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. 2023 Aug 21;8(35):31984–31997. doi: 10.1021/acsomega.3c03804

Thermodynamic Evaluations of Amines as Hydrides or Two Hydrogen Ions Reductants and Imines as Protons or Two Hydrogen Ions Acceptors, as Well as Their Application in Hydrogenation Reactions

Guang-Bin Shen †,*, Bao-Chen Qian †, Guang-Ze Luo †, Yan-Hua Fu ‡,*, Xiao-Qing Zhu §,*
PMCID: PMC10483529  PMID: 37692224

Abstract

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Since the hydrogenation of imines (X) and the dehydrogenation of amines (XH2) generally involve the two hydrogen ions (H– + H+) transfer, the thermodynamic abilities of various amines releasing hydrides or two hydrogen ions as well as various imines accepting protons or two hydrogen ions are important and characteristic physical parameters. In this work, the pKa values of 84 protonated imines (XH+) in acetonitrile were predicted. Combining Gibbs free energy changes of amines releasing hydrides in acetonitrile from our previous work with the pKa(XH+) values, the Gibbs free energy changes of amines releasing two hydrogen ions and imines accepting two hydrogen ions were derived using Hess’s law by constructing thermochemical cycles, and the thermodynamic evaluations of amines as hydrides or two hydrogen ions reductants and imines as protons or two hydrogen ions acceptors are well compared and discussed. Eventually, the practical application of thermodynamic data for amines and imines on hydrogenation feasibility, mechanism, and possible elementary steps was shown and discussed in this paper from the point of thermodynamics.

Introduction

Amines (XH2), one type of important bioactive molecule, have been widely studied in drug design, alkaloid research as well as redox chemical reactions due to the unique electronic effect and redox properties of amino functional groups.1 Generally, amines could be generated by the hydrogenation of imines;2 in contrast, imines (X) could be synthesized by the dehydrogenation of amines.3 The hydrogenations of imines and dehydrogenations of amines are the opposite processes of two hydrogen ions (H– + H+) transfer in which two hydrogen ions transfer from reductants to imines for the hydrogenation reactions of imines while two hydrogen ions transfer from amines to oxidants for the dehydrogenation reactions of amines.2,3 Herein, we try to classify amines into prearomatic amines and general amines (Scheme 1) for better description and comparison. Just as its name implies, prearomatic amines are these amines that could be oxidized into aromatic-ring imines after they release hydrides, mainly including 1,4-dihydropyridines (XIH2), 1,2-dihydropyridines (XIIH2), and 1,2-dihydro-3-substituted-indoline derivatives (XIIIH2) (Scheme 1). It is well known that the prearomatic structures result in the excellent thermodynamic abilities of prearomatic amines releasing hydrides or two hydrogen ions. In addition, general amines are amines that could be oxidized into a simple C=N group after they release hydrides or two hydrogen ions. General amines mainly contain aniline derivatives and alkyl amines (XIVH2) (Scheme 1).

Scheme 1. Classifications of Amines and the Corresponding Four Categories of XH2 in This Work.

Scheme 1

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Examining previous literature, both prearomatic amines and general amines could be used as hydrides or two hydrogen ions reductants in chemical reactions.4−12 For example, Hantzsch ester (HEH2), one of the representative prearomatic amines, was not only applied as a hydride reductant of the NADH model (Scheme 2a)4c but also extensively researched as two hydrogen ions reductants in hydrogenation reactions (Scheme 2b).4a,4b Many groups have been devoted to trying to explore, find, and apply novel and better hydride or two hydrogen ions reductants in reduction reactions.5−8 In addition to prearomatic amines, the general amines could also be employed as novel hydrides or two hydrogen ions reductants in chemical reactions.9−12 In 2013, Akiyama group reported the oxidative kinetic resolution of 2-substituted indolines (Scheme 2c).9 Using chiral phosphoric acid as a catalyst, the (R)-indolines acted as the two hydrogen ions reductants to hydrogenate imines. Furthermore, in 2011, Akiyama group realized the selective activation of α-Csp3–H using chiral phosphoric acid as a catalyst to asymmetrically synthesize tetrahydroquinolines (Scheme 2d).10 Among the reaction process, amines were verified as the hydride donors in which the selective hydrides transferring from the α-Csp3–H of aminogroups to the intramolecular activated C=C bonds was the key initiated step. Moreover, sometimes the metabolic processes of bioactive molecules owning amine structures may involve dehydrogenation or hydrogenation reactions. Such as the well-known dipine drugs, including Nifedipine, Amlodipine, Felodipine, and Benidipine, etc., are the classical calcium antagonists with typical 1,4-dihydropyridine structures to achieve the reduction of blood pressure, which are metabolized into the inactive pyridine derivatives by releasing two hydrogen ions in vivo.13,14

Scheme 2. (a) Prearomatic Amines Are Used as Hydride Reductants, (b) Prearomatic Amines Are Used as Two Hydrogen Ions Reductants, (c) General Amines Are Used as Two Hydrogen Ions Reductants, and (d) General Amines Are Used as Hydride Carriers in Chemical Reactions.

