Hydride, hydrogen, proton, and electron affinities of imines and their reaction intermediates in acetonitrile and construction of thermodynamic characteristic graphs (TCGs) of imines as a molecule ID card

pubs.acs.org/joc

Hydride, Hydrogen, Proton, and Electron Affinities of Imines and

Their Reaction Intermediates in Acetonitrile and Construction

of Thermodynamic Characteristic Graphs (TCGs) of Imines as

a “Molecule ID Card”

Xiao-Qing Zhu,* Qiao-Yun Liu, Qiang Chen, and Lian-Rui Mei

State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University,

Tianjin 300071, China

xqzhu@nankai.edu.cn

Received October 31, 2009

A series of 61 imines with various typical structures were synthesized, and the thermodynamic

affinities (defined as enthalpy changes or redox potentials in this work) of the imines to abstract

hydride anions, hydrogen atoms, and electrons, the thermodynamic affinities of the radical anions

of the imines to abstract hydrogen atoms and protons, and the thermodynamic affinities of the

hydrogen adducts of the imines to abstract electrons in acetonitrile were determined by using titration

calorimetry and electrochemical methods. The pure heterolytic and homolytic dissociation energies

of the CdN π-bond in the imines were estimated. The polarity of the CdN double bond in the imines

was examined using a linear free-energy relationship. The idea of a thermodynamic characteristic

graph (TCG) of imines as an efficient “Molecule ID Card” was introduced. The TCG can be used to

quantitatively diagnose and predict the characteristic chemical properties of imines and their various

reaction intermediates as well as the reduction mechanism of the imines. The information disclosed in

this work could not only supply a gap of thermodynamics for the chemistry of imines but also

strongly promote the fast development of the applications of imines.

Introduction

additions of imines by various chemical agents, such as

reducing agents,^10-17nucleophilic agents,^18-21neutral radi-

cals,²²and many other agents,^23-26to yield various desired

amines are increasingly drawing the attention of many

researchers, especially synthesis chemists. Since reductions

of imines with hydride agents are the most important reac-

tions and thermodynamics and kinetics of the reductions

are not only dependent on the hydride-donating ability

Imines are one class of the most important and funda-

mental unsaturated organic compounds with a CdN double

bond as their characteristic chemical bond and are exten-

sively present in natural products and many drugs.¹Since

imines have many interesting biological activities^2-7and

roles⁸and can be converted into various very useful amines,

imines have received much intense attention of chemists for a

long time.⁹Especially, in recent years, the reductions and

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DOI: 10.1021/jo902332n

r

Published on Web 12/31/2009

J. Org. Chem. 2010, 75, 789–808 789

2009 American Chemical Society

Zhu et al.

JOCArticle

(hydricity) of hydride agents²⁷but also directly dependent on

the hydride-obtaining ability (hydride affinity) of imines, the

hydride affinities of imines in solution can provide a very

useful thermodynamic clue for chemists to diagnose chemi-

cal activities of imines²⁸and select suitable reducing agents to

reduce imines. However, systematic examination of the past

publications on the chemistry of imines shows that, although

there are many chemists who have devoted much time to the

study of imines, the main attention was limited to the

preparation, reactions, and application of imines. Rather

scant attention has been paid to the study on the funda-

mental thermodynamics of the characteristic reactions of

imines, especially to the determination of hydride affinities of

imines in solution by using experimental method. It is evident

that the terrible lack of the knowledge about the hydride

affinities of imines in solution makes it difficulties to under-

stand the characteristic reactions of imines and to further

develop the applications of imines. In addition, since the

reductions of imines by hydride agents could involve a

multistep hydride transfer mechanism, such as e^--H^þ-e^-,

e^--H, and H-e^-, etc. (Scheme 1), it is evident that, besides

the hydride affinity of imines, hydrogen affinity of imines

(X), hydrogen affinity and proton affinity of the radical

anions of imines (X^•-), reduction potentials of imines (X),

and the hydrogen adducts of imines (XH) as well as the

heterolytic and homolytic CdN π-bond dissociation ener-

gies of imines are also very important and desired thermo-

dynamic parameters for chemists to thoroughly elucidate the

reduction mechanism of imines and quantitatively diagnose

the chemical reactivity of imines and their various reaction

intermediates in solution. Therefore, determination of the

hydride affinity, hydrogen affinity, proton affinity, and

electron affinity of imines and their various reaction inter-

mediates in solution has been a strategic goal in our research

program for a long time. In this paper, the following eight

contributions are provided: (1) 61 typical imines (X) (X =

1-11 in Scheme 2) were designed and synthesized according

to the convenient synthetic strategies. (2) Hydride affinities

of the 61 imines in acetonitrile were determined by using

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790 J. Org. Chem. Vol. 75, No. 3, 2010

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SCHEME 1. Possible Pathways of Reduction of Imines (X) by Hydride Anion

SCHEME 2. Chemical Structures of Examined Imines (X = 1-11)

titration calorimetry. (3) Standard reduction potentials of

the 61 imines (X) and their hydrogen adducts (XH) were

determined by using the electrochemical methods of CV

(cyclic voltammetry) and OSWV (Osteryoung square wave

voltammetry), respectively. (4) Hydrogen affinities of the 61

imines in acetonitrile as well as hydrogen affinities and proton

affinities of the 61 X^•-in acetonitrile were estimated quanti-

tatively by using thermodynamic cycle method according to

Hess’s law. (5) Heterolytic and homolytic CdN π-bond

dissociation energies of some typical imines in acetoni-

trile were safely estimated. (6) Polarity of CdN double bond

in some typical imines were rationally examined according

to the effect of remote substituents on the hydride affinities.

(7) Effects of charge and protonation of imines on the hyd-

ride affinities, on the hydrogen affinities, on the proton

affinities, and on the electron affinities of imines and their

various reaction intermediates were examined quantitatively.

(8) Thermodynamic characteristic graphs (TCGs) of imines

in acetonitrile as a “Molecule ID Card” was proposed,

whichcan be used toquantitatively diagnosethe characteristic

chemical properties of imines and their various reac-

tion intermediates. It is clear that all of these important

experimental results not only supply a gap of the chemical

thermodynamics of imines to satisfy chemists’ growing need

for the thermodynamic parameters but also strongly promote

the fast development of the chemistry and applications of

imines.

Results

The hydride affinity of imines (X) [ΔH_H-A(X)] in this

work is defined as the enthalpy change of the reaction of

imines X with a free hydride anion in acetonitrile to form the

corresponding nitranions XH^-(eqs 1 and 2) at 298 K. The

determinations of the enthalpy changes of the 61 imines to

gain hydride anions in acetonitrile were performed according

to three different experimental strategies: (i) For the imines

which have weak ability to accept a hydride anion (1-8), the

hydride affinities can be obtained according to eq 4, which

were formed from hydride exchange reaction of the corre-

sponding nitranions of imines (1H^--8H^-) with the strong

hydride acceptor N-methylacridinium (AcrH^þClO₄^-) in

acetonitrile (eq 3). In eq 4, ΔH_ris the reaction enthalpy

change of eq 3, which can be determined by using titration

calorimetry (Figure 1); ΔH_H-A(AcrH^þ) is the hydride affi-

nity of AcrH^þin acetonitrile, which is available from our

J. Org. Chem. Vol. 75, No. 3, 2010 791

Zhu et al.

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previous work.²⁹(ii) For the protonated imines (9), the

hydride affinities can be obtained according to eq 6. In

eq 6, ΔH_ris the reaction enthalpy change of eq 5 in acetoni-

trile, which can be determined by using titration calorime-

try; ΔH_H-A(PhXn^þ) is the hydride affinity of PhXn^þ

in acetonitrile, which is available from our previous work.³⁰

(iii) For the salts of imines (10 and 11), the hydride affi-

nities can be obtained according to eq 8. In eq 8, ΔH_ris the

reaction enthalpy changes of eq 7 in acetonitrile, which

can be determined by using titration calorimetry; ΔH_H-A(1)

is the hydride affinity of 1 (G = Cl) in acetonitrile,

which is available from this work. The detailed hydride

affinities of the 61 imines in acetonitrile are summarized in

Table 2.

FIGURE 1. Isothermal titration calorimetry (ITC) for the reaction

heat of carbanion 1dH^-with N-methylacridinium (AcrH^þClO₄

)

in acetonitrile solution at 298 K. Titration was conducted by adding

-

ΔH_{H -A}ðXÞ ¼ H_fðXH^-Þ -½H_fðXÞ þ H_fðH^-Þꢀ

Strategy (i) for 1-8:

ð2Þ

-

5 μL of AcrH^þClO₄(2.0 mM) every 300 s into the acetonitrile

solution containing the carbanion 1dH^-(15 mM), which was

obtained in situ from the reactions of the corresponding saturated

neutral compounds of imines 1dH₂with KH.

ΔH_{H -A}ðXÞ ¼ ΔH_{H -A}ð1, G ¼ C1Þ þ ΔH_r

ð8Þ

ΔH_{H -A}ðXÞ ¼ ΔH_{H -A}ðAcrH^þÞ -ΔH_r

Strategy (ii) for 9:

ð4Þ

Hydrogen affinities of the imines (X) and hydrogen affi-

nities and proton affinities of the radical anions of imines

(X^-•), in this work, are also defined as the enthalpy changes

of the imines (X) to gain a neutral hydrogen atom in

acetonitrile and the enthalpy changes of the radical anions

(X^-•) to gain a neutral hydrogen atom or to gain a proton in

acetonitrile, which can be used to measure hydrogen-obtaining

abilities of X, hydrogen-obtaining abilities of X^•-and

proton-obtaining abilities of X^•-, respectively. In order to

obtain the enthalpy change values of the 61 imines to obtain

hydrogen atom in acetonitrile and the enthalpy change

values of the 61 X^•-to obtain hydrogen atom and to obtain

proton in acetonitrile, three thermodynamic cycles were

constructed according to the chemical process of X to obtain

a hydride anion in acetonitrile (Scheme 3). From the three

thermodynamic cycles, eqs 9-11,³¹were formed according

to Hess’s law. In eqs 9-11, ΔH_H-A(X) and ΔH_HA(X) are the

ΔH_{H -A}ð9Þ ¼ ΔH_{H -A}ðPhXn^þÞ -ΔH_r

Strategy (iii) for 10 and 11:

ð6Þ

(31) It should be pointed out here that we used the term free-energy

change ΔG_etto replace the enthalpy change ΔH_etin eqs 9-11for the electron

transfer processes. The validation of this treatment is that entropies asso-

ciated with electron transfer are negligible, which has been verified by the

previous papers: (a) Arnett, E. M.; Amarnath, K.; Harvey, N. G.; Cheng,

J.-P. J. Am. Chem. Soc. 1990, 112, 344. (b) Li, X.; Zhu, X.-Q.; Zhang, F.;

Wang, X.-X.; Cheng, J.-P. J. Org. Chem. 2008, 130, 2501.

