Thermodynamics Evaluation of Selective Hydride Reduction for α,β-Unsaturated Carbonyl Compounds

The selective reduction of α,β-unsaturated carbonyl compounds is one of the core reactions and also a difficult task for organic synthesis. We have been attempting to study the thermodynamic data of these compounds to create a theoretical basis for organic synthesis and computational chemistry. By electrochemical measurement method and titration calorimetry, in acetonitrile at 298 K, the hydride affinity of two types of unsaturated bonds in α,β-unsaturated carbonyl compounds, their single-electron reduction potential, and the single-electron reduction potential of the corresponding radical intermediate are determined. Their hydrogen atom affinity, along with the hydrogen atom affinity and proton affinity of the corresponding radical anion, is also derived separately based on thermodynamic cycles. The above data are used to establish the corresponding “Molecule ID Card” (Molecule identity card) and analyze the reduction mechanism of unsaturated carbonyl compounds. Primarily, the mixture of any carbonyl hydride ions and Ac-tempo+ will stimulate hydride transfer process and create corresponding α,β-unsaturated carbonyl compounds and Ac-tempoH from a thermodynamic point of view.

The polarity of the carbonyl group of α,β-unsaturated carbonyl compounds and the alternate distribution of conjugated chain charges give carbonyl carbon and β-carbon certain positive charges, while carbonyl oxygen and α-carbon have certain negative charges. Such phenomena lead to amphipathic characteristics: nucleophile can be added to carbonyl carbon to produce 1, 2 addition reaction (Grignard reagent as "hard" nucleophile), or added to β-carbon to produce 1, 4 addition reaction (lithium dimethylcuprate as "soft" nucleophile). Therefore, chemical selectivity of reduction reactions is not only the focus of theoretical research but also the difficulty of industrial application. Previous studies [16][17][18][19][20][21] can only control the type of reaction by screening the reducing agent, optimizing the reaction conditions and adding catalysts, but this paper studies the selective reduction of α,β-unsaturated carbonyl compounds from the perspective of thermodynamics. The main purpose of this work is to quantify the hydrogenation process by establishing a database and theoretical foundation. In this paper, the following seven series of compounds in Scheme 1 have been designed and synthesized. All compounds have been reported, and we will not present them as new. It is noteworthy that A'H 2 and B H 2 are synthesized for the Scheme 1 have been designed and synthesized. All compounds have been reported, and we will not present them as new. It is noteworthy that A'H2 and B´H2 are synthesized for the first time by the CeCl3 method mentioned below. By measuring their five thermodynamic parameters, we have analyzed the energy changes of elementary reactions at each step and finally determined the specific pathways of hydrogen transfer, thereby providing theoretical support for the selective reduction of α,β-unsaturated carbonyl compounds. Scheme 1. The compounds synthesized in this work.
We have determined the hydride affinity (Equations (1)-(3)) of the seven series of compounds (Scheme 1). In Equation (3), X represents the structure of a compound that can accept a hydride anion. Since there are two types of unsaturated bonds in α,β-unsaturated carbonyl compounds, and both the double bond and carbonyl group can accept hydride anions, the hydride affinity of carbonyl groups accepting hydride anions in 2-positions is denoted herein as ∆HH-A 2 , while the hydride affinity of the double bond accepting hydride anions in 4-positions is denoted herein as ∆HH-A 4 . (3) Since the free hydride ion in acetonitrile is not available, the process of unsaturated compounds accepting hydride anion is exactly opposite to the heterolytic process of anions (Equation (4)). The thermodynamic driving force of hydride transfer depends on not only the ability of the hydride donor to provide the hydride but also the ability of the hydride acceptor to accept the hydride. However, the hydride affinity of X in solution, ∆HH-A(X), can be obtained from the reaction enthalpy change of the corresponding carbanions XH with a strong hydride acceptor, such as 4-acetylamino-2,2,6,6-tetramethylpi-peridine1-oxoammonium (Ac-tempo + ) [22,23] (Equation (5)). The enthalpy change of hydride transfer and proton transfer in the molecular (Ac-tempo + ClO4 -) were combined: ∆H (Ac-tempo + ) = ∆HH-A(Ac-tempo + ) + ∆HIPT(Ac-tempo + )(Scheme 2). Scheme 1. The compounds synthesized in this work.