Scheme 2

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Our group has long been interested in determining the elementary step thermodynamics of hydride transfer of NADH models and unsaturated compounds in acetonitrile since 2003 (Scheme 3a).15,16 Acetonitrile was selected as a polar organic solvent to imitate the polar organic regions constructed with enzyme proteins due to the fact that the polarity of acetonitrile (ε = 37.5) is very close to that of amide bond in enzyme proteins.15c We established the thermodynamic scale and determined ∼5600 thermodynamic data of 421 organic hydrides and unsaturated compounds releasing or accepting hydride in the past 20 years in acetonitrile.15a Recently, we started turning to study the thermodynamics of two hydrogen ions transfer, which means our thermodynamic research focus transferred from “hydride transfer” to “two hydrogen ions”.15,16 For example, in 2020, we investigated the thermodynamic driving forces of three popular reductants (Hantzsch ester, benzothiazoline, and dihydrophenanthridine) releasing two hydrogen ions (Scheme 3b).16b In 2022, the reducing abilities of polar alkanes as organic hydrogen reductants were revealed and evaluated using thermodynamics (Scheme 3b).15b Moreover, in the same year, we continued to study the thermodynamics abilities of organic hydride/acid pairs as novel organic hydrogen reductants in hydrogenation, which could realize the transformation of organic hydrides from simple hydride reductants to thermodynamics-regulated hydrogen reductants.16a

Scheme 3. Thermodynamic Research on Hydride or Two Hydrogen Ions Transfer from Our Previous Work.

Scheme 3

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(a) A thermodynamic review of NADH models and unsaturated compounds releasing or accepting hydride determined in our group, (b) thermodynamics of three popular reductants (Hantzsch ester, benzothiazoline, and dihydrophenanthridine) releasing two hydrogen ions, (c) discovering and evaluating the reduction abilities of polar alkanes as organic reductants using thermodynamics, and (d) thermodynamics regulated organic hydride/acid pairs as novel organic hydrogen reductants in hydrogenation.

Overall, amines are definite hydrides or two hydrogen ions reductants in chemical reactions. Given that the dehydrogenation of amines and the hydrogenation of imines generally involve the two hydrogen ions transferring, undoubtedly, it is meaningful to investigate the thermodynamic abilities of amines as potential hydrides or two hydrogen ions reductants and imines as protons or two hydrogen ions acceptors. Arguably, this work is the successive work of thermodynamic evaluations on two hydrogen ions transfer for amines and imines.15,16 In this work, the thermodynamic evaluations of 84 amines as hydrides or two hydrogen ions reductants and corresponding 84 imines as protons or two hydrogen ions acceptors would be revealed and compared, and the application of thermodynamic data on hydrogenation are shown and discussed. The structures of 84 amines investigated in this work are displayed in Scheme 4. It should be noted that the two hydrogens are labeled as two different colors, red and blue, in Scheme 4 as well as other schemes. Actually, different colored hydrogens are transferred in different forms (hydrides or protons) during the dehydrogenation and hydrogenation processes. For the dehydrogenations of XH2, the red hydrogens are released in hydride form from XH2, while the blue hydrogens are released in protons form from XH+. Instead, as for the hydrogenation of X, the blue hydrogens are accepted by X in protons form, while the red hydrogens are accepted by XH+ in hydrides form.

Scheme 4. Chemical Structures of 84 Amines (XH2), as Well as the Abbreviations and Structures of Referred Compounds Involved in This Work.

Scheme 4

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Results and Discussion

As for the dehydrogenation reactions of amines, generally, amines release hydrides first to generate protonated imines (XH2 → XH+ + H–), then the protonated imines release protons to generate imines (XH+ → X + H+). Step 1 in Scheme 5 is the chemical process of XH2 releasing hydrides, and the thermodynamic driving forces of Step 1 are described by the corresponding Gibbs free energy changes of XH2 releasing hydrides: ΔGH–R(XH2). Step 2 in Scheme 5 is the chemical process of XH+ releasing protons, and the thermodynamic driving force of Step 2 can be described by the related Gibbs free energy changes of XH+ releasing protons: ΔGPR(XH+). If the pKa of XH+ could be obtained, the ΔGPR(XH+) values should be computed using eq 1 in Table 1. Step 3 in Scheme 5 is the chemical process of XH2 successively releasing hydrides and protons to produce X, XH2 → X + H+ + H–, and the thermodynamic driving forces of Step 3 are described by the relevant Gibbs free energy changes of XH2 successively releasing two hydrogen ions: ΔGH–PR(XH2). According to the thermodynamic cycles constructed based on the process of XH2 releasing two hydrogen ions in Scheme 5, the ΔGH–PR(XH2) values can be derived from eq 2 given in Table 1 by Hess’s law.15

Scheme 5. Thermodynamic Cycles Constructed Based on the Processes of XH2 Releasing Two Hydrogen Ions, and X Accepting Two Hydrogen Ions.

Scheme 5

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Table 1. Chemical Processes, Thermodynamic Parameters, and Data Sources or Computed Equations of Step 1–Step 6 for Amines Releasing Two Hydrogen Ions and Imines Accepting Two Hydrogen Ions in Acetonitrile.

chemical processes thermodynamic parameters sources or computed equations eq X
Step 1 XH2 → XH+ + H– ΔGH–R(XH2) ref (14)  
Step 2 XH+ → X + H+ ΔGPR(XH+) ΔGPR(XH+) = 1.37pKa(XH+) 1
Step 3 XH2 → X + H– + H+ ΔGH–PR(XH2) ΔGH–PR(XH2) = ΔGH–R(XH2) + ΔGPR(XH+) 2
Step 4 X + H+ → XH+ ΔGPA(X) ΔGPA(X) = −1.37pKa(XH+) 3
Step 5 XH+ + H– → XH2 ΔGH–A(XH+) ΔGH–A(XH+) = −ΔGH–R(XH2) 4
Step 6 X + H+ + H– → XH2 ΔGH–PA(X) ΔGH–PA(X) = ΔGPA(X) + ΔGH–A(XH+) 5
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In contrast, for the hydrogenation reactions of imines, generally, the hydride affinities of imines could be improved by imines accepting protons first to generate protonated imines (X + H+ → XH+), then the protonated imines accept hydrides to generate amines (XH+ + H– → XH2). Step 4 in Scheme 5 is the chemical process of X accepting protons, and the thermodynamic driving forces of Step 4 are described by the corresponding Gibbs free energy changes of X accepting protons: ΔGPA(X). ΔGPA(X) values could be computed by eq 3 in Table 1 using the pKa(XH+) values. Step 5 in Scheme 5 is the chemical process of XH+ accepting hydrides, and the thermodynamic driving forces of Step 5 can be described by the related Gibbs free energy changes of XH+ accepting hydrides: ΔGH–A(XH+). Since the chemical processes of XH2 releasing hydrides and XH+ accepting hydrides are opposite, the ΔGH–A(XH+) values can be obtained by eq 4 in Table 1. Step 6 in Scheme 5 is the chemical process of X successively accepting protons and hydrides to generate XH2, X + H+ + H– → XH2, and the thermodynamic driving forces of Step 6 are described by the relevant Gibbs free energy changes of X successively accepting two hydrogen ions: ΔGH–PA(X). Based on the thermodynamic cycles constructed based on the process of X accepting two hydrogen ions in Scheme 5, the ΔGH–PA(X) values can be derived from eq 5 given in Table 1 by Hess’s law.15