(29) Zhu, X.-Q.; Zhang, M.-T.; Yu, A.; Wang, C.-H.; Cheng, J.-P. J. Am.

Chem. Soc. 2008, 130, 2501–2516.

(30) Zhu, X.-Q.; Liang, H.; Zhu, Y.; Cheng, J.-P. J. Org. Chem. 2008, 73,

8403–8410.

792 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

SCHEME 3. Three Thermodynamic Cycles Were Constructed on the Basis of the Reaction of Imines (X) by Hydride Anion (H^-)

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hydride affinities and hydrogen affinities of X in acetonitrile,

respectively; ΔH_HA(X^•-) and ΔH_PA(X^•-) are the hydrogen

affinities and proton affinities of X^•-in acetonitrile, respec-

tively; E^o_red(XH), E^o_red(X), E^o(H^0/-), and E^o(H^þ/0) are the

standard redox potentials of XH, X, H^þ, and H^-in aceto-

nitrile, respectively. Evidently, it is not difficult to obtain the

hydrogen affinities of X in acetonitrile and the hydrogen

affinities and proton affinities of X^•-in acetonitrile, if only

ΔH_H-A(X), E^o_red(XH), E^o_red(X), E^o(H^0/-), and E^o(H^þ/0) are

available. In fact, ΔH_H-A(X) can be available from the

above work (Table 1), the standard redox potentials of

E^o(H^0/-) and E^o(H^þ/0) can be obtained from literature,³²

E^o_red(XH), E^o_red(X) can be obtained from direct experimen-

tal measurements (Table 1, Figures 2 and 3). The detailed

values of ΔH_HA(X), ΔH_HA(X^•-), and ΔH_PA(X^•-) for the 61

imines in acetonitrile are also summarized in Table 2.

directly reduced into the corresponding amines by some well-

known natural reducing agents, such as NADH, Vitamin C,

etc.; the reason is that these natural reducing agents generally

need at least 50 kcal energy to release hydride anion in water

(e.g., 53.6 kcal for NADH to release hydride anion in

water).³⁴However, when the positively charged imines

(9-11) are examined, it is found that the hydride affinities

of the charged imines (9-11) are generally larger (i.e., more

negative) than -70 kcal, which indicates that these positively

charged imines are generally due to strong or good hydride

acceptors and generally can be directly reduced into the

corresponding amines by some natural reducing agents in

living body.

If the hydride affinities of the imines (1-11) and some

primary benzyl carboniums ions in acetonitrile solution

(e.g., -106, -112, -118, and -121 kcal for 4-CH₃OC₆H_þ₄-

CH₂^þ, 4-MeC₆H₄CH₂^þ, C₆H₅CH₂^þ, and 4-ClC₆H₄CH₂

,

ΔH_HAðXÞ ¼ ΔH_{H -A}ðXÞ -F½E^oðH^{0= -}Þ -E^o_redðXHÞꢀ ð9Þ

respectively)³⁵are compared, it is found that the hydride

affinities of the imines (1-11) are much smaller than those of

the corresponding primary benzyl carboniums ions. Examin-

ing reaction 1 shows that, unlike the reduction of benzyl

carbonium ions by hydride, the reduction of imines by

hydride anion does not only involve the formation of one

new C-H bond to release energy but also involves dissocia-

tion of one old CdN π-bond to consume energy; that is, the

magnitude of hydride affinities of the imines should be equal

to the heterolytic dissociation energy of the newly formed

C-H σ-bond minus the heterolytic dissociation energy of the

broken CdN π-bond. Thus, it is easy to understand why the

hydride affinities of imines in acetonitrile are much smaller

than those of the corresponding primary benzyl carbonium

ions in acetonitrille; the reason is that the reduction of the

primary benzyl carbonium ions by hydride anion does not

involve the heterolytic dissociation of any π-bond.

ΔH_HAðX^-•Þ ¼ ΔH_{H -A}ðXÞ -F½E^oðH^{0= -}Þ -E^o_redðXÞꢀ ð10Þ

ΔH_PAðX^-•Þ ¼ ΔH_HAðX^-•Þ - F½E^oðH^þ=0Þ -E^o_redðXHÞꢀ

ð11Þ

Discussion

Hydride Affinities of the Imines in Acetonitrile. The second

column in Table 2 shows that the hydride affinity scale of the

61 imines (1-11) in acetonitrile ranges from -39.0 to -45.8

kcal for 1, from -37.2 to -45.4 kcal for 2, from -37.4 to

-40.3 kcal for 3, from -35.6 to -43.7 kcal for 4, from -35.7

to -42.1 kcal for 5, from -45.9 to -51.5 kcal for 6, from

-39.2 to -39.8 kcal for 7, from -37.2 to -42.8 kcal for 8,

from -68.8 to -74.7 kcal for 9, from -73.9 to -73.6 kcal for

10, and from -72.9 to -75.5 kcal for 11. By simply compar-

ing the hydride affinities of the imines (1-11) with the same

substituent (e.g., G = H in Figure 4), it is found that the

hydride affinity of the imines decreases in the follow-

ing order: 10a (-73.9 kcal, G=CH₃rather than H)>11c

(-73.5 kcal)>9c (-70.9 kcal)>6c (-47.5 kcal)>1c (-40.8

kcal)=2c (-40.8 kcal)>7a (-39.2 kcal)>3c (-38.9 kcal)=

4c (-38.9 kcal) > 8c (-38.1 kcal) > 5c (-37.1 kcal), that is,

the hydride-obtaining abilities of the imines are decreased in

the order: 10a > 11c > 9c > 6c > 1c (2c) > 7a > 3c (4c) >

8c>5c.³³If the neutral imines (1-8) are examined, it is found

that the hydride affinities are generally smaller (i.e., more

positive) than -50 kcal, which indicates that the neutral

imines generally belong to very weak hydride acceptors, and

in living body, these neutral imines generally could not be

In order to estimate the CdNπ-bond heterolytic dissociation

energies of the imines in acetonitrile, the hydride affinities of

some benzyl cations in acetonitrile solution can be regarded as

the approximations of the releasing energy due to the new C-H

σ-bond formation after the CdN π-bond heterolytic dissocia-

tion when the imines 1, 3, 8, and 9 were reduced by hydride

anion; the reason is that the structure of the benzyl cation is

the kindred efficient structure of imines 1, 3, 8, and 9 when

the CdN π-bond was broken by heterolytic dissociation.³⁶

(34) Zhu, X.-Q.; Yang, Y.; Zhang, M.; Cheng, J.-P. J. Am. Chem. Soc.

2003, 125, 15298–15299.

(35) Cheng, J.-P.; Handoo, K. L.; Parker, V. D. J. Am. Chem. Soc. 1993,

115, 2655.

(36) Although the structures of the benzylic cations formed from imines

by π-bond dissociation of CdN are different from the structures of the

corresponding benzyl cations, the relative efficient positive charges on the

center carbon atom in the two cases should be quite close to each other,

the reason is that the F values (F is inductive parameter) of R(Ph)N^-are quite

small, which could be close to zero (the F value of H atom).

(32) Wayner, D. D. M.; Parker, V. D. Acc. Chem. Res. 1993, 26, 287.

(33) Unless specified, the magnitude of the hydride affinities in this paper

indicates the absolute value rather than the pure mathematical values

(negative values) for the sake of convention.

J. Org. Chem. Vol. 75, No. 3, 2010 793

Zhu et al.

JOCArticle

TABLE 1. Reaction Enthalpy Changes of Equations 3, 5, and 7 in Acetonitrile at 298 K (kcal) and Reduction Potentials of X and XH in Acetonitrile at

298 K (V vs Fc^þ/0

)

E_red(X)^b

E_red(XH)^b

OSWV

E_red(X)^b

E_red(XH)^b

imines (X)

ΔH_r^a

CV

OSWV

CV

imines (X)

ΔH_r^a

CV

OSWV

CV

OSWV

1(a-g)

CH₃O (a)

CH₃(b)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

NO₂(g)

6(a-f)

H (c)

Cl (d)

Br (e)

CF₃(f)

-35.2

-34.6

-42.1

-41.2

-40.3

-38.5

-39.0

-36.8

-35.3

-1.974

-1.949

-2.444

-2.415

-2.363

-2.295

-2.290

-2.152

-2.021

-1.933

-1.908

-2.406

-2.377

-2.325

-2.257

-2.252

-2.114

-1.983

-0.821

-0.801

-0.529

-0.519

-0.488

-0.432

-0.430

-0.354

-0.292

-0.790

-0.771

-0.572

-0.562

-0.531

-0.475

-0.473

-0.397

-0.335

-33.6

-31.5

-31.8

-29.6

-1.905

-1.852

-1.850

-1.751

-1.864

-1.811

-1.809

-1.710

-0.766

-0.731

-0.730

-0.706

-0.735

-0.700

-0.699

-0.677

7(a,b)

H (a)

i-C₃H₇(b)

-41.9

-41.3

-2.480

-2.490

-2.446

-2.450

-0.670

-0.566

-0.695

-0.595

8(a-g)

-44.4

-44.0

-43.0

-41.6

-41.5

-39.9

-38.3

-2.663

-2.632

-2.580

-2.505

-2.507

-2.422

-2.341

-2.611

-2.580

-2.528

-2.453

-2.455

-2.370

-2.289

-0.469

-0.463

-0.449

-0.416

-0.417

-0.382

-0.354

-0.497

-0.491

-0.479

-0.444

-0.445

-0.411

-0.382

p-CH₃O (a)

p-CH₃(b)

H (c)

p-Cl (d)

p-Br (e)

2(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-43.9

-42.9

-40.3

-38.2

-38.4

-35.7

-2.451

-2.425

-2.363

-2.301

-2.282

-2.144

-2.413

-2.387

-2.325

-2.263

-2.244

-2.106

-0.554

-0.542

-0.488

-0.396

-0.395

-0.300

-0.597

-0.585

-0.531

-0.439

-0.438

-0.343

p-CF₃(f)

p-NO₂(g)

9(a-f)

p-CH₃O (a)

p-CH₃(b)

H (c)

p-Cl (d)

m-NO₂(e)

p-NO₂(f)

3(a-e)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

NO₂(e)

-28.0

-27.2

-25.9

-25.0

-22.9

-22.1

-1.011

-0.964

-0.885

-0.806

-0.683

-0.665

-0.980

-0.932

-0.856

-0.775

-0.655

-0.634

0.741

0.750

0.762

0.776

0.806

0.810

0.712

0.721

0.731

0.745

0.776

0.781

-43.7

-42.9

-42.2

-40.8

-37.2

-2.654

-2.634

-2.576

-2.447

-2.095

-2.606

-2.586

-2.530

-2.394

-2.018

-0.667

-0.647

-0.611

-0.564

-0.472

-0.713

-0.687

-0.659

-0.607

-0.514

4(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

10(a-c)