We have determined the hydride affinity (Equations (1)-(3)) of the seven series of compounds (Scheme 1). In Equation (3), X represents the structure of a compound that can accept a hydride anion. Since there are two types of unsaturated bonds in α,β-unsaturated carbonyl compounds, and both the double bond and carbonyl group can accept hydride anions, the hydride affinity of carbonyl groups accepting hydride anions in 2-positions is denoted herein as ∆H H -A 2 , while the hydride affinity of the double bond accepting hydride anions in 4-positions is denoted herein as ∆H H -A 4 .
Molecules 2023, 28, x FOR PEER REVIEW 2 of 13 Scheme 1 have been designed and synthesized. All compounds have been reported, and we will not present them as new. It is noteworthy that A'H2 and B´H2 are synthesized for the first time by the CeCl3 method mentioned below. By measuring their five thermodynamic parameters, we have analyzed the energy changes of elementary reactions at each step and finally determined the specific pathways of hydrogen transfer, thereby providing theoretical support for the selective reduction of α,β-unsaturated carbonyl compounds. Scheme 1. The compounds synthesized in this work.
We have determined the hydride affinity (Equations (1)-(3)) of the seven series of compounds (Scheme 1). In Equation (3), X represents the structure of a compound that can accept a hydride anion. Since there are two types of unsaturated bonds in α,β-unsaturated carbonyl compounds, and both the double bond and carbonyl group can accept hydride anions, the hydride affinity of carbonyl groups accepting hydride anions in 2-positions is denoted herein as ∆HH-A 2 , while the hydride affinity of the double bond accepting hydride anions in 4-positions is denoted herein as ∆HH-A 4 .
(3) Since the free hydride ion in acetonitrile is not available, the process of unsaturated compounds accepting hydride anion is exactly opposite to the heterolytic process of anions (Equation (4)). The thermodynamic driving force of hydride transfer depends on not only the ability of the hydride donor to provide the hydride but also the ability of the hydride acceptor to accept the hydride. However, the hydride affinity of X in solution, ∆HH-A(X), can be obtained from the reaction enthalpy change of the corresponding carbanions XH with a strong hydride acceptor, such as 4-acetylamino-2,2,6,6-tetramethylpi-peridine1-oxoammonium (Ac-tempo + ) [22,23] (Equation (5)). The enthalpy change of hydride transfer and proton transfer in the molecular (Ac-tempo + ClO4 -) were combined: ∆H (Ac-tempo + ) = ∆HH-A(Ac-tempo + ) + ∆HIPT(Ac-tempo + )(Scheme 2). (1) Molecules 2023, 28, x FOR PEER REVIEW 2 of 13 Scheme 1 have been designed and synthesized. All compounds have been reported, and we will not present them as new. It is noteworthy that A'H2 and B´H2 are synthesized for the first time by the CeCl3 method mentioned below. By measuring their five thermodynamic parameters, we have analyzed the energy changes of elementary reactions at each step and finally determined the specific pathways of hydrogen transfer, thereby providing theoretical support for the selective reduction of α,β-unsaturated carbonyl compounds. Scheme 1. The compounds synthesized in this work.
We have determined the hydride affinity (Equations (1)-(3)) of the seven series of compounds (Scheme 1). In Equation (3), X represents the structure of a compound that can accept a hydride anion. Since there are two types of unsaturated bonds in α,β-unsaturated carbonyl compounds, and both the double bond and carbonyl group can accept hydride anions, the hydride affinity of carbonyl groups accepting hydride anions in 2-positions is denoted herein as ∆HH-A 2 , while the hydride affinity of the double bond accepting hydride anions in 4-positions is denoted herein as ∆HH-A 4 .
(3) Since the free hydride ion in acetonitrile is not available, the process of unsaturated compounds accepting hydride anion is exactly opposite to the heterolytic process of anions (Equation (4)). The thermodynamic driving force of hydride transfer depends on not only the ability of the hydride donor to provide the hydride but also the ability of the hydride acceptor to accept the hydride. However, the hydride affinity of X in solution, ∆HH-A(X), can be obtained from the reaction enthalpy change of the corresponding carbanions XH with a strong hydride acceptor, such as 4-acetylamino-2,2,6,6-tetramethylpi-peridine1-oxoammonium (Ac-tempo + ) [22,23] (Equation (5)). The enthalpy change of hydride transfer and proton transfer in the molecular (Ac-tempo + ClO4 -) were combined: ∆H (Ac-tempo + ) = ∆HH-A(Ac-tempo + ) + ∆HIPT(Ac-tempo + )(Scheme 2).