The chemical processes, thermodynamic parameters, and data sources or computed equations of Step 1–Step 3 for amines releasing two hydrogen ions and Step 4–Step 6 for imines accepting two hydrogen ions from Scheme 5 are clearly shown in Table 1.

The ΔGH–R(XH2) values are available from our previous work. In 2018, we computed the ΔGH–R(XH2) values of 84 amines (XH2, Scheme 4) releasing hydrides using the density functional theory method in acetonitrile.14 In this work, the pKa values of 84 XH+ were predicted using the prediction method developed by Luo and coworkers in 2020 at http://pka.luoszgroup.com/prediction.17 Prediction Methods: XGBoost with RMSE = 1.79 and r2 = 0.918 (80:20 train test split). The prediction method was well verified with an absolute error of 0.87 pKa units based on 15,338 experimental pKa data.17 Herein, the predicted pKa(XH+)P values and the determined pKa(XH+)D values of 10 XH+ in acetonitrile are compared in Table 2, and the differences (ΔpKa) between predicted pKa(XH+)P and determined pKa(XH+)D,18 ΔpKa = pKa(XH+)P – pKa(XH+)D, are derived and listed in Table 2. From Table 2, given that the ΔpKa scale ranges from 0.23 to −0.97, it is reasonable to deduce that the absolute error of pKa prediction is estimated as ±1 pKa in this work.

Table 2. Predicted pKa(XH+)P and the Determined pKa(XH+)D of 10 XH+ in Acetonitrile, along with the Differences (ΔpKa) between Predicted pKa(XH+)P and Determined pKa(XH+)D.

XH+ predicted pKa(XH+)P determined pKa(XH+)Da ΔpKab
1H+ 11.33 12.30 –0.97
2H+ 13.24 13.32 –0.08
5H+ 14.09 14.47 –0.38
10H+ 13.15 13.66 –0.51
13H+ 14.26 14.17 0.09
15H+ 8.21 8.04 0.17
18H+ 13.65 14.52 –0.87
21H+ 17.20 17.62 –0.42
23H+ 8.73 8.50 0.23
78H+ 6.97 7.16 –0.19
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a

Data are from ref (18).

b

ΔpKa = pKa(XH+)P – pKa(XH+)D.

Based on ΔGH–R(XH2) and pKa(XH+) values, the thermodynamic driving forces of Step 2–Step 6 could be computed by eqs 1–5 in Table 1. The predicted pKa(XH+) and detailed thermodynamic values of Step 1–Step 6 for 84 amines or 84 corresponding imines, including ΔGH–R(XH2), ΔGPR(XH+), ΔGH–PR(XH2), ΔGPA(X), ΔGH–A(XH+), and ΔGH–PA(X), are summarized in Table 3.

Table 3. ΔGH–R(XH2), pKa(XH+), ΔGPR(XH+), ΔGH–PR(XH2), ΔGH–A(XH+), ΔGPA(X), and ΔGH–PA(X) Values of 84 Amines and Their Corresponding Imines in Acetonitrile.

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a

Note: (1) The unit of ΔGH–R(XH2), ΔGPR(XH+), ΔGH–PR(XH2), ΔGH–A(XH+), ΔGPA(X), and ΔGH–PA(X) is kcal/mol. (2) ΔGH–R(XH2) values are from ref (14).

To conveniently compare and discuss the thermodynamic abilities of amines releasing hydrides or two hydrogen ions, in this work, amines are divided into four categories, i.e., prearomatic 1,4-dihydropyridines (XIH2, 1H2–62H2), prearomatic 1,2-dihydropyridine derivatives (XIIH2, 63H2–73H2), prearomatic 1,2-dihydro-3-substituted-indoline derivatives (XIIIH2, 74H2–78H2), and general amines (XIVH2, 79H2–84H2) (Schemes 1 and 6). The ΔGH–R(XH2) and ΔGH–A(XH+), pKa(XH+), ΔGPR(XH+) and ΔGPA(X), ΔGH–PR(XH2), and ΔGH–PA(X) scales of four categories of XH2 in acetonitrile are exhibited in Scheme 6 for clear comparison.

Scheme 6. ΔGH–R(XH2) and ΔGH–A(XH+), pKa(XH+), ΔGPR(XH+) and ΔGPA(X), ΔGH–PR(XH2), and ΔGH–PA(X) Scales of Four Categories of XH2 in Acetonitrile.