CH₃(a)

C₂H₅(b)

n-C₃H₇(c)

-45.5

-44.4

-42.2

-40.7

-40.4

-37.4

-2.674

-2.638

-2.576

-2.444

-2.434

-2.331

-2.624

-2.596

-2.530

-2.394

-2.384

-2.285

-0.711

-0.672

-0.611

-0.550

-0.546

-0.468

-0.760

-0.712

-0.659

-0.596

-0.592

-0.512

-31.3

-31.1

-31.0

-0.959

-0.963

-0.965

-0.924

-0.928

-0.930

0.150

0.131

0.158

0.115

0.095

0.119

11(a-g)

p-CH₃O (a)

p-CH₃(b)

H (c)

p-Cl (d)

p-Br (e)

-30.3

-30.5

-30.9

-31.5

-31.6

-32.2

-32.9

-0.953

-0.949

-0.944

-0.938

-0.936

-0.926

-0.919

-0.927

-0.923

-0.918

-0.912

-0.910

-0.900

-0.893

0.237

0.243

0.257

0.276

0.278

0.303

0.325

0.204

0.210

0.224

0.243

0.245

0.270

0.292

5(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-45.4

-45.0

-44.1

-43.1

-43.6

-41.0

-2.406

-2.385

-2.344

-2.300

-2.295

-2.215

-2.371

-2.350

-2.309

-2.265

-2.260

-2.180

-0.563

-0.541

-0.509

-0.476

-0.475

-0.395

-0.603

-0.581

-0.549

-0.516

-0.515

-0.435

p-CF₃(f)

p-NO₂(g)

^aΔH_robtained from the reaction heats of eqs 3, 5, and 7 by switching the sign; the latter were measured by titration calorimetry in acetonitrile at 298 K.

The data given in kcal were average values of at least three independent runs. The reproducibility is (0.5 kcal. ^bMeasured by CV and OSWV methods in

acetonitrile at 298 K, the unit in volts vs Fc^þ/0and reproducible to 5 mV or better.

Thus, the CdN π-bond heterolytic dissociation enthalpies of 1,

3, 8, and 9 in acetonitrile solution can be estimated according to

the difference in the hydride affinities of the imines and the

corresponding benzyl cations. The detailed CdN π-bond het-

erolytic dissociation enthalpies of imines 1, 3, 8, and 9 in

acetonitrile are listed in Table 3. By using the similar method,

the homolytic CdN π-bond dissociation enthalpies of 1, 3, 8,

for 3, from 70.3 to 86.2 kcal for 8, and from 38.2 to 54.3 kcal

for 9; the homolytic CdN π-bond dissociation enthalpies of

imines 1, 3, 8, and 9 range from 62.6 to 61.3 kcal for 1, from 61.0

to 59.0 kcal for 3, from 66.8 to 63.4 kcal for 8, and from 62.3 to

58.0 kcal for 9. Since the heterolytic CdN π-bond dissociation

enthalpies of the neutral imines (1, 3, and 8) are quite large, it is

not difficult to understand why the hydride affinities of the

neutral imines are generally quite smaller. However, if the

hydride affinities and the heterolytic CdN π-bond dissociation

enthalpies of imines 1a and 1g are examined together (see

Figure 5), an illegitimate result can be surprisingly found that,

for the neutral imines, the larger the heterolytic CdN π-bond

dissociation energy of the imines, the larger the hydride affinity

of the imines. The reason could be that the large CdN π-bond

heterolytic dissociation energy can result in the larger releasing

energy to form the new C-H σ-bond.

and 9 and (CdN)^-•π-bond dissociation enthalpies of 1^-•, 3^-•

^-•, and 9^-•can also be estimated;³⁷the detailed results are also

,

8

listed in Table 3. From Table 3, it is clear that the heterolytic

CdN π-bond dissociation enthalpies of imines 1, 3, 8, and 9

range from 68.0 to 83.2 kcal for 1, from 69.6 to 85.1 kcal

(37) The hydrogen affinity of benzylic cation in acetonitrile is 88.0 kcal/

mol. See: Berkowitz, J. Ellison, G. B.; Gutman, D. J. Phys. Chem. 1994, 98,

2744-2765. Since the remote substituent effect on the hydrogen affinity of

benzyl cation is quite small (Luo, Y.-R. Handbook of Bond Dissociation

Energies, 3rd ed.; Science Press, ISBN: 7-03-014707-3; pp 35-36 (Chinese

Version, 2005), hydrogen affinity of benzyl cation in acetonitrile herein is

used to replace the hydrogen affinities of the other remote substituted

benzylic cations to estimate the CdN π-bond homolytic dissociation energies

of the other remote substituted imines in acetonitrile.

From Table 3, if the heterolytic CdN π-bond dissociation

energies and the corresponding homolytic CdN π-bond

dissociation energies are compared, it is found that,

when the imine is neutral, the heterolytic CdN π-bond

794 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

JOCArticle

the 61 imines (1-11) in acetonitrile ranges from -26.0 to

-27.4 kcal for 1, from -24.8 to -27.1 kcal for 2, from -27.6

to -29.6 kcal for 3, from -26.9 to -29.3 kcal for 4, from

-23.2 to -25.9 kcal for 5, from -37.9 to -40.9 kcal for 6,

from -27.3 to -29.0 kcal for 7, from -22.0 to -25.4 kcal for

8, from -26.2 to -30.5 kcal for 9, from -44.7 to -45.3 kcal

for 10, and from -42.0 to -42.6 kcal for 11. If the hydrogen

affinities of the 11 types of the imines (1-11) are compared, it

is found that when the substituent is same (e.g., G = H) the

hydrogen affinities of the imines decrease in the following

order: 10a (-45.1 kcal, G = CH₃) > 11c (-42.2 kcal) > 6c

(-38.2 kcal) > Hantzch pyridine 7c (-29.0 kcal) > 3c

(-27.9 kcal) > protonated Hantzsch pyridine 9c (-27.8

kcal) > 1c (-26.8 kcal) > 5c (-23.6 kcal) > 4-phenyl

Hantzsch pyridine 8c (-22.9 kcal) (see Figure 6). Since the

hydrogen affinities of the 61 imines all are quite small,

generally much smaller than the corresponding hydride

affinities, the imines whether charged or not should belong

to very weak hydrogen atom acceptors. This result suggests

that, when the imines are reduced by a hydride anion, it is

unlikely that the hydride transfer was initiated by hydrogen

atom transfer. If hydrogen affinity of Hantzsch pyridine 8c

(-22.9 kcal) and the corresponding protonated species 9c

(9c = 8cH^þ) (-27.8 kcal) are compared, it is interesting to

find that, unlike the large difference of the two hydride

affinities, the difference of the corresponding hydrogen

affinities is small; that is, the protonation effect on the

hydrogen affinities of imines is not remarkable, and the main

reason could be that the hydrogen atom does not carry

charge. This finding can be used to diagnose the mechanism

for the reduction of imines by altering the acidity of reaction

medium; that is, if the reductions of imines are initiated by

hydrogen atom transfer, the effect of the acidity of reaction

medium on the reaction rate should not be quite large, but if

the reductions of imines are reduced by hydride anion in one

step, the effect of the acidity of reaction medium on the

reaction rate should be quite large.

FIGURE 2. Cyclic voltammetry (CV) and Osteryoung square wave

voltammetry (OSWV) of 10a in deaerated acetonitrile containing

0.1 M n-Bu₄NPF₆as supporting electrolyte. Dashed line: CV graph

(sweep rate = 0.1 V/s). Solid line: OSWV graph.

Hydrogen Affinities and Proton Affinities of Neutral and

Charged Radical Intermediates of Imines in Acetonitrile. As

stated in the Introduction, if reductions of imines (X) by

hydride donors were initiated by single-electron transfer, the

corresponding charged or uncharged radicals (X^•-) as incipient

reaction intermediates could be formed. Since hydrogen affi-

FIGURE 3. Cyclic voltammetry (CV) and Osteryoung square wave

voltammetry (OSWV) of 1gH^-in deaerated acetonitrile containing

0.1 M n-Bu₄NPF₆as supporting electrolyte. Dashed line: CV graph

(sweep rate = 0.1 V/s). Solid line: OSWV graph.

dissociation enthalpy is quite greater than the corresponding

homolytic CdN π-bond dissociation enthalpy, but when the

imine is positively charged, the heterolytic CdN π-bond

dissociation enthalpy is remarkably smaller than the corre-

sponding homolytic CdN π-bond dissociation enthalpy.

This result indicates that, in the addition reaction of CdN

double bond of imines, the radical mechanism is preferable

to the ionic mechanism for the neutral imines, but for the

positively charged imines, the case is just reverse.

In addition, from Figure 4, if the hydride affinities of

Hantzsch pyridine 8 and the protonated Hantzsch pyridine 9

are compared, it is found that the hydride affinity of proto-

nated Hantzsch pyridine 9 is greater than that of the corre-

sponding neutral Hantzsch pyridine by about 32 kcal, which

means that the protonation of Hantzsch pyridine can greatly

promote its hydride-obtaining ability. This result can be used

to reply why in most cases the reduction of neutral imines

needs catalysts of protonic acids.

nities and proton affinities of the reaction intermediates (X^•-

)

as very important thermodynamic parameters both can be used

to diagnose the chemical activities of the reaction intermediates

and predict the second step reaction for the reductions of

imines, it is necessary to examine and compare the hydrogen

affinities and proton affinities of the reaction intermediates in

acetonitrile. From columns 4 and 5 in Table 2, we found that

the hydrogen affinity scale and proton affinity scale of the

reaction intermediates (X^•-) range from -62.8 to -71.6 kcal

and from 8.3 to -34.5 kcal, respectively. If the hydrogen

affinities of the reaction intermediates X^•-are examined in

detail, it is found that, when the substituent is same (such as,

G = H), the hydrogen affinities of the reaction intermediates

decrease in the order 4c^•-(-71.0 kcal) > 8c^•-(-70.1 kcal)

>7c^•-(-69.3 kcal) > 10a^•-(-69.0 kcal, G = CH₃) > 11c^•-

(-68.5 kcal) > 1c^•-(-68.2 kcal) > 9c^•-(-64.4 kcal) > 6c^•-

(-64.2 kcal) > 5c^•-(-64.1 kcal) (see Figure 7). From Figure 7,

it is clear that whether the reaction intermediates X^•-are

charged (X = 1-8) or uncharged (X = 9-11), the hydrogen

Hydrogen Affinities of the Imines in Acetonitrile. The third

column in Table 2 shows that the hydrogen affinity scale of

J. Org. Chem. Vol. 75, No. 3, 2010 795

Zhu et al.

JOCArticle

TABLE 2. Hydride and Hydrogen Affinities of Imines (X), Hydrogen, and Proton Affinities of X^-•(kcal) and Reduction Potentials of X and XH

(V vs Fc^þ/0) and Activation Coefficients of the CdN π-Bond by Electron Addition (A_e%) in Acetonitrile

imimes (X)

ΔH_H-A(X)^a

ΔH_HA(X)^b

ΔH_HA(X^{•- b}

)

ΔH_PA(X^{•- b}

)

E^o_red(X)^c

E^o_red(XH)^c

A_e%^d

1(a-g)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

-39.0

-39.9

-40.8

-42.6

-42.1

-44.3

-45.8

-26.0

-26.7

-26.8

-27.4

-26.8

-27.3

-68.2

-68.5

-68.2

-68.4

-67.8

-66.8

-65.3

-28.3

-27.3

-26.2

-25.5

-22.8

-19.9

-2.406

-2.377

-2.325

-2.257

-2.252

-2.114

-1.983

-0.572

-0.562

-0.531

-0.475

-0.473

-0.397

-0.335

61.88

61.02

60.70

59.94

60.47

59.13

58.19

CF₃(f)

NO₂(g)

2(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-37.2

-38.2

-40.8

-42.9

-42.7

-45.4

-24.8

-25.5

-26.8

-26.6

-27.1

-66.6

-67.0

-68.2

-68.8

-68.2

-67.7

-27.2

-27.3

-25.8

-25.2

-22.5

-2.413

-2.387

-2.325

-2.263

-2.244

-2.106

-0.597

-0.585

-0.531

-0.439

-0.438

-0.343

62.76

61.94

60.70

61.34

61.00

59.97

3(a-e)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

NO₂(e)

-37.4

-38.2

-38.9

-40.3

-43.9

-27.6

-27.8

-27.9

-28.1

-29.6

-71.2

-71.6

-71.0

-69.2

-64.2

-34.5

-34.3

-33.0

-30.1

-22.9

-2.606

-2.586

-2.530

-2.394

-2.018

-0.713

-0.687

-0.659

-0.607

-0.514

61.23

61.17

60.70

59.39

53.89

4(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-35.6

-36.7

-38.9

-40.4

-40.7

-43.7

-26.9

-27.9

-28.1

-29.3

-69.8

-70.3

-71.0

-69.3

-69.4

-70.1

-34.2

-33.6

-33.0

-29.9

-28.8

-2.624

-2.596

-2.530

-2.394

-2.384

-2.285

-0.760

-0.712

-0.659

-0.596

-0.592

-0.512

61.46

61.73

60.70

59.74

59.51

58.20

5(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-35.7

-36.1

-37.1

-38.0

-37.5

-42.1

-23.4

-23.3

-23.6

-23.7

-23.2

-25.9

-64.1

-64.0

-64.1

-64.0

-63.4

-66.1

-24.9

-24.3

-23.6

-22.7

-22.1

-23.0

-2.371

-2.350

-2.309

-2.265

-2.260

-2.180

-0.603

-0.581

-0.549

-0.516

-0.515

-0.435

63.49

63.59

63.18

62.97

63.41

60.81

6(a-f)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

CF₃(f)

-45.9

-46.5

-47.5

-49.6

-49.3

-51.5

-37.9

-38.1

-38.2

-39.5

-39.2

-40.9

-64.2

-64.3

-64.2

-65.1

-64.8

-64.7

-29.3

-28.9

-28.0

-28.1

-27.7

-27.2

-1.933

-1.908

-1.864

-1.811

-1.809

-1.710

-0.790

-0.771

-0.735

-0.700

-0.699

-0.677

40.97

40.74

40.50

39.32

39.51

36.79

7(a,b)

H (a)

i-C₃H₇(b)

-39.2

-39.8

-29.0

-27.3

-69.3

-70.0

-32.2

-30.6

-2.446

-2.450

-0.695

-0.595

58.15

61.00

8(a-g)

p-CH₃O (a)

p-CH₃(b)

p-H (c)

p-Cl (d)

p-Br (e)

-36.7

-37.1

-38.1

-39.5

-39.6

-41.2

-42.8

-22.0

-22.2

-22.9

-23.5

-23.7

-24.5

-25.4

-70.6

-70.3

-70.1

-69.8

-70.0

-69.6

-69.3

-29.0

-28.5

-28.0

-26.9

-27.1

-25.9

-25.0

-2.611

-2.580

-2.528

-2.453

-2.455

-2.370

-2.289

-0.497

-0.491

-0.479

-0.444

-0.445

-0.411

-0.382

68.84

68.42

67.33

66.33

66.14

64.80

63.35

p-CF₃(f)

p-NO₂(g)

9(a-f)

p-CH₃O (a)

p-CH₃(b)

p-H (c)

p-Cl (d)

m-NO₂(e)

p-NO₂(f)

-68.8

-69.6

-70.9

-71.8

-74.7

-73.9

-26.2

-26.8

-27.8

-28.4

-30.5

-29.8

-65.2

-64.9

-64.4

-63.5

-63.1

-62.8

4.4

5.0

5.6

6.9

8.1

8.3

-0.980

-0.932

-0.856

-0.775

-0.634

-0.655

0.712

0.721

0.731

0.745

0.776

0.781

59.82

58.71

56.83

55.28

52.55

51.66

10(a-c)

CH₃(a)

C₂H₅(b)

n-C₃H₇(c)

-73.9

-73.7

-73.6

-45.1

-45.3

-44.7

-69.0

-68.9

-68.8

-13.2

-13.6

-13.0

-0.924

-0.928

-0.930

0.115

0.095

0.119

34.63

34.25

35.03

796 J. Org. Chem. Vol. 75, No. 3, 2010

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TABLE 2. Continued

imimes (X)

ΔH_H-A(X)^a

ΔH_HA(X)^b

ΔH_HA(X^{•- b}

)

ΔH_PA(X^{•- b}

)

E^o_red(X)^c

E^o_red(XH)^c

A_e%^d

11(a-g)

p-CH₃O (a)

p-CH₃(b)

p-H (c)

p-Cl (d)

p-Br (e)

-72.9

-73.1

-73.5

-74.1

-74.2

-74.8

-75.5

-42.0

-42.1

-42.2

-42.3

-42.4

-42.6

-68.1

-68.2

-68.5

-68.9

-69.0

-69.3

-69.9

-10.2

-10.0

-0.927

-0.923

-0.918

-0.912

-0.910

-0.900

-0.893

0.204

0.210

0.224

0.243

0.245

0.270

0.292

38.33

38.27

38.39

38.61

38.55

38.82

39.06

p-CF₃(f)

p-NO₂(g)

^aΔH_H-A(X) values of imines 1-8 were estimated from eq 4, taking ΔH_H-A(AcrH^þ) = -81.1 kcal from ref 29; ΔH_H-A(X) values of imines 9 were

estimated from eq 6, taking ΔH_H-A(PhXn^þ)=-96.8 kcal;³⁰ΔH_H-A(X) values of imines 10 and 11 were estimated from eq 8, taking ΔH_H-A(1, G=Cl) =

-42.6 kcal. ΔH_HA(X), ΔH_HA(X^•-) and ΔH_PA(X^•-) were estimated from eqs 9-11, respectively, taking E^o(H^þ/0) = -2.307 (V vs Fc^þ/0), E^o(H^0/-) =

b

-1.137 V (V vs Fc^þ/0) (Fc = ferrocene),²³and choosing the reduction potentials of X and XH measured by OSWV method (Table 1) as E^o(X^0/-) and

E^o(XH^0/-), since the values from OSWV were identified to be closer to the corresponding standard redox potentials than the values from CV.^{29 c}The

values derived by OSWV were chosen as the standard reduction potentials of X and XH. ^dDerived from eq 12.

FIGURE 4. Comparison of hydride affinities of some typical neutral and charged imines in acetonitrile.

affinities of X^•-all are quite large (generally more negative than

-62 kcal), which means that whether the reaction intermediates

X^•-are charged or not, they all belong to strong hydrogen

acceptors. When the proton affinities of the reaction intermedi-

ates X^•-are examined in detail, it is found that, when the

substituent is the same (such as, G = H), the proton affinities of

the reaction intermediates X^•-decrease in the order 4^•-(-33.0

kcal) > 7^•-(-32.2 kcal) > 6^•-(-28.0 kcal) ∼ 8^•-(-28.0 kcal)

> 1^•-(-27.3 kcal) > 5^•-(-23.6 kcal) > 10^•-(-13.2 kcal,

G = CH₃) > 11^•-(-10.2 kcal) > 9^•-(5.6 kcal) (see Figure 8),

and from Figure 8, it is found that when the reaction

intermediates X^•-are charged (X = 1-8) the proton affinities

are quite large (generally more negative than -19.0 kcal),

indicating that the negatively charged radicals of imines are

ascribed to strong bases; however, when the reaction inter-

mediates X^•-are uncharged (X = 9-11), the proton affinities

all are quite small (generally more positive than -13.0 kcal);

even more, some of them become positive values (such as 8.3

kcal for X = 9, when G = m-NO₂), indicating that the

uncharged radicals X^•-(X = 9-11) are generally ascribed to

very weak bases, and the basicities of some uncharged reaction

intermediates X^•-, such as X = 9 are weaker than that of

acetonitrile. These results indicate that the charge effect on

proton affinities of the reaction intermediates X^•-is markedly

larger than that on the corresponding hydrogen affinities.

Since the hydrogen affinities of the reaction intermediates

(X), especially the protonated or positively charged imines

(9-11), are reduced by organic hydride donors, such as NADH

or its models, the hydrogen-atom transfer should be much more

favorable than the corresponding proton transfer in the second

step reaction when the reductions of imines were initiated by

electron transfer. As a consequence, we can suggest that the

e^--H^•sequence hydride transfer should be most likely among

the possible multistep mechanisms for the reductions of imines,

especially for the imines with positive charge by organic redu-

cing agents (Scheme 1), if the hydride transfer were initiated by

single-electron transfer.

If the hydrogen affinities of the reaction intermediates X^•-

and their corresponding parent imines (X) were compared

(see columns 3 and 4 in Table 2 or Figures 6 and 7), it is clear

that the hydrogen affinities of the reaction intermediates X^•-

are generally much larger than those of the corresponding

parent imines (X). Since the value of the hydrogen affinity

is dependent not only on the formation energy of new C-H

σ-bond but also on the breaking energy of the old CdN

π-bond, the term that the differences of the two hydrogen

affinities of X^•-and X is divided by the hydrogen affinities of

the reaction intermediates X^•-(eq 12) can be used to scale the

activation degree (or the weaken degree) of the CdN π-bond

in the imines by electron addition. This term, in this work,

may be defined as activation coefficients of CdN π-bond by

electron (A_e% in eq 12). The detailed activation coefficients

of the 61 imines in acetonitrile are summarized in Table 2.

From Table 2, it is clear that when the imines are 1-5 and 8,

the activation coefficients (A_e%) are generally larger than

50% but smaller than 60%; when the imines are 9, the

X

^•-are larger than the corresponding proton affinities by more

than 34.9 kcal for the negatively charged radicals X^•-(X =

1-8) and by more than 55.3 kcal for the uncharged radicals X^•-

(X = 9-11), respectively, it is conceived that when the imines

J. Org. Chem. Vol. 75, No. 3, 2010 797

Zhu et al.

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FIGURE 5. Comparison of potential energy changes for the reductions of imine 1a (G = CH₃O) and imine 1g (G = NO₂) by hydride anion in

acetonitrile.

TABLE 3. Heterolytic and Homolytic Dissociation Energies of CdN

π-Bond in the Imines (kcal)

π-bond activation coefficients (A_e%) are generally larger

than 30% but smaller than 40%. According to the molecular

structure resonance of view,³⁸the objective (or natural)

structure of X^•-could be expressed by several different

subjective (or theoretical) resonance structures, such as

the idealized Lewis-type structure with the CdN π-bond

retained (I), the idealized Lewis-type resonance structure

with CdN π-bond broken (II), and some others. Since the

resonance structure (II) is merely one efficient (or allowable)

Lewis-type structure of X^•-among the resonance structures

of X^•-with CdN π-bond broken to accept hydrogen atom

or proton,³⁹it is conceivable that the activation coefficient

(A_e%) can scale the percent of the resonance structure (II) of

ΔH_het-

ΔH_homo

-

ΔH_homo-

imines (X) (π-bond)^a(π-bond)^b(π-bond)^{•- c}ΔΔH^dΔΔH*^e

1(a-g)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

Br (e)

68.0

72.1

77.2

76.4

77.4

81.5

83.2

62.5

61.8

61.7

61.1

61.7

61.2

20.3

20.0

20.3

20.1

20.7

21.7

23.2

5.5

10.3

15.5

15.3

15.7

20.3

22.0

42.2

41.8

41.4

41.0

39.5

38.0

CF₃(f)

NO₂(g)

3(a-e)

CH₃O (a)

CH₃(b)

H (c)

Cl (d)

NO₂(e)

69.6

76.8

79.1

78.7

85.1

60.9

60.7

60.6

60.4

58.9

17.3

16.9

17.5

19.3

24.3

8.7

16.1

18.5

18.3

26.2

43.6

43.8

43.1

41.1

34.6

X

^•-in the total of the all resonance structures of X^•-

Since the idealized Lewis-type structure with CdN π-bond

broken (II) directly express the localized state of single

electron and negative charge in reaction intermediates X^•-

.

,

8(a-g)

p-CH₃O (a)

p-CH₃(b)

p-H (c)

p-Cl (d)

p-Br (e)

A_e% can be used to measure the relative effective spin

intensity on the molecular spin center atom or to measure

the relative effective negative charge on the molecular nega-

tively charged center atom. Figures 9 and 10 show the

relative effective spin density and the relative effective nega-

tive charge on the center atom in the reaction intermediates

70.3

74.9

79.9

79.5

79.9

84.6

86.2

66.5

66.3

65.6

65.0

64.8

64.0

63.1

17.9

18.2

18.4

18.7

18.5

18.9

19.2

3.8

8.6

48.6

48.1

47.2

46.3

45.1

43.9

14.3

14.5

15.1

20.6

23.1

CF₃(f)

p-NO₂(g)

X

^•-, respectively. From Table 2, it is clear that the relative

9(a-e)

p-CH₃O (a)

p-CH₃(b)

p-H (c)

p-Cl (d)

p-NO₂(e)

effective spin density on the molecular center atom increases

in the order 10a^-•< 11c^-•< 6c^-•< 7c^-•< 9c^-•< 1c^-•

(2c^-•) < 3c^-•(4c^-•) < 5c^-•< 8c^-•. Evidently, for the radical

reaction intermediates of imines (X^-•), the activation coeffi-

cients of CdN π-bond by electron (A_e%) can be used to

predict the kinetic driving force of the radicals for dimeriza-

tion or polymerization with other radicals since the dimer-

ization or polymerization rates of the radicals should be

directly dependent on the effective spin density on the

molecular center atom. Meanwhile, for the charged radicals

of imines (see Figure 10), since the effective spin density on

38.2

42.4

47.1

47.2

54.3

62.3

61.7

60.7

60.1

58.0

23.3

23.6

24.1

25.0

25.4

-24.1

-19.3

-13.6

-12.9

-3.7

39.0

38.1

36.6

35.1

32.6

^aDerived from the eq: ΔH_het(π-bond) = ΔH_H-A(X) - ΔH_H-A[(G)-

PhCH₂^þ].^{35 b}ΔH_homo(π-bond)

=

^cΔH_homo(π-bond)^•-= ΔH_HA(X^•-) - ΔH_HA(PhCH₂). ^dΔΔH = ΔH_het

ΔH_HA(X)

-

ΔH_HA(PhCH₂).³⁷

•

-

e

(π-bond) - ΔH_homo(π-bond). ΔΔH* = ΔH_homo(π-bond) - ΔH_homo

(π-bond)^•-

.

activation coefficients (A_e%) are generally larger than 40%

but smaller than 50%; when the imines are 6, 10, and 11, the

(38) (a) Pauling, L.; Wheland, G. W. J. Chem. Phys. 1933, 1, 362. (b)

Whelang, G. W.; Pauling, L. J. Am. Chem. Soc. 1935, 57, 2086. (c) Wheland,

G. W. The Theory of Resonance and Its Application to Organic Chemistry; John

Wiley: New York, 1955. (d) Pauling, L. Nature of the Chemical Bond, 3rd ed.;

Cormell University Press: Ithaca, NY, 1960.

(39) Although the protonated Hantzsch ester 9 still has some other

resonance structures with two π-bonds in the pyridine ring, such as the

resonance structures with positive charge on the 2-position carbon, these

resonance structures all are regarded as inefficient resonance structures

because they cannot be converted into 1,4-dihydropyridine esters.

798 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

JOCArticle

FIGURE 6. Comparison of hydrogen affinities of some typical neutral and charged imines in acetonitrile.

FIGURE 7. Comparison of hydrogen affinities of some typical neutral and negatively charged radicals of imines in acetonitrile.

FIGURE 8. Comparison of proton affinities of the corresponding neutral or negatively charged radicals of some typical imines (X^•-) in

acetonitrile.

the molecular spin center atom is equal to effective negative

charge density on the molecular negative charge center atom,

the activation coefficients of CdN π-bond by electron (A_e%)

can be also used to measure the kinetic driving force of the

radical anions of imines for nucleophilic additions or nu-

cleophilic substitutions. In fact, these predictions have been

well supported by some experimental observations.^40-43

ΔH_HAðX^{• -}Þ -ΔH_HAðXÞ

A_e% ¼

ð12Þ

ΔH_HAðX^{• -}

Þ

Electron Affinities of the Imines (X) and Their Reaction

Intermediate XH in Acetonitrile. As well-known, the standard

reduction potentials of imines and their reaction intermediates

XH are very important electrochemical parameters, which

can be used as an indicator of the electron-obtaining ability

of X and XH in thermodynamics. From column 6 in Table 2, it

is found that the one-electron reduction potentials of the

imines (1-11) [E^o(X^0/-)] range from -1.710 to -2.624 (V vs

(40) (a) Marquet, J.;Moreno-Manas, M.;Pacheco, P.;Prat, M.;Katritzky, A.

R.; Brycki, B. Tetrahedron 1990, 46, 5333–5346.

(41) (a) Kano, K.; Matsuo, T. Bull. Chem. Soc. Jpn. 1976, 49, 3269–3273.

(b) Kano, K.; Matsuo, T. Tetrahedron Lett. 1975, 16, 1389–1392.

(42) Sato, T.; Inoue, T.; Mukaiyama, T. Chem. Lett. 1975, 637–640.

(43) (a) Khan, N. H.; Zuberi, R. H.; Siddiqui, A. A. Synth. Commun.

1980, 10, 363–371. (b) Zuberi, R. H. Sci. Environ. 1982, 4, 71–76.

J. Org. Chem. Vol. 75, No. 3, 2010 799

Zhu et al.

JOCArticle

FIGURE 9. Relative effective spin density on the center carbon atom for some neutral radicals of imines (* the values are derived from ref 29).

FIGURE 10. Relative effective negative charge on the center atom for some typical radical anions of imines, the effective negative charge on

the atoms in the delocalized molecular resonance structure herein was defined as zero.

Fc^þ/0) for the neutral imines (1-8) and from -0.634 to -0.980

(V vs Fc^þ/0) for the positively charged imines (9-11). Since the

one-electron reduction potentials of the neutral imines are

quite negative values, generally more negative than -1.7 V

relative to ferrocene, the neutral imines (1-8), especially

attached by electron-donating groups, should belong to very

weak one-electron acceptors, but the positively charged imines

(9-11), especially attached by electron-withdrawing groups,

should belong to good electron acceptors. This result suggests

that, in living body, when the neutral imines were reduced by

800 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

JOCArticle

FIGURE 11. Comparison of reduction potentials of some typical neutral and charged imines in acetonitrile.

FIGURE 12. Comparison of electron affinities of some typical neutral and charged radicals of imines in acetonitrile.

natural organic reducing agents (NADH and Vitamin C), the

mechanism initiated by one-electron transfer is impossible

because the oxidation potentials of NADH and Vitamin C in

pH = 7 aqueous solution are 0.280 and -0.276 (V vs Fc^þ/0),

respectively, and electron transfer to the neutral imines takes at

least 46 and 33 kcal heat (or other energy) from NADH and

from Vitamin C, respectively. However, for the positively

charged imines especially attached by one or multiple strong

electron-withdrawing groups, it is likely that the reduction was

initiated by electron transfer, especially when vitamin C was

used as the hydride donor.

In order to more intuitively disclose the effect of structure,

charge, and protonation of imines on the electron-obtaining

abilities of the imines, the 11 imines (1-11, G = H) were

ranked in a row according to their one-electron reduction

potentials from negative (left) to positive (right) (Figure 11).

From Figure 11, it is clear that the electron-obtaining

abilities of 11 imines (1-11, G = H) increase in the order

3c(4c) < 8c < 7c < 1c(2c) < 5c < 6c < 10a < 11c < 9c.

Comparison of imine 8c and its protonated imine 9c shows

that the reduction potential of 9c is more positive than that of

8c by about 1.672 V, which means that protonation of imines

can increase the electron-obtaining ability of imines by about

1.672 V (equivalent to 38.6 kcal), which is not only much

larger than the effect of the protonation on the hydrogen-

obtaining ability of the imine (5.1 kcal) but also markedly

larger than the effect of the protonation on the hydride-

obtaining ability of the imine (32.8 kcal). This result suggests

that the protonation of imines is more propitious to the

reduction of imines by electron transfer than by hydrogen

atom or by hydride anion.

From column 7 in Table 2, it is found that the one-electron

reduction potentials of the reaction intermediates of imines

(XH) [E^o(XH^0/-)] range from -0.790 (V vs Fc^þ/0) for 6aH to

0.781 (V vs Fc^þ/0) for 9fH. Figure 12 shows an intuitive

comparison of some representative reduction potentials of

XH. From Figure 12, it is clear that the reduction potentials

of the positively charged XH (X = 9-11) are much more

positive than those of the neutral XH (X = 1-8), which

suggests that the positive charge on the reaction intermedi-

ates of imines (XH) can markedly promote their electron-

obtaining abilities. If the reduction potentials of 8H and their

corresponding protonated species (9H) are compared, it is

found that protonation can promote the reduction potentials

of XH by about 1.2 V (equivalent to 27.7 kcal), which means

that the effect of protonation on the reduction potentials of

XH is smaller than that on the reduction potentials of the

corresponding parent imine (X) (about 1.7 V).

Effects of the Remote Substituents on the Chemical Affi-

nities of Imines and Their Various Reaction Intermediates.

From Table 2, it is clear that the hydride affinities, hydrogen

affinities, and proton affinities as well as redox potentials of

imines and their various reduction intermediates are not only

strongly dependent on the structure and charge of imines but

also largely dependent on the nature of the remote substit-

uents on the benzene ring. In order to elucidate the relations

of the nature of substituents with the chemical affinities and

the redox potentials, the remote substituent (G) effects on

J. Org. Chem. Vol. 75, No. 3, 2010 801

Zhu et al.

ð16Þ

JOCArticle

ΔH_{H -A}ðXÞ ¼ -9:78σ_p-38:4 for 4

ΔH_{H -A}ðXÞ ¼ -7:12σ_p-37:1 for 5

ΔH_{H -A}ðXÞ ¼ -7:08σ_p-47:7 for 6

ð17Þ

ð18Þ

ΔH_{H -A}ðXÞ ¼ -5:84σ_p-38:2 for 8

ΔH_{H -A}ðXÞ ¼ -5:45σ_p-70:5 for 9

ΔH_{H -A}ðXÞ ¼ -2:47σ_p-73:5 for 11

ð19Þ

ð20Þ

ð21Þ

ΔH_HAðXÞ ¼ -1:05σ_p-26:7 for 1

ΔH_HAðXÞ ¼ -2:57σ_p-26:0 for 2

ΔH_HAðXÞ ¼ -1:86σ_p-28:0 for 3

ΔH_HAðXÞ ¼ -2:86σ_p-27:6 for 4

ð22Þ

ð23Þ

ð24Þ

ð25Þ

FIGURE 13. Plot of ΔH_H-A(X) against Hammett substituent

parameters σ.

ΔH_HAðXÞ ¼ -2:55σ_p-23:6 for 5

ΔH_HAðXÞ ¼ -3:70σ_p-38:6 for 6

ΔH_HAðXÞ ¼ -3:23σ_p-22:8 for 8

ð26Þ

ð27Þ

ð28Þ

the ΔH_H-A(X), ΔH_HA(X), ΔH_PA(X^-•), and ΔH_HA(X^-•) as

well as on the E^o_red(X) and E^o_red(XH) were examined, and

the results show that ΔH_H-A(X), ΔH_HA(X), and ΔH_PA(X^-•

)

as well as E^o_red(X) and E^o_red(XH) of the 45 chemical and

electrochemical processes all are linearly dependent on the

Hammett substituent parameters σ with very good correla-

tion coefficients (see Figure 13 and Figures S1-S4 in Sup-

porting Information), which indicates that the Hammett

linear free-energy relationships all hold in the 45 chemical

and electrochemical processes. From the slopes and the

intercepts of the 45 straight lines in Figure 13 and Figures

S1-S4 in the Supporting Information, the corresponding 45

mathematical formulas (eqs 13-57) can be easily derived.

Evidently, for any substituted imines X (1-6, 8, 9, and 11) at

the para- and/or meta-position on the benzene ring, it is

not difficult to safely estimate the values of ΔH_H-A(X),

ΔH_HA(X), and ΔH_PA(X^-•) according to eqs 13-39 as long

as the corresponding Hammett substituent parameters (σ)

are available and the standard deviation of the estimations is

less than ( 0.50 kcal. In the same way, for any substitution at

para- and/or meta-position imines X (1-6, 8, 9, and 11) and

their corresponding reduction intermediates XH, the redox

potentials E^o_red(X) and E^o_red(XH) can also be reliably esti-

mated from eqs 40-57 if only the corresponding Hammett

substituent parameters are available and the standard devia-

tion of the estimations is less than 30 mV. Since the family of

the substituent groups is very large, and the Hammett

parameters of most substituents located at the para- and

meta-position can be easily obtained from literature,⁴⁴it is

evident that the 45 formulas should have very extensive

application in the prediction of the related chemical potency

of the imines and their various reaction intermediates to

capture hydride, hydrogen atom, proton, and electron.

ΔH_HAðXÞ ¼ -3:96σ_p-27:5 for 9

ð29Þ

ΔH_HAðXÞ ¼ -0:52σ_p-42:2 for 11

ΔH_PAðX^-•Þ ¼ 8:06σ_p-27:1 for 1^-•

ΔH_PAðX^-•Þ ¼ 5:82σ_p-26:4 for 2^-•

ΔH_PAðX^-•Þ ¼ 11:47σ_p-32:3 for 3^-•

ΔH_PAðX^-•Þ ¼ 7:42σ_p-32:3 for 4^-•

ΔH_PAðX^-•Þ ¼ 2:80σ_p-23:7 for 5^-•

ΔH_PAðX^-•Þ ¼ 2:45σ_p-28:4 for 6^-•

ΔH_PAðX^-•Þ ¼ 3:78σ_p-27:9 for 8^-•

ΔH_PAðX^-•Þ ¼ 3:51σ_pþ 5:6 for 9^-•

ΔH_PAðX^-•Þ ¼ 0:22σ_p-10:2 for 11^-•

E^o_redðXÞ ¼ 0:395σ_p-2:321 for 1

E^o_redðXÞ ¼ 0:371σ_p-2:324 for 2

E^o_redðXÞ ¼ 0:576σ_p-2:492 for 3

E^o_redðXÞ ¼ 0:446σ_p-2:511 for 4

ð30Þ

ð31Þ

ð32Þ

ð33Þ

ð34Þ

ð35Þ

ð36Þ

ð37Þ

ð38Þ

ð39Þ

ð40Þ

ð41Þ

ð42Þ

ð43Þ

E^o_redðXÞ ¼ 0:232σ_p-2:311 for 5

ð44Þ

ð45Þ

ΔH_{H -A}ðXÞ ¼ -6:39σ_p-40:8 for 1

ΔH_{H -A}ðXÞ ¼ -10:28σ_p-40:2 for 2

ΔH_{H -A}ðXÞ ¼ -6:11σ_p-39:0 for 3

ð13Þ

ð14Þ

ð15Þ

E^o_redðXÞ ¼ 0:269σ_p-1:864 for 6

E^o_redðXÞ ¼ 0:304σ_p-2:528 for 8

E^o_redðXÞ ¼ 0:324σ_p-0:872 for 9

E^o_redðXÞ ¼ 0:032σ_p-0:918 for 11

ð46Þ

ð47Þ

ð48Þ

(44) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.

802 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

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E^o_redðXHÞ ¼ 0:231σ_p-0:522 for 1H

E^o_redðXHÞ ¼ 0:330σ_p-0:520 for 2H

E^o_redðXHÞ ¼ 0:188σ_p-0:657 for 3H

E^o_redðXHÞ ¼ 0:300σ_p-0:667 for 4H

E^o_redðXHÞ ¼ 0:197σ_p-0:552 for 5H

E^o_redðXHÞ ¼ 0:146σ_p-0:742 for 6H

E^o_redðXHÞ ¼ 0:113σ_p-0:472 for 8H

E^o_redðXHÞ ¼ 0:065σ_p-0:731 for 9H

E^o_redðXHÞ ¼ 0:084σ_p-0:225 for 11H

ð49Þ

ð50Þ

ð51Þ

ð52Þ

ð53Þ

ð54Þ

ð55Þ

ð56Þ

ð57Þ

the remote substituent on the hydride affinities of imines 1

and 2 were examined together for comparison. From Fig-

ure 13, it is clear that the enthalpy changes for 1 and 2 to

accept hydride anions all are excellently linearly dependent

on the Hammett substituent parameters σ_pwith line slopes

of -6.39 and -10.28. According to the root cause of the

Hammett substituent effect, it is conceived that the negative

sign of the line slope values reflects increase of negative

charge density on the reaction center atom during the

reduction process of the imines, and the magnitude of

the line slope values reflects the sensitivity of the two reduc-

tions of imines to the effects of the substituent G changes;

that is, the magnitude of the line slope values is a measure of

the distance between the molecular negative center and the

location of the substituents G in XH^-. Since the absolute

value of the line slope for the reduction of imines 2 (-10.28)

is much larger than that of the line slope for the reduction of

imines 1 (-6.39), it is evident that the negative center atom

in 1H^-should be farther away from the substituent G than

that in 2H^-. Since both 1H^-and 2H^-have the same parent

structure, which allows us to safely make a reasonable

proposal that the negative center atom in 1H^-and 2H^-

should be the nitrogen atom rather than the carbon atom (see

eqs 58 and 59), that is, the terminal carbon atom of CdN

double bond in 1 and 2 carries partial positive charge and the

acidity of hydrogen atom attached at the carbon atom in 1H₂

and 2H₂is weaker than that of the hydrogen atom at the

nitrogen atom (see Scheme 4). By the same way, if the imines 3

and 4 were examined, the case is just the same as in 1 and 2;

that is, the terminal carbon atoms of CdN double bond in 3

and 4 carry partial positive charge and the acidity of hydrogen

atom attached at the carbon atom in 3H₂and 4H₂is also

weaker than that of the hydrogen atom at the nitrogen atom.

However, if 6 is examined, it is found that the line slope for the

reduction of 6 is -7.08. This value is markedly smaller than

that of the line slope for the reduction of 2 (-10.28) but quite

close to that of the line slope for the reduction of 1 (-6.39).

Thisresult meansthatthe reductionroute of imines6shownin

eq 60 is unreasonable, but the route in eq 61 is reasonable; that

is, the terminal carbon atom of CdN double bond in 6 carries

partial negative charge and the acidity of hydrogen atom

attached at the carbon atom in 6H₂is stronger than that of the

hydrogen atom at the nitrogen atom (see Scheme 4). If 5 is

examined, it is found thatthe line slope for the reductionof5 is

-7.12, which seems to show that the polarity of CdN double

bond in 5 is the same as the case of the CdN double bond in 6.

However, if the r values of the line slopes in Figure 13 are

examined carefully, it is found that the r value for 5 is not good

(0.928) (see Figure 13), which means that only according to

the line slope (-7.12), the prediction of polarity of CdN in

imine 5 is in lack of safety. However, if the effects of the

substituents (G) on the ΔH_H-A(5) were examined in detail, it

is found that, when G is electron-withdrawing groups, the

line slope is more negative than -10 (see Figure S5 in

Supporting Information), which means that the polarity of

CdN double bond in 5 is like the case of CdN double

bond in 1 rather than in 6, but when G is electron-donating

groups, the line slope is -5.26 (r = 0.996), which means that,

in these cases, the polarity of CdN double bond in 5 is like

the case in 6. Here, we were interested to find that, when

G changes from electron-withdrawing groups to electron-

donating groups, the polarity of CdN in 5 has a reversion

In addition, from the line slopes in Figure 13 and Figures

S1-S4 in the Supporting Information, it is clear that electron-

withdrawing groups (G) not only can increase the hydride-

accepting ability and electron-obtaining ability of the imines

but also can increase the hydrogen-obtaining ability of the imines,

which can support the viewpoint that the neutral hydrogen atom

has significant nucleophilicity in the organic reaction system.²⁹

Determination of Polar Direction of CdN Double Bond in

the Imines. As is well-known, CdN double bond is an eigen

bond of imines. Since the electronegativity of the carbon

atom (2.5) is smaller than that of nitrogen atom (3.0),⁴⁵

a

common credendum has been accepted by many chemists

that CdN double bonds of imines are regarded as a polar

chemical bond and the terminal of carbon carries partial

positive charge. According to this viewpoint, the following

conclusions can be drawn: (i) when imines are reduced by

hydride anion, the terminal carbon atom of CdN double

bond should be a privileged atom to accept the hydride

anion; (ii) for the amines formed from the corresponding

imines, acidity of the hydrogen atom contacted with the

nitrogen atom should always be larger than that of hydrogen

atom contacted with the adjacent carbon atom. However,

since the difference in the electronegativities between the

carbon atom (2.5) and nitrogen atom (3.0) are not great, this

credendum is not always appropriate for all imines. So, it is

necessary to develop an efficient method to determine the

polar direction of CdN double bond for some well-known

and important imines. From our previous papers,⁴⁶it has

been found that Hammett linear free-energy analysis of

the remote substituents effect on thermodynamics and/or

kinetics of reaction has been verified to be able to provide a

very efficient method to estimate the distance between the

molecular charge center and the substituent location. If

Hammett linear free-energy relationship analysis method

were applied in the reduction process of imines by hydride

anions, one efficient access could be available to diagnose the

polar direction of CdN double bond in the imines. In order

to clearly show how to use of the method to diagnose the

polar direction of CdN double bond in imines, the effects of

(45) Umland, J. B.; Bellama, J. M. General Chemistry, EISBN: 0-534-

35872-1, a division of Thomson Learning Asia Pte Ltd. 2001.

(46) (a) Zhu, X.-Q.; Liu, Y.; Zhao, B.-J.; Cheng, J.-P. J. Org. Chem. 2001,

66, 370–375. (b) Zhu, X.-Q.; Dai, Z.; Yu, A.; Wu, S.; Cheng, J.-P. J. Phys.

Chem. B 2008, 112, 11694–11707. (c) Page, M.; Williams, A. Organic and Bio-

organic Mechanisms; Longman, 1997; Chapter 3, pp 52-79.

J. Org. Chem. Vol. 75, No. 3, 2010 803

Zhu et al.

JOCArticle

(see Scheme 4); the reason could be that the acidities of

aniline and diphenylmethane are quite close to each other.⁴⁷

For imine 8 and the corresponding protonated derivative 9,

since the line slopes for the reductions of 8 (-5.84) and 9

(-5.45) are close to the line slope for the reductions of 1

(-6.39), the reduction route of 8 or 9 in eq 62 should be

reasonable, but the reduction route in eq 63 should be

incorrect; that is, the terminal nitrogen atoms of CdN

double bond in 8 could carry partial negative charge, and

the acidity of hydrogen atom at the 4-position in 8H₂should

be weaker than that of the hydrogen atom at the 1-position

(see Scheme 4).

characteristic chemical information graph of a molecule can

be produced and can be efficiently used to quantitatively

diagnose or scale the characteristic chemical properties of the

molecule and its various reaction intermediates, which is like

the case of the NMR spectrum and IR spectrum of a

molecule, where it can be used to determine the molecular

structure, the chemists’ dream for a long time could become

reality in that the characteristic graphs of molecules could be

reliably designed with various new chemical reactions, safely

predicting the possible products of reactions and exactly

parse the reaction mechanism. Therefore, developing a

characteristic graph of molecule as its “Molecule ID Card”,

which contains the essential information about the chemical

properties of molecule and its various reaction intermedi-

ates, has been my ambition for a long time.

In Table 2, it is found that there are six primary thermo-

dynamic parameters about the characteristic chemical or

electrochemical properties of imines (X) and their reaction

intermediates (X^-•and XH), which have been obtained by

using experimental methods in this work. Since the sizes of

proton, hydride anion, hydrogen atom, and electron all are

quite small, it is conceived that the hydride affinity, hydrogen

affinity, proton affinity, and electron affinity of imines and

their various reaction intermediates should be the most

intrinsic thermodynamic parameters to quantitatively scale

the characteristic chemical properties of imines and their

various reaction intermediates, such as acidity, basicity,

nucleophilicity, electrophilicity, reducibility, oxidizability,

and so on, which gives us one efficient access to quantita-

tively scale the chemical properties of imines and their

various reaction intermediates. If the six thermodynamic

parameters scaling the different chemical characters of imine

and its various reaction intermediates are gathered together

according to their mutual conversion to build a graph, it is

clear that, for any species among the imines and their various

reaction intermediates, one can obtain three characteristic

thermodynamic parameters from the graph to quantitatively

diagnose the characteristic chemical properties of the species.

Since this graph only consists of thermodynamic parameters

of imine and its reaction intermediates, this graph, in this

work, is defined as the thermodynamic characteristic graph

(TCG) of imine, which can be used as a “Molecule ID Card”

of the imine to quantitatively diagnose the characteristic

chemical properties of the imines and their various reaction

intermediates in acetonitrile solution.

Schemes 5 and 6 are the thermodynamic characteristic

graphs of imines 6c and 7c. From the TCGs of 6c and 7c, the

characteristic chemical properties of 6c and 7c as well as their

various reaction intermediates in acetonitrile can be easily

and quantitatively diagnosed (see Tables 4 and 5). In addi-

tion, if the reaction system of imines 6c and 7cH^-is examined

or diagnosed according to the TCGs of 6c and 7c, the

following predictions can be safely made (Scheme 7): (i) when

6c and 7cH^-are mixed in acetonitrile, hydride anion transfer

is allowed from 7cH^-to 6c to yield 7c and 6cH^-, but

hydrogen atom transfer and electron transfer are both for-

bidden; (ii) when radical anion 6c^-•and neutral radical 7cH

contacted each other in acetonitrile, 6cH^-and 7c as well as 6c

and 7cH^-can be formed by hydrogen atom transfer and

electron transfer, respectively, but 7c^-•and 6cH^•cannot be

formed by proton transfer; (iii) when 6cH and 7c^-•met

together in acetonitrile, 6c and 7cH^-, 6c^-•and 7cH, as well as

Thermodynamic Characteristic Graphs (TCGs) of Imines

as a “Molecule ID Card”. It is well-known that the structure

of an organic compound (such as an imine) can be safely

diagnosed or determined according to its characteristic

spectra, such as NMR spectrum, IR spectrum, and MS,

but the chemical properties of an organic molecule (such as

an imine) and its various reaction intermediates could not be

directly diagnosed or determined only according to a certain

spectrum or graph of the molecule until now. If a certain

(47) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.

804 J. Org. Chem. Vol. 75, No. 3, 2010

Zhu et al.

JOCArticle

SCHEME 4. Polar Direction of CdN Double Bond of the Imines and Relative Acidity of the Two Hydrogen Atoms Attached at the

Carbon Atom and the Nitrogen Atom in the Corresponding 2H Adduct of Imines

SCHEME 5. Thermodynamic Characteristic Graph (TCG)

of 6c

SCHEME 6. Thermodynamic Characteristic Graph (TCG) of

Imine 7c

imines to accept a hydride anion and to accept a neutral

hydrogen atom as well as the enthalpy changes of their

corresponding reaction intermediate (X^-•) to accept a hy-

drogen atom and to accept a proton in acetonitrile were

estimated by using experimental method. The standard

reduction potentials of the 61 imines (X) and their corre-

sponding radicals (XH) were examined by using CV and

OSWV methods, respectively. After detailed examination of

the determined enthalpy changes and redox potentials as well

as the remote substituent effects on the enthalpy changes and

the redox potentials, the following conclusions can be made:

(1) The neutral imines, especially attached by strong

electron-donating groups, belong to very weak hydride

acceptors; they cannot directly be reduced by some

organic reducing agents, such as NADH and its model

BNAH. However, if the neutral imines are positively

charged or protonated, especially carrying strong

electron-withdrawing groups, they become strong or

midstrong hydride acceptors and can be directly re-

duced by some natural reducing agents and many

man-made models without any aid. These results

6cH^-and 7c all can be formed by hydrogen atom transfer,

proton transfer, and electron transfer, respectively, which

means that the couple of 7c^-•and 6cH is the most active

couple of the species in the reaction system; (iv) when

imines 7c and 6cH^-were mixed in acetonitrile, no reaction

was found, which means that the couple of 7c and 6cH^-is the

most stable couple of the species in this reaction system.

Evidently, the thermodynamic characteristic graph (TCG) of

the molecule is a very useful chemical information memor-

izer of molecules, which not only can be used to diagnose the

chemical characters of molecules and their various reaction

intermediates but also can be used to construct a thermo-

dynamic analysis platform to predict reaction products and

analyze the reaction mechanism.

Conclusions

In this work, 61 typical neutral and positively charged

imines (X) as a class of very important unsaturated organic

compounds were synthesized. Enthalpy changes of the 61

J. Org. Chem. Vol. 75, No. 3, 2010 805

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TABLE 4. Chemical Properties of Imine 6c and Its Various Reaction Intermediates Are Diagnosed According to the TCG of 6c (Scheme 5)

^*Note: ΔH_PD(6cH), ΔH_HD(6cH), ΔH_H-D(6cH^-), and ΔH_HD(6cH^-) are defined as the enthalpy changes of 6cH to release proton, to release hydrogen

atom, and the enthalpy changes of 6cH^-to release hydride anion and to release in acetonitrile, respectively. The values are equal to the enthalpy changes

of the corresponding opposite species to capture proton, to capture hydrogen atom, or to capture hydride anion in acetonitrile by switch the signs.