Since the free hydride ion in acetonitrile is not available, the process of unsaturated compounds accepting hydride anion is exactly opposite to the heterolytic process of anions (Equation (4)). The thermodynamic driving force of hydride transfer depends on not only the ability of the hydride donor to provide the hydride but also the ability of the hydride acceptor to accept the hydride. However, the hydride affinity of X in solution, ∆H H -A (X), can be obtained from the reaction enthalpy change of the corresponding carbanions XH with a strong hydride acceptor, such as 4-acetylamino-2,2,6,6-tetramethylpiperidine1oxoammonium (Ac-tempo + ) [22,23] (Equation (5)). The enthalpy change of hydride transfer and proton transfer in the molecular (Ac-tempo + ClO 4 -) were combined: ∆H (Ac-tempo + ) = ∆H H -A (Ac-tempo + ) + ∆H IPT (Ac-tempo + ) (Scheme 2). ∆HH-A(X) = −∆HH-D(XH) ∆HH-A(X) = ∆H (Ac-tempo + ) − ∆Hrxn A hydride anion consists of a proton and two electrons, so there are three p available for hydride transfer: (1) one-step hydride anion transfer; (2) hydroge electron transfer; (3) electron-initiated e-H + -e or e-H • multi-step transfer. The sam for the acceptance of hydride by unsaturated carbonyl compounds. General hydri transfer mainly involves the following bond energy changes.
In this work, in acetonitrile at 298 K, hydride affinity, ∆H H -A (X), is defined as lar enthalpy change of X capturing a hydride anion. Hydrogen atom affinity, ∆H defined as the molar enthalpy change of X capturing a hydrogen atom. Hydrog affinity, ∆HHA(X •− ), is defined as the molar enthalpy change of a radical anion X • ing a hydrogen atom. Proton affinity, ∆HPA (X •− ), is defined as the molar enthalpy of a radical anion X •− capturing a proton.
The thermodynamic parameters of reactants and reaction intermediates (F may be detected based on the electrochemical and calorimetric data, and the corr ing derivation equations are shown in Equations (6)- (8). E 0 red(X) is the reduction p of compound A, AH2, and A'H2. E 0 red(XH • ) is the reduction potential of interm of compound A, AH2, and A'H2 gaining hydrogen atoms ( Figure 1). We have repl with ∆GET and referred to the literature value [24] for determining reversible p taking E1/2(H +/0 ) = −2.307 (V vs Fc +/0 ), E1/2(H 0/− ) = −1.137 (V vs Fc +/0 ) (Fc = ferrocene). for Faraday's constant (23.05 kcal mol −1 V −1 ).   A hydride anion consists of a proton and two electrons, so there are three pathways available for hydride transfer: (1) one-step hydride anion transfer; (2) hydrogen atomelectron transfer; (3) electron-initiated e-H + -e or e-H • multi-step transfer. The same is true for the acceptance of hydride by unsaturated carbonyl compounds. General hydride anion transfer mainly involves the following bond energy changes.
In this work, in acetonitrile at 298 K, hydride affinity, ∆H H -A (X), is defined as the molar enthalpy change of X capturing a hydride anion. Hydrogen atom affinity, ∆H HA (X), is defined as the molar enthalpy change of X capturing a hydrogen atom. Hydrogen atom affinity, ∆H HA (X •− ), is defined as the molar enthalpy change of a radical anion X •− capturing a hydrogen atom. Proton affinity, ∆H PA (X •− ), is defined as the molar enthalpy change of a radical anion X •− capturing a proton.
( A hydride anion consists of a proton and two electrons, so there are three pathw available for hydride transfer: (1) one-step hydride anion transfer; (2) hydrogen ato electron transfer; (3) electron-initiated e-H + -e or e-H • multi-step transfer. The same is t for the acceptance of hydride by unsaturated carbonyl compounds. General hydride an transfer mainly involves the following bond energy changes.
In this work, in acetonitrile at 298 K, hydride affinity, ∆H H -A (X), is defined as the m lar enthalpy change of X capturing a hydride anion. Hydrogen atom affinity, ∆H HA (X defined as the molar enthalpy change of X capturing a hydrogen atom. Hydrogen at affinity, ∆HHA(X •− ), is defined as the molar enthalpy change of a radical anion X •− cap ing a hydrogen atom. Proton affinity, ∆HPA (X •− ), is defined as the molar enthalpy cha of a radical anion X •− capturing a proton.