Scheme 6

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Thermodynamic Abilities of XH2 Releasing Hydrides as Hydride Reductants and XH+ Accepting Hydrides as Hydride Acceptors

It is well known that 1-benzyl-1,4-dihydronicotinamide (BNAH)19,20 and 10-methyl-9,10-dihydroacridine (AcrH2)21 are great and weak hydride donors, respectively (the chemical structures of BNAH and AcrH2 are shown in Scheme 4). The ΔGH–R(XH2) values are 59.3 kcal/mol for BNAH22 and 76.2 kcal/mol for AcrH2.22 Therefore, it is reasonable to suggest that (a) if the ΔGH–R(XH2) value of an XH2 is smaller than 60.0 kcal/mol, XH2 is considered as a thermodynamically strong hydride reductant, and the corresponding XH+ is considered as a thermodynamically weak hydride acceptor.15a (b) If the ΔGH–R(XH2) value of an XH2 is larger than 60.0 kcal/mol and smaller than 80.0 kcal/mol, the XH2 is considered as a thermodynamically medium-strong organic hydride reductant, and the corresponding XH+ is considered as a thermodynamically medium-strong hydride acceptor. (c) Last, if the ΔGH–R(XH2) value of an XH2 is larger than 80.0 kcal/mol, the XH2 is identified as a thermodynamically weak hydride reductant, and the corresponding XH+ is considered as a thermodynamically strong hydride acceptor.

As can be seen from Scheme 6 and Table 3, the ΔGH–R(XH2) scale of 84 amines ranges from 36.6 kcal/mol for 21H2 to 83.3 kcal/mol for 44H2, which spans a very large energy range of 46.7 kcal/mol. The 84 XH2 could establish a hydride reductants library covering thermodynamically strong hydride reductant to weak hydride reductant, which has the potential to be used in hydride reduction reactions. We all know that NaBH4 [ΔGH–R(NaBH4) = 50.0 kcal/mol]23 is a very excellent hydride reductant; therefore, 6 XH2, including 21H2 (36.6 kcal/mol), 5H2 (44.2 kcal/mol), 13H2 (48.3 kcal/mol), 18H2 (48.7 kcal/mol), 74H2 (48.7 kcal/mol), and 63H2 (49.0 kcal/mol), are identified as thermodynamically better hydride reductants than NaBH4. To show more clearly and intuitively, the ΔGH–R(XH2) and −ΔGH–A(XH+) scales of four categories of XH2, along with ΔGH–R values of common hydride donors, containing HCO2– (44.0 kcal/mol),24 NaBH4 (50.0 kcal/mol), BNAH (59.3 kcal/mol), AcrH2 (76.2 kcal/mol), 9H-xanthene (XT, 91.3 kcal/mol),15a and 4-acetylamino-2,2,6,6-tetramethylpiperidin-1-ol (TEMPOH, 100.7 kcal/mol),25 in acetonitrile are displayed in Scheme 7 (the chemical structures of BNAH, AcrH2, XT, and TEMPOH are shown in Scheme 4).

Scheme 7. ΔGH–R(XH2) and ΔGH–A(XH+) Scales of Four Categories of XH2, along with the ΔGH–R Values of HCO2–, NaBH4, BNAH, AcrH2, XT, and TEMPOH in Acetonitrile.

Scheme 7

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From Scheme 7, it is found that the ΔGH–R(XH2) [or −ΔGH–A(XH+)] scales range from 36.6 to 83.3 kcal/mol for XIH2, from 49.0 to 67.5 kcal/mol for XIIH2, from 48.7 to 70.8 kcal/mol for XIIIH2, and from 64.9 to 78.7 kcal/mol for XIVH2. Though XIH2, XIIH2, and XIIIH2 all belong to prearomatic amines, the thermodynamic hydride reduction abilities are quite different from each other. It is clear that the ΔGH–R(XH2) [or −ΔGH–A(XH+)] scale of XIH2 (36.6–83.3 kcal/mol) spans a very large range of 46.7 kcal/mol, covering from thermodynamically strong hydride reductants to weak hydride reductants. While for XIIH2 (49.0–67.5 kcal/mol) and XIIIH2 (48.7–70.8 kcal/mol), they are thermodynamically strong and medium-strong hydride reductants. As for prearomatic amines, 62 XIH2 (36.6–83.3 kcal/mol), 11 XIIH2 (49.0–67.5 kcal/mol), and 5 XIIIH2 (48.7–70.8 kcal/mol) could establish the library of hydride reductants ranging from thermodynamically strong hydride reductants to weak hydride reductants. Chemists can choose suitable hydride reductants to reduce various hydride acceptors with different degrees of difficulty. Instead, these 62 XIH+, 11 XIIH+, and 5 XIIIH+ could also be constructed as the library of hydride acceptors spanning from thermodynamically strong hydride acceptors to weak hydride acceptors, which can be used as potential hydride acceptors to initiate the following chemical reactions.

Interestingly, XIVH2 (64.9–78.7 kcal/mol) belong to thermodynamically medium-strong hydride reductants, meaning that the thermodynamic hydride reduction abilities of XIVH2 are smaller than that of BNAH (59.3 kcal/mol). It can be deduced that the common organic hydride reductants, such as BNAH (59.3 kcal/mol),22 HEH2 (64.6 kcal/mol),22 NaBH4 (50.0 kcal/mol),23 and HCO2– (44.0 kcal/mol),24 could reduce protonated general amines (XIVH+) from the view of thermodynamics. Correspondingly, XIVH+ are considered as thermodynamically medium-strong hydride acceptors, and they could be used as the hydride acceptors to oxidize many highly active NADH models, such as BNAH (59.3 kcal/mol), some prearomatic amines (ΔGH–R(XH2) ≤ 60 kcal/mol), etc.

