nuclear magnetic resonance spectrometer. Stopped-flow measurement was performed on Hi-Tech Scientific SF-51 stoppedflow set-up and UV-Vis measurements on Hitachi U-3900H UV-Vis spectrophotometer.

Condition optimization for thermodynamic determination
According to Hess' Law, thermodynamic cycles for α-C-H bond scission of tertiary amines and its radical intermediates were established (Scheme 3 in main text). And to identify optimal conditions for the data acquisition, especially for the hydricity ΔHH-A, we made a lot of explorations, which are shown below.
Unfortunately, for Ph2CH + , nucleophilic attack by tertiary amine to form Lewis adduct is the dominant pathway, interrupting hydride transfer (Scheme S1). Considering that O-N/N-N bond is much weaker than C-N bond, heteroatom-centred cations AcNH-TEMPO + and PTZ + are recommended to minimize the disturbance of Lewis adducts. In order to construct rapid and complete hydride transfer required in thermodynamic determinations, reactions with one of substrates in excess were further examined. However, reactions with excess AcNH-TEMPO + or PTZ + are roughly 10 kcal mol -1 more exothermic than those with tertiary amine in excess.
The absence of thermodynamic self-consistency doubtlessly suggests the disturbance of side reactions. Detailed investigations disclose that when acceptors AcNH-TEMPO + and PTZ + are used excessively, residual acceptors would further react with resultant AcNH-TEMPOH and PTZH through either comproportionation (Semmelhack et al., 1984) or dimerization (Hanson et al., 1973) (Scheme S1b and c, Fig. S1). Thus we detected the reaction of PTZ + and PTZH in NMR experiments (Fig. S1b) and the dimerization of PTZ + and PTZH was also verified by former research (Hanson et al., 1973). Such undesired reactions can be well avoided when tertiary amine is used in excess. Eventually, less dosage of AcNH-TEMPO + ClO4or sometimes, excess Ph3C + ClO4is selected as optimal acceptors for thermodynamic measurements. Then the heat of the hydride exchange reaction ΔHrxn was measured by isothermal titration calorimetry.
Strategy 2 When tertiary amines with open chains (e.g. substrates 1-5) were put in the same test condition, unexpected results appeared that complex side reactions were stimulated between neutral amines and oxidants. Then an inverse strategy was adopted: iminium cation was prepared beforehand, which was supposed to be product in previous scheme; and a proper hydride donor was screened out to react with iminium salts. The selected hydride donor is required to possess strong hydride donating ability, guaranteeing the complete and fast hydride transfer process. 1-benzyl-3-methyl-1,4-dihydropyridine displayed more excellent performance among several candidate hydride donors, with hydricity HH-D = 48.0 kcal mol -1 . Then the heat of the hydride exchange reaction ΔHrxn was measured by isothermal titration calorimetry.
Reaction heat determination was conducted on MicroCal VP-ITC. Acetonitrile used in measurement was treated in the dry column (water ≤ 10 ppm), and the test temperature was kept at 298 K. For substrate2-5, iminium salts were prepared at first and reacted with hydride donor 1-benzyl-3-methyl-1,4-dihydropyridine; For the other substrates, most were reacted with hydride acceptor AcNH-TEMPO + and a few with Ph3C + to exclude unexpected side reactions.

Determination of the redox potentials of tertiary amines [Eox(HD)] and iminium cations [Ered(D + )]
The oxidation potentials of neutral tertiary amines and reduction potential of iminium cations were determined by cyclic voltammogram (CV, details seeing below) in anaerobic 0.1 M nBu4NPF6/Acetonitrile solution. The reference electrode, Ag/AgNO3 was calibrated versus Fc +/0 .
For substrate 1 and 6-14, the reduction potentials of iminium cations were measured when amines were oxidized by AcNH-TEMPO + ClO4or Ph3C + ClO4in the electrolytic cell to in-situ generate iminium cations; For substrate 2-5, the oxidation potentials of neutral amines were measured when iminium salt were reduced by NaBH4 in the electrolytic cell to in-situ generate neutral amines.