Results
Common electrochemical measurement method mainly includes cyclic voltam try (CV) and Osteryoung square wave voltammetry (OSWV). In this study, we have u these methods to determine the single-electron reduction potentials of three types of

Results
Common electrochemical measurement method mainly includes cyclic voltammetry (CV) and Osteryoung square wave voltammetry (OSWV). In this study, we have used these methods to determine the single-electron reduction potentials of three types of unsaturated carbonyl compounds (Scheme 1) and the reduction potentials of radical intermediates corresponding to unsaturated carbonyl compounds in Figure 2 and Supporting Information. The obtained data is listed in Table 1. These data were calculated based on data obtained via the OSWV method.
Molecules 2023, 28, x FOR PEER REVIEW 4 of saturated carbonyl compounds (Scheme 1) and the reduction potentials of radical inte mediates corresponding to unsaturated carbonyl compounds in Figure 2 and Supporti Information. The obtained data is listed in Table 1. These data were calculated based data obtained via the OSWV method.  ∆Hrxn is the molar enthalpy change of the reaction (Equation (5)) in acetonitri which can be determined by using titration calorimetry. In our previous work, we fir determined the molar enthalpy change (∆Hrxn) of the reaction between Ac-tempo + ClO  ∆Hrxn is the molar enthalpy change of the reaction (Equation (5)) in acetonitrile, which can be determined by using titration calorimetry. In our previous work, we first determined the molar enthalpy change (∆Hrxn) of the reaction between Ac-tempo + ClO 4 -Molecules 2023, 28, 2862 5 of 13 and BNAH directly by isothermal titration calorimetry (ITC), calibrated the hydride affinity of Ac-tempo + ClO 4 -−∆H (Ac-tempo + ) to −105.60 kcal/mol. We determined the molar enthalpy change (∆Hrxn) of the reaction between the anions (BH 4 ) and Ac-tempo + ClO 4 - (Figure 3 and Supporting Information), relevant data are listed in Table 1. es 2023, 28, x FOR PEER REVIEW ity of Ac-tempo + ClO4 -−∆H (Ac-tempo + ) to −105.60 kcal/mol. We determ thalpy change (∆Hrxn) of the reaction between the anions (BH4) and Ac ure 3 and Supporting Information), relevant data are listed in Table 1.  Table 2.  Based on the electrochemical data E 1/2 (H +/0 ) = −2.307 (V vs. Fc +/0 ) and E 1/2 (H 0/− ) = −1.137 (V vs. Fc +/0 ) and ∆H(Ac-tempo + ), we substituted the thermodynamic data (directly measured) into Equations (4)-(7) to obtain the hydride affinity ∆H H -A (X) and hydrogen-atom affinity ∆H HA (X) of unsaturated carbonyl compounds as well as the hydrogen-atom affinity ∆H HA (X •− ) and proton affinity ∆H PA (X •− ) of the corresponding radical anions. All the data are summarized in Table 2.  Table 2 indicates that the hydride affinity of the carbonyl group in these three types of compounds is generally small, with absolute values roughly distributing in the range of −18.77-−52.74 kcal/mol. The corresponding oxygen anions formed by carbonyl compounds accepting hydride anions are good hydride donors, which can reduce most hydride acceptors. However, hydride donors with moderate strength such as BNAH (64.2 kcal/mol) or HEH (69.3 kcal/mol) [25] can barely reduce the carbonyl groups in α,β-unsaturated ketones or saturated ketones.
In comparison of the hydride affinity of carbonyl groups in three types of unsaturated compounds with the same distal substituent (R = H), these data are found to increase in this order: |∆H H -A (A)| > |∆H H -A (B)| > |∆H H -A (AH 2 )|. The absolute value of the hydride affinity of the saturated carbonyl group is much smaller than that of two unsaturated carbonyl compounds (A and B); therefore, the presence of a conjugated structure increases the molecular stability, and alcohol anion attached double bone is more unstable than oxygen anions and more likely to lose a hydride anion.
A comparison of B and BH 2 with the same substituent shows that the value of |∆H H -A (A)-∆H H -A (AH 2 )| (conjugation energy) is from 11.63 to 15.54 kcal/mol, and electrondonating groups increase this difference. Since benzyl can still transmit the substituent effect of the benzene ring para-position, the hydride affinity varies as much for BH 2 as for A and B when the substituent is not conjugated with the carbonyl. The carbonyl groups in A and B are all in the conjugated system, and the change of the substituent position may cause a slight effect on the hydride affinity of the carbonyl group in the unsaturated system. Therefore, the difference between the two values is small (approximately 2 kcal/mol). Table 2 indicates that ∆H H -A (X) of the C=C double bond in the conjugated system is in the range of −27.66~−40.08 kcal/mol. The absolute value of ∆H H -A (A) 4 (the hydride affinity for the carbon-carbon double bond of A) is higher than that of ∆H H -A (B) 4 of B, and the absolute value of their difference is slightly higher than the absolute value of the difference in hydride affinity between corresponding carbonyl compounds ( Table 2). This is due to the fact that the distance between the substituent and the reaction site in A is shorter than that in B, and the distance between the substituent and the active center affects the corresponding reactivity; the closer the distance is, the greater the effect will be.

Hydride Affinity of Carbon-Carbon Double Bond in α,β-Unsaturated Carbonyl Compounds
A comparison of hydride affinity between carbon-carbon double bond in α,β-unsaturated carbonyl compounds and benzylic carbocation (e.g., hydride affinities of 4-CH 3 [26]), shows that the absolute value of the former is much smaller than that of latter. Because the latter releases energy by forming a new C-H σbond, while the former involves not only the formation process of the C-H σbond, but also the breaking process of the C=C πbond, which requires a large amount of absorbed energy.