In all, the prearomatic amines [XIH2, XIIH2, and XIIIH2, ΔGH–R(XH2) = 36.6–83.3 kcal/mol] are hydride reductants owning various thermodynamic abilities from strong, medium-strong, to weak hydride reductants. While general amines [XIVH2, ΔGH–R(XH2) = 64.9–78.7 kcal/mol] generally belong to thermodynamically medium-strong hydride reductants. Meanwhile, XIH+, XIIH+, and XIIIH+ [ΔGH–A(XH+) = −36.6––83.3 kcal/mol] are hydride acceptors owning various thermodynamic abilities from strong, medium-strong, to weak hydride acceptors. While XIVH+ [ΔGH–A(XH+) = −64.9 to −78.7 kcal/mol] generally belong to thermodynamically medium-strong hydride acceptors.

Acidities of XH+ and Basicity of X

To intuitively exhibit and compare the pKa(XH+) scales of four categories of XH+, the pKa(XH+) scales of four categories of XH+, along with the pKa values of TfOH (0.7),18d TsOH (8.5),18b PhNH3+ (10.64),18a PyH+ (11.33),18e TFA (12.7),18e NH4+ (16.46),18a Et3NH+ (18.83),18a and AcOH (23.5)18b in acetonitrile are shown in Scheme 8.18 We all know that TfOH (0.7),18d PyH+ (11.33),18e and AcOH (23.5)18b are strong, medium-strong, and weak acids in acetonitrile, respectively. Therefore, it is acceptable to roughly infer that (a) if the pKa of an acid is smaller than 10 in acetonitrile, the acid should belong to a strong acid, and its conjugated base belongs to a weak base in acetonitrile solution. (b) If the pKa of an acid is larger than 10 and smaller than 25 in acetonitrile, the acid should belong to a medium-strong acid, and its conjugated base belongs to a medium-strong base in acetonitrile solution. (c) Finally, if the pKa of an acid is larger than 25 in acetonitrile, the acid should belong to a weak acid, and its conjugated base belongs to a strong base in acetonitrile solution.

Scheme 8. pKa(XH+) Scales of Four Categories of XH+, along with pKa Values of TfOH, TsOH, PhNH3+, PyH+, TFA, NH4+, Et3NH+, and AcOH in Acetonitrile.

Scheme 8

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From Scheme 6 and Table 3, it is clear that the pKa(XH+) scale of 84 XH+ ranges from 3.15 for 9H+ to 17.20 for 21H+, which spans a very large range of 14.05 pKa units, indicating all the 84 XH+ belong to strong or medium-strong acids in acetonitrile. Further investigating the pKa distributions of various protonated imines (XH+), the pKa(XH+) distributions of 84 XH+ in acetonitrile are presented in Figure 1. As can be shown in Figure 1, the pKa range of 79 XH+ (94.0%) is between 8 and 16, meaning the pKa of most imines ranges from 8 to 16 in acetonitrile. In addition, the pKa values of 4 XH+ (4.8%) are smaller than 8, while the pKa of 1 XH+ (1.2%) is larger than 16. Since the pKa of benzenesulfonic acid (PhSO3H) and NH4+ are determined as 8.2 and 16.46 in acetonitrile, respectively,18a,18b so to speak, the acidities of most imines (∼94%, pKa: 8–16) in acetonitrile are between PhSO3H (8.2) and NH4+ (16.46).18a,18b Given the acidity values of XH+, the 84 XH+ could be used as potential alternatives to medium-strong organic acids in chemical reactions. Moreover, protonated imines (XH+) also have the potentials to be used as potential acid catalysts themselves to initiate or achieve the catalytic cycles.

Figure 1.

Figure 1

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pKa(XH+) distributions of 84 XH+ in acetonitrile.

From Scheme 8, the pKa(XH+) scales range from 3.15 to 17.20 for XIH+, from 9.15 to 14.14 for XIIH+, from 6.97 to 14.56 for XIIIH+, and from 11.03 to 15.61 for XIVH+. It is clear that the scale of XIH+ spans the widest range among the four categories of XH+, and the acidities of XIH+ are situated between TfOH (0.7)18d and Et3NH+ (18.83).18a The acidity range of XIH+ means that XIH+ with protonated pyridine structure belong to strong or medium-strong organic acids. Meanwhile, the corresponding imines XI are weak or medium-strong organic bases. Since the structures of XIIH+ are similar to XIH+,26 the XIIH+ (9.15–14.14) also belong to strong or medium-strong organic acids, and their conjugated bases XII are weak or medium-strong organic bases. Some XI and XII [pKa(XH+) > 10] could be used as excellent organic bases like pyridines [denoted as Py, pKa(PyH+) = 11.33]18a to capture protons to trigger the following addition or degradation reactions. In fact, XIH+ (1H+–62H+) and XIIH+ (63H+–73H+) are various pyridine derivatives, we can speculate that the pKa values of pyridine derivatives could be regulated from 3.15 to 17.20 in acetonitrile. Given the pKa of PyH+ is 11.33 in acetonitrile, it is rational to conclude that the pKa values of pyridine derivatives could be regulated to pKa(PyH+) ± 8 (11.33 ± 8) by designing various chemical structures in acetonitrile. Considering the pKa scale of XIVH+ (11.03–15.61) in acetonitrile, the acidities of XIVH+ are between PhNH3+ (10.64) and NH4+ (16.46) in acetonitrile.18a XIVH+ belong to medium-strong organic acids, and their conjugated bases XIV are medium-strong organic bases.

Thermodynamic Abilities of XH2 Releasing Two Hydrogen Ions as Hydrogen Reductants and X Accepting Two Hydrogen Ions as Dehydrogenation Reagents

Herein, the ΔGH–PR(XH2) and ΔGH–PA(X) scales of four categories of XH2 are compared and shown in Scheme 9. Since HCO2H,27 H2,28 HEH2,4 and iPrOH29 are widely used two hydrogen ions reductants in hydrogenation reactions, their ΔGH–PR(XH2) [ΔGH–PA(X)] values determined in acetonitrile are simultaneously listed in Scheme 9 for intuitively diagnosing the thermodynamic reduction abilities of amines.