Preparation of substrates
A 50 mL schlenk-tube was evacuated and back filled with argon for 3 times. Anhydrous Et2O (25 mL) and benzaldehydes (5 mmol) were added. Then pentamethylsilanamine (5 mmol) and TMSOTf (5 mmol) were dropwise added successively. The solution was stirred at rt for 12 h. The precipitated salt was washed by Et2O for several times (Schroth et al., 1994). K2CO3 (20 mmol) was added into a Schlenk-tube. The tube was evacuated and back filled with argon for 3 times. AN (15 mL), 1,2,3,4-tetrahydroisoquinoline (10 mmol), and benzyl bromide (10 mmol) were added at rt. The reaction mixture was refluxed for 12 h. After cooling to rt, the resulted mixture was filtered, concentrated and purified by column chromatography on silica gel using EtOAc/PE . K2CO3 (20 mmol) was added into a Schlenk-tube. The tube was evacuated and back filled with argon for 3 times. AN (15 mL), 1,2,3,4-tetrahydroisoquinoline (10 mmol), and diphenylbromomethane (10 mmol) were added at rt. The reaction mixture was refluxed for 12 h. After cooling to rt, the resulted mixture was filtered, concentrated and purified by column chromatography on silica gel using EtOAc/PE . 1,2,3,4-Tetrahydroisoquinoline was dissolved in 10 mL of acetonitrile, triethylamine was added dropwise. After 10 min, benzyl chloroformate was added dropwise and the temperature was kept at 0 °C for another 10 min. The reaction mixture stirred at rt for 2 h. The reaction mixture was washed with water (3 × 20 mL) and dried with anhydrous sodium sulfate. The organic solution was concentrated under reduced pressure and purified with flash chromatography .
After 16 h, the mixture was cooled, and water (20 mL) was slowly added. The solids were filtered through a plug of Celite and then washed with ethyl ether (20 mL). The mixture was then further extracted with ethyl ether three times, and the combined extracts were dried and concentrated to give the 2,3,4,5-tetrahydro-1Hbenzo[c]azepine without further purification (Shonberg et al., 2015).
Bis(dibenzylideneacetone)palladium(0) (0.15 mmol), BINAP (0.3 mmol) were added into dry toluene (10 mL) under argon. The mixture was heated to 110 °C for 15 min. Then the solution was cooled to rt and sodium tert-butoxide (6 mmol), 2,3,4,5-tetrahydro-1Hbenzo[c]azepine (S31, 3 mmol), and iodobenzene (3 mmol) were added. The solution was refluxed for 18 h. After cooling to rt, the resulted mixture was filtered through a short plug of Celite and washed with toluene. The solvent was removed under vacuum and the residue was purified by chromatography using EtOAc/PE (Min et al., 2014). A solution of 2-phenylisoindoline-1,3-dione (3.75 mmol) in dry THF (30 mL) under argon was cooled to 0 °C., and a solution of borane in THF (1.0 M, 25 mL) was slowly added. The reaction mixture was then refluxed for 12 h. After cooled to rt, the mixture was poured into ice water (500 mL) and filtered. The precipitate was further purified by filtration over silica as a white powder using EtOAc/PE (Kelber et al., 2015). CuI (1mmol) and K3PO4 (20 mmol) were added into a Schlenk-tube. The tube was evacuated and back filled with argon for 3 times. i-PrOH (10 mL), ethylene glycol (20 mmol), 1,2,3,4-tetrahydroisoquinoline (15 mmol), and iodobenzene (10 mmol) were added at rt. The reaction mixture was refluxed for 24 h. After cooling to rt, diethyl ether (20 mL) and water (20 mL) were added to the reaction. The resulted mixture was extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using toluene/PE (Pandey et al., 2016).
To a stirred solution of N-phenyltetrahydro-β-carboline (S34, 1.21 mmol) in DMF were added MeI (1.45 mmol), and NaH (1.81 mmol, 60% dispersion in mineral oil) at 0 °C. Then the reaction temperature was increased to rt. After 9 h, the reaction mixture was poured into saturated aqueous NH4Cl, and the resulting mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel . A 50 mL schlenk-tube was evacuated and back filled with argon for 3 times. THF (25 mL), 1,2,3,4-tetrahydroisoquinoline (20 mmol), and iodomethane (10 mmol) were added. The solution was stirred at rt for 12 h. The precipitated quinolinium salt was collected by filtration without further purification (Xu et al., 2016).
The quinolinium salt (S6) was dissolved in THF under argon. And then a solution of LiHBEt3 in THF (1 M, 7.5 mL) was added slowly at -25 °C.. The temperature was increased to 25 °C. and kept for 2 h. The solvent was removed under reduced pressure and the residue was extracted with dry pentane three times. Combined extracts were concentrated to give the product (Chernyshov et al., 2010).
50% Perchloric acid (9.2 mmol) was added dropwise in 15 min. And then fresh 10% sodium hypochlorite (4.6 mmol) was added dropwise in 30 min. The resulted mixture was cooled in ice and yellow solid precipitated. The solid was washed with 5% NaHCO3, icy water, and icy CH2Cl2 successively. Then the crude product was recrystallized in water (Bobbitt, 1998).