Selective Reduction of α,β-Unsaturated Carbonyl Compound
To quantitatively examine the selectivity of the hydride addition process, two types of hydride affinities analyzed, and the following inferences are drawn.
First, the conjugated system makes these compounds (A and B) relatively stable, while the unsaturated bonds are relatively weak in accepting hydride ions, and they work in a range of −27.66~−52.74 kcal/mol. It is difficult for BNAH, HEH, etc., to reduce carbonyl groups or carbon-carbon double bonds in α,β-unsaturated carbonyl compounds. The energy released by any hydride acceptor to bond with a hydride ion is not sufficient to compensate for the energy consumed by any hydride donor to dissociate a hydride ion. Therefore, the reaction may be induced by using strong reducing agents (Figure 4) including NaBH 4 , LiAlH 4 [27], etc., or by changing the reaction conditions after the addition of catalysts [28]. In this study, HEH is used as the hydride donor to reduce α,β-unsaturated carbonyl compounds (Scheme 3), Pd/C catalyst is added, and the reaction is carried out under the heating reflux condition.
Molecules 2023, 28, x FOR PEER REVIEW 7 of 13 groups or carbon-carbon double bonds in α,β-unsaturated carbonyl compounds. The energy released by any hydride acceptor to bond with a hydride ion is not sufficient to compensate for the energy consumed by any hydride donor to dissociate a hydride ion. Therefore, the reaction may be induced by using strong reducing agents ( Figure 4) including NaBH4, LiAlH4 [27], etc., or by changing the reaction conditions after the addition of catalysts [28]. In this study, HEH is used as the hydride donor to reduce α,β-unsaturated carbonyl compounds (Scheme 3), Pd/C catalyst is added, and the reaction is carried out under the heating reflux condition. Second, the absolute value of the hydride affinity of the carbonyl group is generally larger than that of the corresponding carbon-carbon double bond. Thermodynamically, the carbonyl group is better than the double bond, that is, the carbonyl group is reduced first. However, their difference is not large, so the selective reduction of such a molecule is only marginally controllable.
Third, oxygen contains a lone pair of electrons and is more electronegative than carbon in an unsaturated system. Adding protic or Lewis acids and metal ions to change the polarity of the carbonyl group may induce the reaction to occur in a directional manner. For example, the hydride affinity of NaBH4 is close to that of both types of unsaturated bonds in the unsaturated system. However, the electron deficiency of B makes this hydride donor easily bond with electronegative O atoms [29], so NaBH4 mainly demonstrates 1,2-position addition during the reduction of α,β-unsaturated carbonyl compounds, or the reaction site may be activated by adding CeCl3 [30].
Finally, the selectivity of the reduction reaction can be improved by introducing electron-withdrawing substituents. As the electron-withdrawing capability of the substituent increases, the difference between the hydride affinities of the carbonyl group and the C=C bond of α,β-unsaturated carbonyl compounds increases.

Hydrogen-Atom Affinity of α,β-Unsaturated Carbonyl Compounds
Studies on the hydrogen-atom affinity lead to the following inferences. First, the hydrogen atom affinity ∆HHA(X) of the three types of carbonyl compounds is in the range of −4.93~−40.61 kcal/mol, indicating that they are all very weak hydrogen atom acceptors.
Second, in the three types of compounds, |∆HH-A(X)| is higher than the corresponding |∆HHA(X)|. Among them, the difference between A and B is approximately 10 kcal/mol, and the difference of B and BH2 is approximately 14 kcal/mol. Third, hydrogen affinity of A at position 2 |∆HHA(A2)| > hydrogen affinity of B at position 2 |∆HHA(B2)| >> hydrogen affinity of BH2 at position 2 |∆HHA(BH22)|, the presence of the unsaturated system increases the ability of carbonyl compounds to accept hydrogen Molecules 2023, 28, x FOR PEER REVIEW 7 groups or carbon-carbon double bonds in α,β-unsaturated carbonyl compounds. The ergy released by any hydride acceptor to bond with a hydride ion is not sufficient to c pensate for the energy consumed by any hydride donor to dissociate a hydride ion. Th fore, the reaction may be induced by using strong reducing agents ( Figure 4) inclu NaBH4, LiAlH4 [27], etc., or by changing the reaction conditions after the addition of c lysts [28]. In this study, HEH is used as the hydride donor to reduce α,β-unsaturated bonyl compounds (Scheme 3), Pd/C catalyst is added, and the reaction is carried out un the heating reflux condition. Second, the absolute value of the hydride affinity of the carbonyl group is gene larger than that of the corresponding carbon-carbon double bond. Thermodynamic the carbonyl group is better than the double bond, that is, the carbonyl group is redu first. However, their difference is not large, so the selective reduction of such a mole is only marginally controllable.
Third, oxygen contains a lone pair of electrons and is more electronegative than bon in an unsaturated system. Adding protic or Lewis acids and metal ions to change polarity of the carbonyl group may induce the reaction to occur in a directional man For example, the hydride affinity of NaBH4 is close to that of both types of unsatur bonds in the unsaturated system. However, the electron deficiency of B makes this dride donor easily bond with electronegative O atoms [29], so NaBH4 mainly demonstr 1,2-position addition during the reduction of α,β-unsaturated carbonyl compound the reaction site may be activated by adding CeCl3 [30].
Finally, the selectivity of the reduction reaction can be improved by introducing tron-withdrawing substituents. As the electron-withdrawing capability of the substit increases, the difference between the hydride affinities of the carbonyl group and the bond of α,β-unsaturated carbonyl compounds increases.