Scheme 9. ΔGH–PR(XH2) and −ΔGH–PA(X) scales of four categories of XH2, along with the ΔGH–PR values of common two hydrogen ions reductants (HCO2H, H2, HEH2, and iPrOH) in acetonitrile.

Scheme 9

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From Scheme 9, ΔGH–PR [−ΔGH–PA] values are 70.1 kcal/mol for HCO2H,24 76.0 kcal/mol for H2,30 83.1 kcal/mol for HEH2,15 and 84.3 kcal/mol for iPrOH,31 respectively, implying the thermodynamic reduction abilities are decreasing in the order of HCO2H (70.1 kcal/mol) > H2 (76.0 kcal/mol) > HEH2 (83.1 kcal/mol) > iPrOH (84.3 kcal/mol). Given that HCO2H (70.1 kcal/mol) and H2 (76.0 kcal/mol) are very excellent two hydrogen ions reductants, and HEH2 (83.1 kcal/mol) and iPrOH (84.3 kcal/mol) are medium-strong two hydrogen ions reductants in hydrogenation reactions; therefore, it is acceptable to make the following judgments. (a) If the ΔGH–PR(XH2) value of an amine is smaller than 80 kcal/mol, the amine belongs to a thermodynamically strong two hydrogen ions reductant, and the corresponding imine belongs to a thermodynamically weak two hydrogen ions acceptor. (b) If the ΔGH–PR(XH2) value of an amine is larger than 80 kcal/mol and smaller than 90 kcal/mol, the amine belongs to a thermodynamically medium-strong organic two hydrogen ions reductant, and the related imine belongs to a thermodynamically medium-strong two hydrogen ions acceptor. (c) If the ΔGH–PR(XH2) value of an amine is larger than 90 kcal/mol, the amine belongs to a thermodynamically weak organic two hydrogen ions reductant, and the corresponding imine belongs to a thermodynamically strong two hydrogen ions acceptor.

According to the above diagnostic criteria, as can be seen from Scheme 6 and Table 3, the ΔGH–PR(XH2) scale of 84 XH2 ranges from 60.2 kcal/mol for 21H2 to 98.0 kcal/mol for 44H2, which spans a very large energy range of 37.8 kcal/mol, indicating that 84 amines could establish the molecule library of organic two hydrogen ions reductants covering from thermodynamically strong to weak two hydrogen ions reductants for chemists selecting and applying in hydrogenation reactions. Among the 84 amines, 48 XH2 are recognized as thermodynamically strong two hydrogen ions reductants (<80 kcal/mol), 29 XH2 are recognized as thermodynamically medium-strong two hydrogen ions reductants (80–90 kcal/mol), and 7 XH2 are recognized as thermodynamically weak two hydrogen ions reductants (>90 kcal/mol). To sum up, 77 XH2 out of 84 XH2 (91.7%) belong to thermodynamically strong or medium-strong organic two hydrogen ions reductants with ΔGH–PR(XH2) < 90 kcal/mol, meaning most amines could be used as thermodynamically potential two hydrogen ions reductants in hydrogenation reactions. In fact, among the 84 amines, 5 XH2, including 27H2,467H2,669H2,774H2,8 and 78H2,5 have already been used as two hydrogen ions reductants in hydrogenation reactions.

As for prearomatic 1,4-dihydropyridines XIH2 (1H2–62H2, 60.2–98.0 kcal/mol) and prearomatic 1,2-dihydropyridine derivatives XIIH2 (63H2–73H2, 64.5–84.5 kcal/mol), they have various thermodynamic reduction abilities, including thermodynamically strong, medium-strong, and weak two hydrogen ions reductants. Among XIH2 and XIIH2, the thermodynamic two hydrogen ions reduction abilities of 29 XH2, consisting of 1H2–7H2, 9H2–13H2, 18H2–23H2, 30H2, 32H2–33H2, 46H2, 48H2, 51H2, 52H2, 57H2, 63H2–65H2, are better than that of H2 (76.0 kcal/mol)30 with ΔGH–PR(XH2) < 76.0 kcal/mol. Moreover, 12 XH2, consisting of 1H2–2H2, 4H2–5H2, 10H2, 13H2, 18H2, 20H2–21H2, 33H2, 57H2, and 63H2, are even better thermodynamic two hydrogen ions reductants than HCO2H (70.1 kcal/mol)24 with ΔGH–PR(XH2) < 70.1 kcal/mol. In addition, 25 XH2 out of XIH2 and XIIH2 belong to thermodynamically weak two hydrogen ions reductants with 80 kcal/mol < ΔGH–PR(XH2) < 90.0 kcal/mol. In fact, 27H2, 67H2, and 69H2 have been extensively used as two hydrogen ions reductants in chemical reactions. For prearomatic 1,2-dihydro-3-substituted-indoline derivatives XIIIH2 (68.6–85.5 kcal/mol), they all belong to thermodynamically potential strong or medium-strong organic two hydrogen ions reductants. Examining previous literature, 74H28 and 78H25 have already been applied as two hydrogen ions reductants in hydrogenation reactions.

