Imine or Enamine? Insights and Predictive Guidelines from the Electronic Effect of Substituents in H-Bonded Salicylimines

Article abstract of DOI:10.1021/acs.joc.0c00130

Imine and enamine bonds decorate the skeleton of numerous reagents, catalysts, and organic materials. However, it is difficult to isolate at will a single tautomer, as dynamic equilibria occur easily, even in the solid state, and are sensitive to electronic and steric effect, including π-conjugation and H-bonding. Here, using as model Schiff bases generated from salicylaldehydes and TRIS in a set of linear free energy relationships (LFER), we disclose how the formation of either imines or enamines can be controlled and provide a comprehensive framework that captures the structural underpinning of this prediction. This work highlights the potentiality of tailor-made designs en route to compounds with desirable functionality.

Full text of DOI:10.1021/acs.joc.0c00130

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Article
Imine or Enamine? Insights and Predictive Guidelines from the
Electronic Effect of Substituents in H-Bonded Salicylimines
R. Fernando Martínez, Esther Matamoros, Pedro Cintas, and Juan C. Palacios
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00130 • Publication Date (Web): 07 Apr 2020
Downloaded from pubs.acs.org on April 14, 2020
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Imine or Enamine? Insights and Predictive Guidelines from the Electronic Effect
of Substituents in H-Bonded Salicylimines
R. Fernando Martínez,* Esther Matamoros, Pedro Cintas, and Juan C. Palacios*
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Departamento de Química Orgánica e Inorgánica, Facultad de Ciencias and IACYS-Unidad de Química
Verde y Desarrollo Sostenible, Universidad de Extremadura, E-06006 Badajoz, Spain
ABSTRACT: Imine and enamine bonds decorate the skeleton of numerous reagents, catalysts, and
organic materials. However, it is difficult to isolate at will a single tautomer, as dynamic equilibria occur
easily, even in the solid state, and are sensitive to electronic and steric effect, including π-conjugation and
H-bonding. Here, using as model Schiff bases generated from salicylaldehydes and TRIS in a set of linear
free energy relationships (LFER), we disclose how the formation of either imines or enamines can be
controlled and provide a comprehensive framework that captures the structural underpinning of this
prediction. This work highlights the potentiality of tailor-made designs en route to compounds with
desirable functionality.
INTRODUCTION AND BACKGROUND
Hydrogen bonding is an important non-covalent interaction playing central roles in chemistry, biology,
and materials design.1,2 The key aspect of the H-bond arises from its directionality, a fact accounting for,
among others, molecular packing in crystals or stabilization of the second-order structure of proteins.1
Besides, formation of intramolecular hydrogen bonds is often responsible for stabilization of particular
conformers and tautomers of heterocyclic systems.3 Not by chance, the nature and strength of
intramolecular hydrogen bonds has been thoroughly investigated in recent decades by both theoretical and
experimental analyses.4
In terms of stabilization energy H-bonds are usually classified as strong (>15 kcal/mol), moderately
strong (4-15 kcal/mol), and weak (<4 kcal/mol).4a Gilli and co-workers suggested, based on a large
collection of neutron and X-ray crystal data, that one of the three classes of really strong H-bonds are
5
6
1b
resonance-assisted H-bonds, or π-cooperative H-bonds, where the two oxygen atoms are connected by
a π-conjugated system of single and double bonds. The team introduced in the late 1980s the concept of
resonance-assisted hydrogen bonds (RAHBs), whereby the synergistic interplay between hydrogen bond
and heteroconjugated systems can strengthen significantly the hydrogen bond itself.6
Intramolecular RAHBs have been generally invoked in six-membered rings created by typical covalent
7
bonds and one H-bond interaction as enaminone-iminoenol resonant fragment. Experimental support
largely comes from NMR data as the strong hydrogen bonds have unusual downfield proton shifts (δ
6-20 ppm).6
H
=
1
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The strongest nonconventional hydrogen bonds (RAHB) have been rationalized in terms of the extra
stabilization associated to the partial delocalization of the π-electrons through the entire conjugated
system of single and doble bonds. Some authors have however criticized this original concept of RAHB;
the characteristics of the σ-skeleton, not the π-electron delocalization, would rather be behind the stability
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of this interaction. Without explicitly denying the existence of π-effects, these researchers attribute the
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additional stabilization of RAHBs to a shorter distance between the hydrogen donor and the acceptor.