Hydrogen-Atom Affinity of α,β-Unsaturated Carbonyl Compounds
Studies on the hydrogen-atom affinity lead to the following inferences. First, the hydrogen atom affinity ∆HHA(X) of the three types of carbonyl compou is in the range of −4.93~−40.61 kcal/mol, indicating that they are all very weak hydro atom acceptors.
Second, in the three types of compounds, |∆HH-A(X)| is higher than the correspo ing |∆HHA(X)|. Among them, the difference between A and B is approximately kcal/mol, and the difference of B and BH2 is approximately 14 kcal/mol.
Third, hydrogen affinity of A at position 2 |∆HHA(A2)| > hydrogen affinity of position 2 |∆HHA(B2)| >> hydrogen affinity of BH2 at position 2 |∆HHA(BH22)|, the pres of the unsaturated system increases the ability of carbonyl compounds to accept hydro Second, the absolute value of the hydride affinity of the carbonyl group is generally larger than that of the corresponding carbon-carbon double bond. Thermodynamically, the carbonyl group is better than the double bond, that is, the carbonyl group is reduced first. However, their difference is not large, so the selective reduction of such a molecule is only marginally controllable.
Third, oxygen contains a lone pair of electrons and is more electronegative than carbon in an unsaturated system. Adding protic or Lewis acids and metal ions to change the polarity of the carbonyl group may induce the reaction to occur in a directional manner. For example, the hydride affinity of NaBH 4 is close to that of both types of unsaturated bonds in the unsaturated system. However, the electron deficiency of B makes this hydride donor easily bond with electronegative O atoms [29], so NaBH 4 mainly demonstrates 1,2position addition during the reduction of α,β-unsaturated carbonyl compounds, or the reaction site may be activated by adding CeCl 3 [30].
Finally, the selectivity of the reduction reaction can be improved by introducing electron-withdrawing substituents. As the electron-withdrawing capability of the substituent increases, the difference between the hydride affinities of the carbonyl group and the C=C bond of α,β-unsaturated carbonyl compounds increases.

Hydrogen-Atom Affinity of α,β-Unsaturated Carbonyl Compounds
Studies on the hydrogen-atom affinity lead to the following inferences. First, the hydrogen atom affinity ∆H HA (X) of the three types of carbonyl compounds is in the range of −4.93~−40.61 kcal/mol, indicating that they are all very weak hydrogen atom acceptors.
Second, in the three types of compounds, |∆H H -A (X)| is higher than the corresponding |∆H HA (X)|. Among them, the difference between A and B is approximately 10 kcal/mol, and the difference of B and BH 2 is approximately 14 kcal/mol. Third, hydrogen affinity of A at position 2 |∆H HA (A 2 )| > hydrogen affinity of B at position 2 |∆H HA (B 2 )| >> hydrogen affinity of BH 2 at position 2 |∆H HA (BH 22 )|, the presence of the unsaturated system increases the ability of carbonyl compounds to accept hydrogen atoms. If the reduction reaction starts with the transfer of hydrogen atoms, the carbonyl group is easier to be reduced than this group in the saturated system. Fourth, the difference ∆∆H HA (B-BH 2 ) of the hydrogen atom affinity of the carbonyl group is not far from the difference ∆∆H H -A (B-BH 2 ) of hydride affinity in B and AH 2 , which indicates that the effect of the conjugation system on the hydride affinity and hydrogen atom affinity of carbonyl groups is comparable, and the conjugation energy of the conjugated structure is approximately 15 kcal/mol.
Finally, the absolute value of the hydrogen atom affinity of the carbonyl group in the same compound is higher than that of the corresponding C=C bond, which is consistent with the trend of hydride affinity. The addition of hydrogen atoms to unsaturated bonds is similar to the addition of hydride ions. Hydrogen atoms are partially electronegative. However, because of their relatively small charge density, hydrogen atoms are less selective for reduction compared to hydride ions. Therefore, the difference in hydride affinity between the two types of unsaturated bonds in the same compound (∆∆H H -A (X 2 − X 4 )) is slightly greater than their difference in hydrogen atom affinity (∆∆H HA (X 2 − X 4 )).