Based on the −ΔGH–PA(X) scales of XI (60.2–98.0 kcal/mol), XII (64.5–84.5 kcal/mol), and XIII (68.6–85.5 kcal/mol), it can be concluded that not all XI, XII, and XIII could be hydrogenated by the excellent reductants HCO2H (70.1 kcal/mol)24 or H2 (76.0 kcal/mol).30 When some weak two hydrogen ions acceptors, XI, XII, and XIII, are to be hydrogenated, the strong acid additives are necessary to construct the reductant/acid pairs to further improve the thermodynamic reduction abilities of reductants.16a

Finally, for general amines XIVH2 [ΔGH–PR(XH2) = 86.3–94.3 kcal/mol], they belong to thermodynamically medium-strong or weak two hydrogen ions reductants. Some amines of XIVH2, such as 80H2 (86.3 kcal/mol) and 81H2 (87.6 kcal/mol), are considered as potential two hydrogen ions reductants for the thermodynamic alternative of HEH2 (83.1 kcal/mol) or iPrOH (84.3 kcal/mol) in hydrogenation reactions. Instead, for the two hydrogen ions reductions of general imines XIV by common reductants, HCO2H (70.1 kcal/mol),24 H2 (76.0 kcal/mol),18e,30 HEH2 (83.1 kcal/mol),15 and iPrOH (84.3 kcal/mol),31 are thermodynamically feasible.

In summary, not all prearomatic amines (XIH2, XIIH2, and XIIIH2) are thermodynamically strong or medium-strong two hydrogen ions reductants; the general amines (XIVH2) generally belong to thermodynamically medium-strong or weak two hydrogen ions reductants. For the hydrogenation of imines, not all XI, XII, and XIII could be hydrogenated by the excellent reductants HCO2H or H2, while the two hydrogen ions reductions of XIV by common reductants, such as HCO2H, H2, HEH2, and iPrOH, are thermodynamically feasible.

Practical Application of Thermodynamic Data of Amines and Imines in Hydrogenation Reactions

Since the values of thermodynamic driving forces in Step 1–Step 6 reflect the thermodynamic reduction and oxidation abilities for amines and imines, it can be inferred that these thermodynamic data (Step 1–Step 6) of 84 amines and imines obtained in this work may be helpful to the diagnoses of mechanism and thermodynamic feasibility of hydrogenation reactions. It is well known that HEH2 (27H2) is an excellent hydrogen reductant in chemical reactions;4 herein, we choose the hydrogenation reaction between HEH2 (27H2) and 1-phenylethan-1-imine (80) as an example to display the application of thermodynamic data. Herein, the related thermodynamic analyses on hydrogenation reaction between HEH2 (27H2) and 1-phenylethan-1-imine (80) are shown in Scheme 10. In Scheme 10, the thermodynamic data of HEH2 releasing two hydrogen ions (Step 1–Step 3) are shown in Scheme 10a, while the thermodynamic data of 80 accepting two hydrogen ions (Step 4–Step 6) are shown in Scheme 10b. In addition, Scheme 10c exhibits the overall Gibbs free energy change of the hydrogenation reactions, and Scheme 10d is the most possible hydrogenation mechanism and related thermodynamic driving forces of every elementary step.

Scheme 10. (a) Thermodynamic Data of HEH2 (27H2) Releasing Two Hydrogen Ions in Acetonitrile, (b) the Thermodynamic Data of 80 Accepting Two Hydrogen Ions in Acetonitrile, (c) the Gibbs Free Energy Change of Two Hydrogen Ions Transferring from HEH2 (27H2) to 80 in Acetonitrile, (d) the Thermodynamic Data of the Most Possible Elementary Steps for the Two Hydrogen Ions Transferring from HEH2 (27H2) to 80 in Acetonitrile.

Scheme 10

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From Scheme 10, it is found that the Gibbs free energy change of HEH2 releasing two hydrogen ions [ΔGH–PR(HEH2)] is 83.3 kcal/mol (Scheme 10a), while the Gibbs free energy change of 80 accepting two hydrogen ions [ΔGH–PA(80)] is −87.6 kcal/mol (Scheme 10b). Due to the fact that the ΔGH–PR(HEH2) value is smaller than −ΔGH–PA(80), the Gibbs free energy change of the hydrogenation reaction is computed as −4.3 kcal/mol (ΔGH–PT < 0, Scheme 10c), meaning that the hydrogenation reaction of 80 by HEH2 is thermodynamically feasible. In our previous work, we determined the hydride affinities of various imines in acetonitrile, and the estimated thermodynamic driving force of 80 accepting hydrides is larger than −40 kcal/mol, ΔGH–A(80) > −40 kcal/mol (Scheme 11).4c Since the Gibbs free energy change of HEH2 releasing hydride [ΔGH–R(HEH2)] is 64.6 kcal/mol, if the hydride transfer from HEH2 to 80 is the first elementary step, the related Gibbs free energy change of hydride transfer is larger than 24.6 kcal/mol (Scheme 11), which is a very high energy barrier to prevent the proceeding of hydride transfer from HEH2 to 80. So far, it seems the hydrogenation reaction could not occur by stepwise transfer of hydride and proton from HEH2 to 80, even though the overall Gibbs free energy change of the hydrogenation reaction is smaller than 0 (ΔGH–PT = −4.3 kcal/mol in Scheme 10c). In addition, as shown in Scheme 10c, it seems that the concerted one-step mechanism of two hydrogen ions (H– + H+) transferring from HEH2 to 80 is thermodynamically feasible (ΔGH–PT = −4.3 kcal/mol). The concerted one-step mechanism involves a cyclic 8-membered ring transition state (TS) which is kinetically not possible, so this way is reasonably ruled out.

Scheme 11. Thermodynamic Analysis on Hydride Transfer from HEH2 to 80.

Scheme 11

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Interestingly, if the Gibbs free energy changes of 80H+ and 80 accepting hydrides are compared, i.e., ΔGH–A(80H+) = −68.4 kcal/mol vs ΔGH–A(80) > −40 kcal/mol, it is clear that the protonation of 80 significantly improves the hydride-accepting ability by at least 28.4 kcal/mol. Inspired by this, it is reasonable to assume that the hydrogenation reaction between 80 and HEH2 needs a suitable acid as a catalyst to initiate the first elementary step of hydride transfer. According to the above analysis, HEH+ is identified as the medium-strong organic acid, which is also the oxidation product of HEH2 after releasing hydride. Therefore, a small amount of HEH+ is selected as an acid catalyst to make the hydrogenation reactions take place. Because the Gibbs free energy of the sum of HEH+ releasing protons and HEH2 releasing hydrides is equal to ΔGH–PR(HEH2), ΔGH–PR(HEH2) = ΔGPR(HEH+) + ΔGH–R(HEH2). The acid-catalyzed hydrogenation mechanism and thermodynamic analysis are shown in Scheme 10d.