That said, numerous papers witness a direct relationship between the π-electron skeleton and the
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structural parameters involved in RAHB. The π-electronic effects could then favor the stabilization
caused by hydrogen bonding and, in addition, the quasi-ring formed through the H-bridge can partially
adopt the role of a typical aromatic ring. Accordingly, the concept of aromaticity can be extended to
pseudo-aromatic rings (or quasi-aromatic rings), for which -electron delocalization mediated by
hydrogen bonding can be evaluated through indices based on geometrical considerations.10,11 Application
of the NBO theory reveals that the π-component of the electron density within the resonant spacer
determines the dominant characteristics of hydrogen bonding while σ-skeleta only reflect the π-
polarization.12
1
Recently, we have studied in detail the tautomeric and conformational equilibria of mono- [Ar -NH-
2
1
2
1
CH=CAr -CH=O] and di-azaderivatives [Ar -NH-CH=CAr -CH=N-Ar ] of malondialdehydes, namely
acrolein and vinamidines structures with extended conjugation.13 The major stabilizing effect favoring a
…
…
given tautomer or conformer is provided by intramolecular hydrogen bonding (O-H N and N-H N
bonds), which contributes to further electron delocalization.
The search for evidences in imines derived from salicylaldehyde constitutes a major challenge, because
the structure in solution may be different from that in the solid state.7,14 They can be regarded as
phenoliminic (1), ketoaminic (2) or zwitterionic (3) tautomers. Average bond distances values (from the
Cambridge Structural Database, CSD) for characteristic bond lengths in enol-imino and keto-amino
tautomers are shown in Scheme 1 (see this scheme for numbering of aromatic carbons along the
manuscript).15
R
N
R
N
R
8
(
2
)
1)
0(
N +
1.2
1.3
.41(2)
H
O
H
O
H
O
1
1.45(2)
1.41
-
1
(
2
)
1
.4
3(
1)
6
35(
1
)
9(
2)
2
.
.2
1
1
5
3
X
4
1
X
X
2
3
Scheme 1
More than 90% of N-substituted salycilaldimines derived from aliphatic and aromatic amines, registered
during the last fifty years in the CSD, exist predominately in enolimine form (1) in crystaline state.15,16
Nevertheless, literature search from 1970 to the present, shows that some of such derivatives adopt an
enamine structure (2) in the lattice. Some come from aliphatic amines16a,16d and others from aromatic
amines.16c,17 In a few cases, previously misassigned structures have been corrected,18 notably cases in
which the imine is described with a zwitterion structure (3).16b,19 Similar results emerge from 15N and 13
C
2
0
NMR spectra in the solid state. Furthermore, the structural elucidation is complex indeed as these Schiff
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bases are sensitive to heat and light leading to thermochromism and photochromism, respectively.21 In
general, the imine form is more stable than its enamine counterpart and changing populations of both
tautomers with temperature causes the thermochromism phenomenon.
While the imine form predominates in gas phase or in solution, the enamine form in crystalline state
adopts essentially a zwitterionic structure, stabilized by electrostatic interactions and intermolecular
hydrogen bonds. Thus, DFT calculations modeling the crystal lattice in the derivative of
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tris(hydroxymethyl)aminomethane (TRIS) and 5-bromosalicylaldehyde show that in solid state the
enamine is more stable than the iminic form, in total agreement with data obtained by X-ray diffraction.22.
The opposite occurs with N-(2-t-butylphenyl)salicylaldimine.22a
A priori, it remains uncertain to predict whether a particular salicylamine will present either imine or
enamine structures in the solid state or in solution. To a significant extent, substituents on the salicyl
aromatic core may bias the structural outcome. For example, derivatives of 2,3-dihydroxybenzaldehyde
show both imine23 and enamine24 structures in crystals. When the hydroxyl group at C-3 is alkylated, the
resulting compound adopts a phenoliminic disposition,25 although ketoamine structures have been
detected as well.26 Likewise, two compounds derived from 2,4-dihydroxybenzaldehyde presenting
enamine structures in the solid state have been reported.20,27 More complex structures are formed when
more than one o-hydroxyarylaldehyde moiety are involved.28 Thus, stable keto-enamine forms are
described for diimines of 3,6-diformylcatechol28a, triimines of 2,4,6-triformylphloroglucinol (mixtures of
regioisomers),28e and tetraimines of tetraformylresorcin[4]arene.29 Although this behavior seems to be
capricious, it appears that various factors, most likely electronic and steric, do affect the tautomeric
equilibria of salicyl imine/enamine structures. It is worth pointing out that this rapid equilibrium also
influences reactivity as disclosed recently by a mild deuteration method of aromatic compounds, whic is
facilitated by a keto-enamine tautomeric intermediate.30
It has been claimed that the position of proton in the intramolecular hydrogen bond is strongly determined
by substituents at salicylaldehyde and by substituents on the imine nitrogen atom (X and R, respectively
in Scheme 1). Substituents at the aromatic ring increasing acidity of the OH proton (i.e. electron
withdrawing group, EWG) promote proton transfer from oxygen to nitrogen. The same effect can be
obtained by increasing the basicity of the imine nitrogen atom by appropriate substitution patterns
electron donating group, EDG).20
(
However, on the basis of previous literature, the prediction of enol-imine versus ketoenamine forms is far
from being straightforward. There are no experimental quantitative studies on the electronic effect of
substituents on the tautomeric equilibrium in salycilimine derivatives, the purpose of the present paper is
to bridge this gap, looking for predictive rules, from which the major or unique structure adopted in the
solid state or solution could be inferred. Accordingly, we shall consider the influence of substituents on
…
the N-H O bonding of heteronuclear RAHBs in enaminone-iminoenol equilibria. This investigation is
also motivated by the fact that Schiff bases have received considerable attention owing to their
potentiality in so diverse areas such as liquid crystals,31 organic dyes,32 catalysts,33 and intermediates in
3
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5
o
r
g
a
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i
c
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e
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i
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c
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;
salicylideneaniline derivatives for instance were found to be effective against Mycobacterium
tuberculosis H37Rv.36
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RESULTS AND DISCUSSION
The electronic structure of aromatic Schiff bases and their conformation are interlocked issues.
Introduction of substituents at the aromatic ring modifies the properties of Schiff bases by changing their
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electronic structure and conformation.37 Thus, the anomalous substituent effects observed for
benzylideneanilines were explained by changes in the molecular conformation induced by substituents.38
Likewise, the correlation between 13C chemical shifts and the Hammett parameters evidenced a twisted
conformation of salicylideneanilines.39 To remove the conformational complexity, we chose Schiff bases
derived from salicylaldehydes and TRIS. The geometry of the tris(hydroxymethyl)methyl group
eliminates interference of possible conformations and electronic changes that they can cause. To this end,
the influence of substituents at the aromatic ring on the tautomeric ketoamine-phenolimine equilibrium
was investigated.
Synthesis of Salicyliden Derivatives of TRIS. A wide series of Schiff bases 4-33 could easily be
obtained by reaction of TRIS whith both monosubstituted and polysubstituted salicylaldehydes (see SI).