Hydrogen Atom Affinity and Proton Affinity of Radical Anion Intermediate in α,β-Unsaturated Carbonyl Compounds
The experimental results in Table 2 show that the hydrogen atom affinity ∆H HA (X •− ) of the radical anion intermediates in the three types of carbonyl compounds falls in the range of −45.26 to −67.39 kcal/mol. They are all large absolute values, making them good hydrogen atom acceptors.
The hydrogen atom affinity of the saturated ketone radical anion is very similar to the values of the other two types of compounds (A and B), indicating that the electrons activate the carbonyl group and weaken the π-bond, and the activation of the unsaturated system by electrons is less than that of the saturated system. A comparison of hydrogen atom affinity between the radical anions in position 2 and position 4 in the same compound indicates that the latter is still large in value, although its absolute value is reduced compared to the former. It can be seen that an electron obtained by the neutral compound is more likely to be added to the carbonyl group, and the radical anion formed is more inclined to accept a hydrogen atom to form a negative oxygen ion than a carbanion. Table 2 shows that the proton affinity ∆H PA (X Generally, the absolute value of hydrogen atom affinity in radical anion X •− is approximately 38 kcal/mol greater than that of the corresponding proton affinity, which means that the radical anion is much more capable of accepting hydrogen atoms than protons under the same conditions. Therefore, for the electron transfer-initiated hydride reduction reactions of such compounds, electron-hydrogen atom (e − -H • ) transfer is most likely subject to the multi-step hydride transfer mechanism.

Single-Electron Reduction Potentials of α,β-Unsaturated Carbonyl Compounds
The data in Table 1 show that the single-electron reduction potentials of these three types of carbonyl compounds are negative and large in value between −1.771 and −2.595 (V vs. Fc +/0 ). Because these compounds are extremely weak single-electron acceptors, it is difficult for electron-initiated hydride transfer to occur.
For the same substituent, the reduction potentials of A and B are very close, and their values are both higher than that of BH 2 , indicating that the presence of the conjugated system enhances the ability of compounds to accept electrons, and newly added electrons can be dispersed in the conjugated system.
Both A and B are irreversible reduction potentials, while BH 2 is a partially reversible reduction potential ( Figure 5). The radical anion formed by unsaturated carbonyl compounds accepting one electron is unstable.
(V vs. Fc +/0 ). Because these compounds are extremely weak single-electron acceptors, it is difficult for electron-initiated hydride transfer to occur.
For the same substituent, the reduction potentials of A and B are very close, and their values are both higher than that of BH2, indicating that the presence of the conjugated system enhances the ability of compounds to accept electrons, and newly added electrons can be dispersed in the conjugated system. Both A and B are irreversible reduction potentials, while BH2 is a partially reversible reduction potential ( Figure 5). The radical anion formed by unsaturated carbonyl compounds accepting one electron is unstable.

Single-Electron Reduction Potentials of Radical Intermediate in α,β-unsaturated Carbonyl Compounds
The single-electron reduction potentials of a radical intermediate in carbonyl compounds (A, B and AH2) is obtained by detecting the oxidation potentials of the corresponding anions. Given two types of unsaturated bonds in unsaturated carbonyl compounds, corresponding carbon and oxygen radical intermediates can be generated. The reduction potentials of radical intermediates in these three types of carbonyl compounds are in the range of −0.486 to −0.787 (V vs. Fc +/0 ), indicating that the free radicals of these compounds are weak electron acceptors, and only partially stable to certain extent. Compared with BNAH (0.219 V) and HEH (0.479 V), they have a high electron-donating capacity and can be used as a single-electron reducing agent.
The reduction potentials of unsaturated ketone radical intermediates is lower than that of corresponding saturated ketone radical intermediates, with a difference of more than 100 mV. The presence of the conjugated system stabilizes radical intermediates and reduces their electron-accepting capability. The reduction potentials of carbon radical intermediates at position 3 in the same compound is less than that of oxygen radical intermediates at position 1, e.g., Ered(AH2) < Ered(A´H2), which may be due to the fact that carbon radical intermediates at position 3 can form more stable "resonant" oxygen radical intermediates (Scheme 4), while oxygen radical intermediates at position 1 cannot resonate with the benzene ring double bond due to the blocking of the saturated carbon bond. The reduction potentials of A and B radical intermediates are very close to each other, indicating that the change in the position of the substituent has little effect on the reduction potentials of radical intermediates.