As can be seen from Scheme 10d, due to the acidity of HEH+ and the basicity of 80, the proton transfers from HEH+ to 80 is the initial elementary step, whose Gibbs free energy change (ΔGPT) is computed as −0.5 kcal/mol by combining ΔGPR(HEH+) with ΔGPA(80). After the proton transfer step, the Gibbs free energy change of followed hydride transfer from HEH2 to 80H+ (ΔGH–T) is computed as −3.8 kcal/mol by combining ΔGH–A(80H+) with ΔGH–R(HEH2). Finally, the generated HEH+ is involved in another cyclic reaction. Obviously, the Gibbs free energy changes of the two elementary steps (ΔGPT and ΔGH–T) are smaller than 0, which indicates that both the first proton transfer from HEH+ to 80 and followed hydride transfer from HEH2 to 80H+ are thermodynamically feasible. In fact, the acid-catalyzed hydrogenation reductions of imines by HEH2 have been extensively studied and reported in the published literature,2,4,32 strongly proving the correctness of thermodynamic analyses and the value of these important thermodynamic data.

Further considering the reduction abilities of amines as two hydrogen ions reductants, the thermodynamic reduction abilities of amines could be regulated by combining different acids with various acidities as additives to construct amine/acid pairs, which could change the chemical reactions from thermodynamically impossible into thermodynamically feasible. The related investigations and discussions were reported in our previous work in 2022 (Scheme 3d),16a where we studied the thermodynamics-regulated organic hydride/acid pairs as novel organic hydrogen reductants in hydrogenation reactions.

In fact, our group has conducted many thermodynamic evaluations of unsaturated compounds, including polar alkenes, activated alkynes, aldehydes ketones, activated dienes, accepting hydrides, or continuously accepting protons and hydrides.15,16 We are sure that the thermodynamic data of 84 amines obtained in this work have a wider application on the hydrogen reductions of various unsaturated substrates as two hydrogen ions reductants.

Conclusions

In this work, the pKa values of 84 protonated imines (XH+) are predicted. Combining with ΔGH–R(XH2) values from our previous work, the ΔGH–PR(XH2) were derived based on ΔGH–R(XH2) and ΔGPR(XH+) using Hess’ law. The thermodynamic abilities of amines as potential hydrides or two hydrogen ions reductants, and imines as protons or two hydrogen ions acceptors are well evaluated and discussed according to the chemical structural features. Several conclusions could be drawn from the thermodynamic data. (1) The prearomatic amines (XIH2, XIIH2, and XIIIH2) are hydride reductants owning various thermodynamic abilities ranging from strong, medium-strong, to weak hydride reductants, while general amines (XIVH2) generally belong to medium-strong hydride reductants. Meanwhile, XIH+, XIIH+, and XIIIH+ are hydride acceptors owning various thermodynamic abilities from strong, medium-strong to weak hydride acceptors. While XIVH+ generally belong to thermodynamically medium-strong hydride acceptors. (2) The pKa(XH+) scale of 84 XH+ ranges from 3.15 to 17.20. Based on the pKa(XH+) distributions, the pKa scale of most XH+ (∼94%) ranges from 8 to 16. XH+ generally belong to strong or medium-strong acids, and the corresponding imines (X) belong to weak or medium-strong bases in acetonitrile. (3) Not all prearomatic amines (XIH2, XIIH2, and XIIIH2) are thermodynamically strong or medium-strong two hydrogen ions reductants. The general amines (XIVH2) generally belong to thermodynamically medium-strong or weak two hydrogen ions reductants. Among the 84 amines, 48 XH2 are recognized as thermodynamically strong two hydrogen ions reductants, 29 XH2 are recognized as thermodynamically medium-strong two hydrogen ions reductants, and 7 XH2 are recognized as thermodynamically weak two hydrogen ions reductants. For the hydrogenation of imines, not all XI, XII, and XIII could be hydrogenated by the excellent reductants HCO2H or H2, while the two hydrogen ions reductions of XIV by common reductants, such as HCO2H, H2, HEH2, and iPrOH, are thermodynamically feasible. (4) These important thermodynamic data (Step 1–Step 6) of 84 amines and imines obtained in this work are helpful to the diagnosis of mechanism and thermodynamic feasibility of hydrogenation reactions. According to the thermodynamic analysis, the hydrogenation of imines experiences the acid-catalyzed mechanism. It is indisputable the thermodynamic data may help chemists identify new hydrides or two hydrogen ions (atom) reductants of amines and offer thermodynamic guidance on the hydrogenation of imines and dehydrogenation of amines.

Experimental Section

Prediction Methods: XGBoost with RMSE = 1.79 and r2 = 0.918 (80:20 train test split). SPOC (structural and physical-organic-parameter-based descriptor) was employed to represent the structural and electronic features of a molecule. The models were trained with a neural network or the XGBoost algorithm to show a low MAE value of 0.87 pKa units. The pKa values of 84 XH+ in acetonitrile were predicted using the method developed by Luo and coworkers in 2020 at http://pka.luoszgroup.com/prediction.

Acknowledgments

This study was supported by the doctoral scientific research foundation of Jining Medical University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c03804.

  • Original pKa prediction data of 84 XH+ (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c03804_si_001.pdf (6.5MB, pdf)

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