C(CH OH)
C(CH2OH)3
N
C(CH2OH)3
N
C(CH OH)3
N
C(CH OH)3
N
2
3
2
2
N
OH
OH
OH
X
MeO
OH
X
OH
X
X
Y
4
5
6
X = NO2
20 X = OEt
21 X = OMe
22 X = OH
23
1
4 X = NO2
24 X = Me, Y = OH
25 X = Y = OMe
X = CO Me
2
15 X = F
X = F
1
1
1
1
6 X = Cl
7 X = Br
8 X = OMe
9 X = NEt2
7 X = Cl
8
9
X = Br
X = I
1
0 X = H
11 X = Me
1
1
2 X = OMe
3 X = OH
C(CH OH)
N
C(CH OH)3
C(CH OH)3
C(CH OH)3
2
3
2
2
2
N
N
N
OH
OH
OH
OH
OH
X
X
X
OMe
Br
Br
OH
OMe
27 X = F
31 X = NO2
32 X = Br
26
33
28 X = Cl
29 X = Br
3
0 X = NO2
Structure and Tautomeric Equilibrium in the Solid State. In the absence of single-crystal data,
accurate structural elucidation is not always obvious from other techniques. FT-IR spectroscopy is a
valuable tool, nevertheless. The streching vibrations of the C=N (imine) and C=O (enamine) bonds
usually overlap; however, the intensity of the latter is much higher than the less polar C=N bond (in fact
the carbonyl absorption becomes the most intense band). This comparative assessment should be taken
with caution as diagnostic criterium in assigning the predominant tautomer in the solid state. Table 1S
lists the most significant IR absorptions of all Schiff bases synthesized. The existence of multiple
hydrogen bonds, both inter- and intramolecular, is reflected by the broad absorption of OHs and NHs
streching vibrations, almost covering the entire 3500-2000 cm-1 region. In general, and as mentioned
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above, the more intense absorption appears at 1650-1625 cm-1 (휈C=O) and, frequently, it has a similar
intensity as the band at 1610-1590 cm-1 (휈NC=C), often overlapped. The intensity of both absorptions,
typical of intramolecularly linked NH-C=C-CO enaminic systems, allow to conclude that in solid state at
room temperature all have enaminic structure (34-63). This conclusion is supported by the background on
the solid state structure of Schiff bases derived from TRIS, as some salicylaldehyde derivatives have been
previously prepared and their solid state structures studied by X-ray diffractometry (see SI).22b,40,41
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C(CH OH)
NH
C(CH2OH)3
NH
C(CH2OH)3
NH
C(CH OH)3
NH
C(CH OH)3
NH
2
3
2
2
O
O
O
X
MeO
O
X
O
X
X
Y
3
4 X = NO2
50 X = OEt
51 X = OMe
52 X = OH
53
54 X = Me, Y = OH
55 X = Y = OMe
4
4
4 X = NO2
3
3
3
5 X = CO Me
6 X = F
7 X = Cl
2
5 X = F
46 X = Cl
7 X = Br
8 X = OMe
4
4
4
38 X = Br
3
4
4
9 X = I
0 X = H
1 X = Me
9 X = NEt2
42 X = OMe
3 X = OH
4
C(CH OH)3
C(CH OH)3
C(CH OH)3
C(CH OH)3
2
2
2
2
NH
NH
NH
NH
O
O
O
O
OH
X
X
X
OMe Br
Br
OH
56
OMe
63
5
5
5
7 X = F
8 X = Cl
9 X = Br
61 X = NO2
62 X = Br
60 X = NO2
In summary, all imines derived from salicylaldehydes and TRIS determined by X-ray diffraction, both by
ourselves (38 , 48, 53, 57 and 6422b) and other teams (34,40e,g 37,40c,40h 38,40e 40,40a-40d 50,40g, 51,40d
4
2
22b
42
42
42
40f
5
2,40d 66, and 67,26,40f,40i 68,40j 69,41a 7041b,41c 71,41d 72,41e 73,41e 74,41e 75,41a 76,41c 77,41f 78 ) show either
enaminic or zwitterionic structure, which applies to 65 as well.22b Therefore, it is plausible to conclude
that all Schiff bases derived from TRIS synthesized in this work (4-33) should have solid state enamine
structures (34-63). Interestingly, another group,40f based on IR data alone, conjectured that Schiff bases
7
2
9 (Y = F, Cl, Br, I, Et, NO , Ac) should most likely be enamine tautomers in solid state.
C(CH2OH)3
C(CH2OH)3
N
H
N
H
O
O
C(CH2OH)3
N
C(CH2OH)3
NH
N
N
OMe
N
N
OH
O
X
66 X = 2-Cl
X
64
65
75 X = 2-Cl
7
7
6 X = 3-Cl
7 X = 4-Et
67 X = 3-Cl
68 X = 2-Me
69 X = 4-Me
78 X = H
9 X = 4-Y
7
70 X = 3-CF3
71 X = 4-nBu
72 X = 2,6-Cl2
73 X = 4-MeO
74 X = 3-MeO
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Structure and Tautomeric Equilibrium in Solution. As noted above, compounds 4-33 may exhibit in
solution a tautomeric behavior different to that adopted in the solid state. The imine form can be inferred
1
from the presence of two singlet signals in H NMR spectra, one shifted downfield (~13-15 ppm) for the
phenolic proton bound intramolecularly, and the other for the imino proton (~8.5-9.5 ppm). Conversely,
an enamine structure will show two doublet signals that are coupled each other, one corresponding to the
intramolecularly bound NH group (~14-16 ppm), along with the ethylene proton (~8.5-10 ppm). Since
chemical shifts are similar in both structures, only the multiplicity of signals matters as diagnostic