Single-Electron Reduction Potentials of Radical Intermediate in α,β-Unsaturated Carbonyl Compounds
The single-electron reduction potentials of a radical intermediate in carbonyl compounds (A, B and AH 2 ) is obtained by detecting the oxidation potentials of the corresponding anions. Given two types of unsaturated bonds in unsaturated carbonyl compounds, corresponding carbon and oxygen radical intermediates can be generated. The reduction potentials of radical intermediates in these three types of carbonyl compounds are in the range of −0.486 to −0.787 (V vs. Fc +/0 ), indicating that the free radicals of these compounds are weak electron acceptors, and only partially stable to certain extent. Compared with BNAH (0.219 V) and HEH (0.479 V), they have a high electron-donating capacity and can be used as a single-electron reducing agent.
The reduction potentials of unsaturated ketone radical intermediates is lower than that of corresponding saturated ketone radical intermediates, with a difference of more than 100 mV. The presence of the conjugated system stabilizes radical intermediates and reduces their electron-accepting capability. The reduction potentials of carbon radical intermediates at position 3 in the same compound is less than that of oxygen radical intermediates at position 1, e.g., E red (AH 2 ) < E red (A H 2 ), which may be due to the fact that carbon radical intermediates at position 3 can form more stable "resonant" oxygen radical intermediates (Scheme 4), while oxygen radical intermediates at position 1 cannot resonate with the benzene ring double bond due to the blocking of the saturated carbon bond. The reduction potentials of A and B radical intermediates are very close to each other, indicating that the change in the position of the substituent has little effect on the reduction potentials of radical intermediates.

Single-Electron Reduction Potentials of Radical Inter Carbonyl Compounds
The single-electron reduction potentials of a radical pounds (A, B and AH2) is obtained by detecting the oxidati ing anions. Given two types of unsaturated bonds in uns corresponding carbon and oxygen radical intermediates c potentials of radical intermediates in these three types of range of −0.486 to −0.787 (V vs. Fc +/0 ), indicating that the fr are weak electron acceptors, and only partially stable to BNAH (0.219 V) and HEH (0.479 V), they have a high elec be used as a single-electron reducing agent.
The reduction potentials of unsaturated ketone radi that of corresponding saturated ketone radical intermedi than 100 mV. The presence of the conjugated system stab reduces their electron-accepting capability. The reduction termediates at position 3 in the same compound is less th mediates at position 1, e.g., Ered(AH2) < Ered(A´H2), which m radical intermediates at position 3 can form more stable " mediates (Scheme 4), while oxygen radical intermediate with the benzene ring double bond due to the blocking of reduction potentials of A and B radical intermediates are v ing that the change in the position of the substituent has l tentials of radical intermediates.

Establishment of Molecule ID Card for Carbonyl Compounds
Can the chemical properties of organic molecules and reaction intermediates be shown on a single spectrum? To this end, in 2010, we proposed the concept of the "Molecule ID Card" for organic compounds [31]; it contains the thermodynamic and electrochemical data related to the compound, through which we can visually and quantitatively predict the chemical properties of the organic compounds and its reaction intermediates, such as its pH value, electrophilicity, nucleophilicity, and redox capacity. We can also predict the reaction process and possible products and resolve the reaction mechanism for the purpose of designing a variety of chemical reactions.
Based on the abovementioned four thermodynamic parameters ∆H H − A (X), ∆H HA (X), ∆H HA (X •− ) and ∆H PA (X •− ), and the electrochemical parameters E red (X) and E red (XH), we created our own "Molecule ID Cards" for the three studied systems ( Figure 6). The reaction processes of all reactants can also be studied according to the "Molecule ID Cards". For the thermodynamic determination herein (Supporting Information), we studied the corresponding hydride transfer process using carbonyl compounds as hydride donors and Ac-tempo + as hydride acceptors.

Conclusions
In this paper, a series of three carbonyl compounds and their corresponding reduction products were synthesized [29,30,[32][33][34]. The reduction potentials of carbonyl compounds and their corresponding radical intermediates were determined by two electrochemical techniques [35], namely CV and OSWV, and the hydride affinity of unsaturated bonds in two types of α,β-unsaturated carbonyl compounds and one type of saturated carbonyl compounds were determined by ITC [36]. We further calculated the hydrogen atom affinity of X and the hydrogen atom affinity and proton affinity of reaction intermediates based on thermodynamic cycles.
The following conclusions were drawn: