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Redox Property of Enamines Yao Li, Dehong Wang, Long Zhang, and Sanzhong Luo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02003 • Publication Date (Web): 23 Aug 2019 Downloaded from pubs.acs.org on August 24, 2019
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The Journal of Organic Chemistry
Redox Property of Enamines Yao Li,†,§ Dehong Wang,‡,§ Long Zhang, †,‡ and Sanzhong Luo*,†,‡ †
Center
of
Basic
Molecular
Science
(CBMS),
Department
of
Chemistry, Tsinghua
University, Beijing 100084, China ‡
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China E-mail:
[email protected] Oxidation Potential Scale of Enamines N
N
NH
O
NH
O
NH
OEt
NH
O
NH
O
NH
O
O OEt
CF3
OEt
OEt
H OTf
N
N
N
N
Cl
0.80 Ph N
Ph OH
0.50
0.90 Ph
N N NH
1.00
Ph OTMS
0.60
O N Ar Bn N N OTMS Ar = 3,5-diCF3Ph
-
Ar
N
COOH
0.70
0.80
Exp. Ep (V vs. SCE)
1.20
1.10 N
H OTf Bn
O N N
NH
0.90
Cal. Eox (V vs. SCE)
ABSTRACT: Enamines are electron-rich compounds bearing intriguing redox properties. Herein, a series of secondary enamines condensed from primary amine and β-ketocarbonyls were synthesized and their electrochemical oxidation properties were systematically studied by cyclic voltammetry. Furthermore, theoretical calculation of oxidation potentials of enamines, particularly those catalytic intermediates, was also conducted to further broaden the scope investigated. Possible structural factors on oxidation as well as the nature of the resulted radical cation intermediates were revealed and discussed. Correlation of redox potentials with molecular properties such as HUMO energies, NPA charge were explored, and there appears no simple linear correlation. On the other hand, a good correlation with Mayr’s nucleophilicity parameter N was noted among a range of catalytically relevant enamines. Spin population analysis disclosed that enamine radical cations mainly exhibit carbon-center free radical feature. Taking experimental and computation data together, a comprehensive picture about the redox property of enamines is presented, which would provide guidance in the development of oxidative enamine catalysis and transformations. 1
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INTRODUCTION Enamines chemistry is a classical yet fundamental tool in carbonyl transformations. In the field of organocatalysis, enamine has been extensively explored as a nucleophilic intermediate, known as HOMO-enhancing enamine activation (Scheme 1).1 On the other hand, the redox property of enamine, especially their single-electron oxidation via chemical or electrochemical or photo process,2 is also quite intriguing. Such processes lead to open shell enamine intermediates such as enamine radical cation (Scheme 1), also known as SOMO activation,
2s,3
or -iminio radical from secondary
enamine,2c which lay the basis for a plethora of oxidative enamine transformations beyond the classical HOMO-activation pathway.3a,4 Hence, redox properties of enamine are highly desirable in the pursuit of oxidation enamine transformations. Unfortunately, unlike the well-investigated nucleophilicity of enamines,5 information on the redox properties are only sparsely available and has not been systematically investigated, particularly in the context of enamine catalysis (Scheme 2).6 Half a century ago, Fritsch et al. investigated the electrolytic oxidations of N,N-dimethylaminoalkenes.6a,6b Besides, factors affecting the lifetimes of the cation radicals were also discussed.6b In 1984, Masui et al. explored the electrochemical properties of 2-cyano-2-phenylvinylamines and reported the anodic dimerization of these enamines.6c A few years later, Schoeller et al. and Renaud et al.6d,6e studied the redox properties of enamines derived from cyclic ketones and cyclic amines and irreversible oxidation processes were found. In 1995, Cossy et al.6f investigated the redox properties of several types of amidoenamines bearing unsaturated groups, i.e. allyl, propargyl, in an attempt to achieve electrochemical cyclization. In the same year, Tabaković disclosed anodic oxidation of enaminones and the dimerization of corresponding radical cations.6g
2
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The Journal of Organic Chemistry
Typical enamine catalysis: HOMO activation O
N
E
+
E: electrophile
E
Oxidative enamine catalysis: SOMO activation N
+
O
[O]
Nu
Nu: nucleophile
Nu
SET
N
R
-H+
N
R=H Enamine radical cation
-iminio radical
Scheme 1. Aminocatalytic mode. X m N N
CN
N
R2 N
N Fritsch 1968, 1970
R1
R
3
n Masui 1984
R4
X = CH2, m = 1-3 X = O, NH, m = 1
N
n = 0-3
Schoeller, Renaud 1988, 1990
N
H
O
O 5 N R 6 R
N R7
Cossy 1995
Tabakovic 1995
Scheme 2. Previous systematical studies of enamines’ redox properties.
Herein, we wish to present our systematic studies on the redox property of enamines using both experimental and computational approaches. Stabilized enamines such as secondary enamines derived from β-ketocarbonyls were synthesized and analyzed by cyclic voltammetry (CV). The obtained experimental data were then served as bench mark on which DFT calculations on those catalytically interesting enamine intermediates could be formulated. Taken together, we aim to provide a coherent picture of one-electron oxidation chemistry of enamines. We also discussed the possible structural effect on redox properties as well as the structure of the resulted enamine radical cation intermediates.
EXPERIMENTAL METHODS 3
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1. Synthesis and characterization of enamines All secondary enamines were synthesized from corresponding primary amines (1-6) with β-ketocarbonyls (A-D) using the protocol described in literature (Scheme 3).7 O 1
R NH2 +
R1
O Fe(OTf)3
R2
R R
Amines
R1-NH2 =
1
2
NH2
NH2
NH2
NH2
R2 R3
NH2
N
O
R
neat
3
NH
N NH2
4
3
5
HOTf
6
-ketocarbonyls O
O R2 n A
A1, n = 1, R2 = OEt A2, n = 2, R2 = OEt A3, n = 3, R2 = OEt A4, n = 1, R2 = NHPh A5, n = 1, R2 = NHBn
O
O R2 B
B1, R2 = OEt B2, R2 = Ph B3, R2 = Me B4, R2 = CF3 B5, R2 = NHPh B6, R2 = NHBn
O
O R2 R3
C1, R2 = OEt, R3 = Cl C2, R2 = OEt, R3 = Me C3, R2 = Et, R3 = Me
O D1, n = 2 D2, n = 1
n
C
O
D
Secondary enamines R1
NH
O R2 n
X = 1-6 R1-NH2 = 1-6
XA1, n = 1, R2 = OEt R1 NH XA2, n = 2, R2 = OEt 2 XA3, n = 3, R = OEt XA4, n = 1, R2 = NHPh XA5, n = 1, R2 = NHBn
O R2
XB1, R2 = OEt R1 XC1, R2 = OEt, R3 = Cl NH O XB2, R2 = Ph XC2, R2 = OEt, R3 = Me XB3, R2 = Me R2 XC3, R2 = Et, R3 = Me n XB4, R2 = CF3 R3 XB5, R2 = NHPh XB6, R2 = NHBn
R1
NH XD1, n = 2 XD2, n = 1
O
Scheme 3. Secondary enamines investigated in electrochemical study.
2. Cyclic voltammetric details We evaluated the redox properties of the enamines by cyclic voltammetry. Our setup comprised of an undivided cell, a glassy carbon working electrode (3mm diameter), a platinum wire counter electrode, and a saturated Ag/AgCl reference electrode. Each cyclic voltammogram (CV) was measured at a sweep rate of 100 mV/s. Measurements were carried out with 0.01 M enamines in dry CH3CN using Bu4NPF6 (0.10 M) as the supporting electrolyte.
CALCULATION METHODS Theoretical approaches have been found to give a precise prediction of electrochemistry properties in solution,8 we also explored similar methods to predict the oxidation potentials of 4
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enamines by using Gaussian09.9 After benchmarked several conventional functions,10 we found that Truhlar’s M06-2X hybrid functional provided accurate predictions of oxidation potentials.11 Geometry optimizations and frequency computations were performed at the M06-2X/6-311G(d,p) level of theory, in conjunction with the IEF-PCM model to account for the solvation effects of acetonitrile.12 The calculated oxidation potentials were scaled to saturated calomel electrode (SCE).13 Free energies include unscaled zero-point vibrational energies. Low frequencies (