TABLE 5. Chemical Properties of Imine 7c and Its Various Reaction Intermediates Are Diagnosed According to the TCG of 7c (Scheme 6)

^*Note: ΔH_PD(7cH), ΔH_HD(7cH), ΔH_H-D(7cH^-), and ΔH_HD(7cH^-) are defined as the enthalpy changes of 7cH to release proton, to release hydrogen

atom, and the enthalpy changes of 7cH^-to release hydride anion and to release in acetonitrile, respectively. The values are equal to the enthalpy changes

of the corresponding opposite species to capture proton, to capture hydrogen atom, or to capture hydride anion in acetonitrile by switch the signs.

suggest that reduction of neutral imines generally

needs promotion by protonation or methylation at

the nitrogen atom in advance.

(3) The one-electron reduction potentials of neutral imines

aregenerally closetoormorenegativethan-2.000 (V vs

Fc^þ/0), which suggests that neutral imines should be very

poor one-electron acceptors; that is, reduction of the

neutral imines should be difficult with general single-

electron reducing agents. However, for the positively

charged imines, it is possible that the reductions take

place with general single-electron reducing agents be-

cause the one-electron reduction potentials of the posi-

tively charged imines are not quite negative (generally,

more positive than -1.000 V vs Fc^þ/0).

(2) Since the hydrogen atom affinities of imines, whether

charged or not, all are quite small (generally close to

or more positive than -45 kcal), all of the imines

should belong to very weak hydrogen atom acceptors.

The hydrogen atom-obtaining abilities are smaller

than that of O₂(the hydrogen affinity of O₂is

estimated to be -48.2 kcal).⁴⁸As the hydrogen affi-

nities of imines are quite smaller (or much more

positive) than the corresponding hydride affinities, it

is conceived that the reduction of imines is much more

favorable by hydride anion over the neutral hydrogen

atom.

(4) For the radicals of imines (X^-•), since the enthalpy

changes of the radicals, whether charged or not, to

accept a hydrogen atom all are quite negative, gen-

erally much more negative than -60.0 kcal/mol, the

radicals whether charged or not should belong to

strong or midstrong hydrogen atom acceptors, which

indicates that the radicals of imines (X^-•), especially

(48) Fisher, E. R.; Armentrout, P. B. J. Phys. Chem. 1990, 94, 4396–4398.

806 J. Org. Chem. Vol. 75, No. 3, 2010

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SCHEME 7. Thermodynamic Diagnoses of Possible Hydride Transfer Mechanisms between 7cH^-and 6c

without charge (X = 9-10), are easy to form di-

mers.⁴⁹With the proton-accepting ability of the

radicals, if the radical is neutral, the radicals belong

to weak proton acceptors (weak base), but if the

radical is negatively charged, the radical becomes

a strong proton acceptor (strong base). Since the

oxidation potentials of the charged radicals of imi-

nes are generally negative at -2.000 (V vs Fc^þ/0), it

should be very difficult to directly detect the charged

radicals of imines in the lab because trace oxygen is

enough to oxidize them (the reduction potential of

O₂is about -1.200 (V vs Fc^þ/0) in 1 atm). However,

for the neutral radicals of imines, since the oxidation

potentials are generally more positive than -1.000

(V vs Fc^þ/0), it should not be very difficult to directly

detect them by using conventional experimental

methods in the lab.

of any substituted imines X all can be safely estimated

from the corresponding Hammett linear free-energy

relationship formulas (eqs 13-57) if only the Ham-

mett substituent parameters (σ) are available and the

standard derivation of the estimations is less than

0.50 kcal and 30 mV for the enthalpy changes and

for the redox potentials, respectively.

(7) For the neutral imines, protonation not only increases

their ability to accept a hydride anion and electron but

also promotes their ability to accept a hydrogen atom.

However, for the radical anions of the imines (X^-•),

protonation not only greatly decreases their proton-

accepting ability but also markedly decreases their

hydrogen-accepting ability. In addition, the proton-

ation of XH can markedly enhance their electron-

accepting ability. These results can be used to examine

the reduction mechanism of imines catalyzed by proto-

nic acids.

(5) The hydrogen adduct of the imine (XH) is the good

one-electron oxidizing agent, especially with positive

charge. Among the 11 classes of imines, 9H is the most

strong one-electron oxidation agent; the one-electron

oxidizing power is close_þto that of NO^þ(E_1/2= 0.8265

V vs Fc^{þ/0 50}and NO₂(E_1/2= 0.91 V vs Fc^þ/0).⁵¹

(8) The polarity of the CdN bond in the imines has

been examined according to Hammett substituent

effect, and the results show that, if the imines are

5 (diphenyl imines) with electron-donating groups and

6 (fluorenyl imines), the nitrogen terminal of the CdN

bond should carry partial positive charge, but if the

imine is the others, the carbon terminal carries partial

positive charge.

)

Since the electron-accepting ability of XH is much

larger than that of the corresponding parent imines

(X), it is conceived that, if the reduction of the imines

was initiated by electron transfer from a two-electron

reducing agent, the second electron transfer could not

be the rate-determining step.

(9) The CdN π-bond heterolytic and homolytic dissocia-

tion energies of imines 1, 3, 8, and 9 were estimated for

the first time. The results show that, when the imines are

neutral, the CdN π-bond heterolytic dissociation en-

ergies are larger than that corresponding π-bond homo-

lytic dissociation energies, but if the imines are positively

charged, the CdN π-bond heterolytic dissociation en-

ergies become much smaller than the corresponding π-

bond homolytic dissociation energies.

(6) The substituent effects have excellent Hammett linear

free-energy relationships on the enthalpy changes of

X to accept hydride and to accept a hydrogen atom

and on the enthalpy changes of X^-•to accept a proton

as well as on the reduction potentials of X and XH,

respectively, which means that ΔH_H-A(X), ΔH_HA

-

(X), and ΔH_PA(X^-•) as well as E^o_red(X) and E^o_red(XH)

(10) Thermodynamic characteristic graphs of imines as a

novel chemical term were proposed for the first time,

which not only quantitatively diagnoses the chemical

properties of imines and their various reaction inter-

mediates but also predicts the most likely products

and reaction mechanisms.

(49) The radicals with like charge can repel.

(50) Zhu, X.-Q.; Li, Q.; Hao, W.-F.; Cheng, J.-P. J. Am. Chem. Soc. 2002,

124, 9887–9893.

(51) Lee, K. Y.; Amatore, C.; Kochi, J. K. J. Phys. Chem. 1991, 95, 1285–

1294.

J. Org. Chem. Vol. 75, No. 3, 2010 807

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It is evident that these important and hard-to-get hydride

affinities, hydrogen affinities, proton affinities, and electron

affinities of imines and their various reaction intermediates

in acetonitrile, and the conclusions drawn from the effects of

substitute, structure of imines, protonation, and the charge

on the hydride affinities, hydrogen atom affinities, proton

affinities, and electron affinities can provide very important

clues to examine the electron structure of imines, design the

reduction route of imines, analyze the reaction mechanism,

capture the reaction intermediates, predict the reaction

direction and tendency, and develop the applications of

imines. Especially, the thermodynamic characteristic graphs

(TCGs) of imines as an efficient “Molecule ID Card” are

proposed for the first time, which can be used to quantita-

tively diagnose reactivities of organic compounds and their

various reaction intermediates.

dissolved in dry acetonitrile, and then a slightly excess amount

of KH was added. The mixture was stirred at room temperature

for about 20 min and then filtered directly into the reac-

tion vessel. All operations were carried out in an argon-filled

glovebox.

Measurment of Redox Potentials. The electrochemical experi-

ments were carried out by cyclic voltammetry (CV) and Oster-

young square wave voltammetry (OSWV) using a BAS-100B

electrochemical apparatus in deaerated acetonitrile under argon

atmosphere at 298 K as described previously.⁵⁰n-Bu₄NPF₆

(0.1 M) in acetonitrile was employed as the supporting electro-

lyte. A standard three-electrode cell consists of a glassy carbon

disk as work electrode, a platinum wire as a counter electrode,

and 0.1 M AgNO₃/Ag (in 0.1 M n-Bu₄NPF₆/acetonitrile) as

reference electrode. The ferrocenium/ferrocene redox couple

(Fc^þ/0) was taken as the internal standard. The reproducibili-

ties of the potentials were usually e5 mV for ionic species and

e10 mV for neutral species.

Isothermal Titration Calorimetry (ITC). The titration experi-

ments were performed on a CSC4200 isothermal titration

calorimeter in acetonitrile at 298 K as described previously.⁵⁷

The performance of the calorimeter was checked by measuring

the standard heat of neutralization of an aqueous solution of

sodium hydroxide with a standard aqueous HCl solution. Data

points were collected every 2 s. The heat of reaction was

determined following eight automatic injections from a 250 μL

injection syringe containing a standard solution (≈2 mM) into

the reaction cell (1.30 mL) containing 1 mL of other concen-

trated reactant (≈15 mM). Injection volume (5 μL) was deliv-

ered at 0.5 s time interval with 300 s between every two

injections. The reaction heat was obtained by integration of

each peak except the first.⁵⁸

Experimental Section

Materials. All reagents were commercial quality from freshly

opened containers or were purified before use.⁵²Reagent grade

acetonitrile was refluxed over KMnO₄and K₂CO₃for several

hours and was doubly distilled over P₂O₅under argon before

use. The commercial tetrabutylammonium hexafluoropho-

sphate (Bu₄NPF₆, Aldrich) was recrystallized from CH₂Cl₂

and was vacuum-dried at 110 °C overnight before preparation

of supporting electrolyte solution. 9-Phenylxanthylium

(PhXn^þClO₄^-) was synthesized according to literature meth-

ods.⁵³N-Methylacridinium (AcrH^þClO₄^-) was obtained from

the exchange of Na^þClO₄with AcrH^þI^-in hot water; the

-

latter was prepared according to literature methods.⁵⁴The 61

imines (X in Scheme 1) were synthesized according to conven-

tional synthetic strategies from the corresponding ketones or

aldehydes with primary amines by condensations.⁵⁵Com-

pounds XH₂were obtained from the reductions of the corre-

sponding parent imines by NaBH₄in THF or by Zn in alkalized

Acknowledgment. Financial support from the Mini-

stry of Science and Technology of China (Grant No.

2004CB719905), the National Natural Science Foundation

of China (Grant Nos. 20921120403, 20832004, 20721062,

and 20672060), and the 111 Project (B06005) is gratefully

acknowledged.

1

C₂H₅OH, and the final products were identified by H NMR

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according to Arnett’s method.⁵⁶The anion precursor (XH₂) was

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pubs.acs.org.

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to diffusion across the tip of the needle.

808 J. Org. Chem. Vol. 75, No. 3, 2010

Article Doi

Hydride, hydrogen, proton, and electron affinities of imines and their reaction intermediates in acetonitrile and construction of thermodynamic characteristic graphs (TCGs) of imines as a molecule ID card

DOI: 10.1021/jo902332n

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Article abstract of DOI:10.1021/jo902332n

Full text of DOI:10.1021/jo902332n

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