element.43-45 Besides, there are also significant differences in 13C NMR spectra, because the phenolic
carbon of imines appears at a higher field than the carbonyl signal of enamines (~155-160 ppm versus
~170-181 ppm),45,46 and 15N NMR spectra, where the iminic nitrogen appears at a higher field than the
enaminic nitrogen (~ -63 ppm versus ~ -247 ppm).43,47 In addition, one cannot forget that, like in the solid
state, the structure in solution often varies with temperature.47,48
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Table 2S collects both H and 13C NMR data of Schiff bases 4-33. Although in the solid state at room
1
temperature all have enamine structures (34-63); half of them in DMSO-d solution adopt an imine
6
structure (JH,NH = 0 Hz). In contrast, Schiff bases 4, 5, 14, 15, 18, 20, 21, 23-25 and 28-33 appear to
exhibit enamine structures, consistent with non-zero appreciable couplings (JH,NH ≠ 0 Hz). Nevertheless,
the unequivocal assignment is not as simple as thought due to a rapid equilibrium between the two
tautomeric forms. The observed chemical shifts (δexp) are an average of those corresponding to the "pure"
i e i i e e i e
imine and enamine forms (δ and δ , respectively). In other words: δexp = n δ + n δ , where n and n are
the populations of molecules with imine and enamine structures, respectively. The same happens with the
coupling constants (varying between 0 and 14.6 Hz), which for the tautomeric equilibrium can be
represented by equation Jexp = n
have coupling constants JH,NH ≠ 0 Hz, which would indicate an enamine structure, chemical shifts of C-2
~159 ppm) are typical of an imine structure. That is, in the imine-enamine equilibrium the population of
i i e e i e
J + n J (Obviously, n + n = 1). This explains why even if 20 and 21
(
molecules with imine structure is predominant, although the existence of residual coupling suggests the
coexistence with enamine tautomers.
Substituent Effects on the Tautomeric Equilibrium: Predominant Structures in Solution. The
3
presence of a strong intramolecular hydrogen bond (~10-20 kcal/mol), consistent with a chelate ring, is a
valuable motif that can be harnessed in structural elucidation. The position of the hydrogen atom,
covalently linked to oxygen in phenolimines or to nitrogen in ketoenamines, obviously depends on the
relative basicity of both atoms: hydrogen will bind to the most basic atom. In this sense the proton
transfer process can be interpreted as an intramolecular acid-base reaction between a donor (D) and an
acceptor (:A):
R-D-H…..:A-R1
R-D:….. H-A-R1
Moreover, this hydrogen bonding will be stronger as the difference of basicity in solution (ΔpK
proton affinity in the gas phase (ΔPA) decrease, which is known as the "pKa/PA equalization principle"
ΔpK
or ΔPA ≈ 0).49 A conspicuous example of this principle is provided by malondialdehyde, in which
a
) or
(
a
the transfer of the intramolecularly bound proton of the cyclic enolic form and the delocalization lead to a
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structure identical to the initial one. It is obvious that ΔpK
formed (15-25 kcal/mol). On the other hand, between an alcohol and a ketone, R O-H O=CR
21-25 and the resulting bond is very weak indeed (4-5 kcal/mol).49a In our case both ends basic centers are
a
= 0 and a very strong hydrogen bond is
1
….
2
, ΔpKa ≈
a
not equal and ΔpK ≠ 0, so the hydrogen bridge is not as strong (2-15 kcal/mol) as that of
malondialdehyde.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
It is therefore pertinent to ascertain how the electronic character of the substituents affects the basicity of
the oxygen and nitrogen atoms involved in the tautomeric equilibrium. Their basicity depends in turn on
the electron density of each atom, which is otherwise reflected by the chemical shift of the proton, the
nitrogen atom, and the iminic and phenolic carbons in their NMR spectra. Although previous
investigations address the effect of the substituents on the chemical shift of the iminic hydrogen and
carbon atoms in simple imines,50 it is surprising to note that little or no experimental studies have been
conducted to evaluate their influence on the imine-enamine structures of Schiff bases from
salicylaldehydes, thus making it impossible to predict the prevalent tautomer in solution.
In our study, for simplicity, only the substituents at the aromatic rings were taken as variables. Scheme 2
illustrates the whole phenolimine-ketoenamine tautomeric equilibrium.
R
NH+
OH
KaNH+
KaOH+
H+
-H+
+
X
R
N
R
R
+
H+
N O
KT
-
+H+
NH+
NH
OH
O-
O
R
N
R
N-
-H+
+H+
X
X
X
+
-
NO
H+
-H+
N O
+
O-
O
KaOH
KaNH
X
NO-
X
-
N O
Scheme 2
The acid dissociation constants are defined by the following equations [1]:
-
+
-
+
[
NO ][H ]
[NO ][H ]
KaOH
=
KaNH
,
,
=
+
-
[NO]
[N O ]
[1]
[
NO][H+]
[N O ][H ]
+
-
+
KaNH+
=
KaOH+
,
=
+
+
[N O]
[N O]
The pK
tautomeric equilibrium constant K
values, measured experimentally for some salicylimines, lie within ~7.8-10.51 Acordingly, the
a
T
can be expressed from equation [2] as:
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
-
KaOH
KaNH
KaOH+
[
N O ]
K =
=
=
T
KaNH+
[
NO]
[2]
By considering the electronic effects exerted by the substituents on the phenolic hydroxyl and the iminic
nitrogen, and assuming independent behavior of both groups, the substituent effect on the former can be
described by the Hammett equation [3]:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
= ρOH
OH
log K
a
σ
x
+ a
[3]
[4]
In a similar way, the effect on the imine functionality can be described by equation [4]:
NH
= ρNH
NH
log K
a
σ
x
+ b
OH
x
OH
x
NH
Where σ
x
= σpara if the substituent is placed at C-5 and σ
x
= σmeta if it is at C-4. Analogously, σ
x
=
x
NH
x
σ
para when the substituent is located at C-4 and σ
x
= σmeta when it is at C-5.
Conversion of both equations into the logarithmic form of equation [2] leads to [5], where c = a-b.
OH
NH
= ρOH
OH
- ρNH
NH
log K
T
= log K
a
- log K
a
σ
x
σ
x
+ c
[5]
In strict sense, however, the imino and phenolic groups do not act independently, since they are connected
through a spacer that allows a continuous delocalization between them and, in addition, united to each
other by the hydrogen bonding. Gilli et al.49d have suggested that Schiff bases derived from
salicylaldehydes are a fine example of synergy between the strength of the hydrogen bond and the degree
of π-delocalization, whereas Krygowski et al.52 state that the most important factor affecting the
delocalization of π-electrons through the linker is the effect of groups attached to the ring, one of whose
bonds is part of the spacer itself. In addition, Solà et al.9h indicate that the effect of the substituents and
the effect of the mesomeric assistance on the hydrogen bond are mutually cooperative, and both effects
can then be treated as components of the same phenomenon. In this way, any electronic alteration is
transmitted along the spacer and the hydrogen bond, which results in leveling of the electronic density
and matches the pK
a a
of both termini. The argument merely reinforces the principle of equalization of pK
values (ΔpK ≈ 0).
a
Since the effect of two different substituents (X and Y) on a chemical function attached to an aromatic
ring can be represented by the same value of ρ, thereby making effects additive in Hammett's equation,
log Kxy = ρ
salicylidene derivatives one can accept the hypothesis that ρOH = ρNH = ρ, thus simplifying equation [5] to
6]:
x x y y x y x y x y
σ +ρ σ = ρ(σ +σ ) = ρΣσxy, where ρ = ρ = ρ, Σσxy = σ +σ ; similarly, in the case of
[
OH
NH) + c = ρ σef + c
log K
T
= ρ (σ
x
- σ
x
[6]
OH
- σ
x
NH, represents the net or effective effect that a given substituent X exerts on
The difference σef = σ
x
the delocalized cyclic tautomeric system, while c is a constant, which should in principle be different
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from zero, due to the different termini of the tautomeric skeleton. However, as we shall see later, for
TRIS derivatives c ≈ 0 (c = 0.04).
It is well known that the electronic effect of a substituent in meta-position is essentially inductive,
whereas in para-substitution it is composed of inductive and resonance effect. Hence it is evident that σef
largely represents the mesomeric effect of a substituent on the tautomeric system. With the adopted
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
T
definition of K the values of σef have a parallel interpretation to those of σ; that is, a negative value of σef
indicates a positive mesomeric or electron-releasing effect, while a positive one implies a negative
mesomeric or electron-withdrawing effect.
OH
NH, then σef = 0 and K
Accepting that c = 0, if σ
x
= σ
x
T
= 1; that is, both forms, imine and enamine, are in
< 1 and the imine structure
>1 and the enamine structure is the
OH
NH, then σef ≤ 0, K
x T
equilibrium in identical proportions. If σ
x
≤ σ
NH, then σef ≥ 0, K
T
OH
predominates; on the other hand, if σ
x
≥ σ
x
prevalent form. Table 1 shows the values of σef for various salicylidene derivatives monosubstituted at C-
3
and C-5 positions, which are related to their structures in solid state and solution.
Table 1. Correlations of tautomeric preferences in solid state and solution with Hammett constants of
monosubstituted salicyl derivatives.
Solid
state
a
a
b
σ -OHc
σ +NHd
±e
Solutionh
Compound
X
σ
OH
σ
NH
σ
ef
σ
e f
i
4
5
6
7
8
9
5-NO
2
0.81
0.44
0.15
0.24
0.26
0.18
0.00
-0.14
-0.28
-0.38
0.71
0.34
0.37
0.37
0.10
-0.23
0.39
0.71
0.35
0.34
0.37
0.37
0.34
0.00
-0.06
0.10
0.13
0.81
0.15
0.24
0.26
-0.28
-0.72
0.32
d
0.10
0.09
-0.19
-0.13
-0.11
-0.16
0.00
-0.08
-0.38
-0.51
-0.10
0.19
0.13
0.11
0.38
0.49
0.07
1.23
0.74
0.15
0.24
0.26
0.18
0.00
-0.14
-0.28
-0.38
0.71
0.34
0.37
0.37
0.10
-0.23
0.39
-
0.71
0.35
0.34
0.37
0.37
0.34
0.00
-0.16
0.10
0.13
0.81
-0.07
0.11
0.15
-0.78
-1.70f
0.32
f
0.52
0.39
-0.19
-0.13
-0.11
-0.16
0.00
-0.08
-0.38
-0.51
-0.10
0.41
0.26
0.22
0.88
1.47
0.07
enamine
enamine
imine
enamine
2
5-CO Me
5-F
5-Cl
5-Br
5-I
imine
enamine
enamine
enamine
enamine
imine
imine
1
1
0
1
H
imine
5-Me
5-OMe
5-OH
imine
12
imine
enamine
enamine
1
1
3
4
imine
4-NO
4-F
2
imine
15
enamine
enamine
enamine
enamine
enamine
enamine
enamine
1
1
1
1
6
7
8
9
4-Cl
4-Br
4-OMe
4-NEt
5-PhN
enamine
enamine
enamine
h
2
67g
2
aReference 53a. bσOH - σNH. Reference 53b. Reference 53c. σ OH – σ +NH. σ (4-NMe
c
e
). References 26,40f; In DMSO-d
g
.
2
6
iFrom X-ray data.
It can be seen that all substituents having σef ≤ 0 values, which are fundamentally substituents at the C-5
position, afford imine structures in solution. In stark contrast, for values of σef ≥ 0, largely substituents at
C-4, an enamine structure is prevalent in solution. Obviously, for σef ~0 values there is ambiguity in the
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assignment of either imine or enamine structure as the predominant species. Examples of calculated σef
values are shown in Figure 1. As expected, there is no correlation between the effect of the substituents
and the resulting solid state structure, as packing forces in the crystal can reverse the structure observed in
solution. It is also worth mentioning that as solid state structures are often obtained at low temperatures,
the enamine tautomer may be preferred under these conditions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
0
1
2
3
4
5
6
7
8
9
0
C(CH OH)
2
3
NH
C(CH OH)
2
3
N
O
OH
OMe
48
MeO
12
OMe
= σparaOMe – σmetaOMe
OMe
= σmetaOMe – σparaOMe
=
σ
ef
=
σ
ef
=
-0.28-0.10= -0.38
= 0.10-(-0.28)= 0.38
Enamine: δC2 174.2 ppm, JCH,NH 6.0 Hz
Imine: δC2 156.6 ppm, JCH,NH 0.0 Hz
C(CH OH)
C(CH OH)3
2
3
2
N
NH
OH
MeO
O
OMe
21
53
OMe
= σortoOMe – σmetaOMe
OMe
= σmetaOMe – σparaOMe
=
σ
ef
=
σ
ef
=
0.00-0.10= -0.10
= 0.10-(-0.28)= 0.38
Enamine: δC2 170.8 ppm, JCH,NH 6.4 Hz
Imine: δC2 158.8 ppm, JCH,NH 4.0 Hz
Figure 1. Calculated Hammett constants (OMe substitution) and preferential tautomer composition in
solution from proton NMR data.
For either imine or phenol functionality, the electronic effect supplied by a substituent depends on their
relative positions. As shown in Scheme 3, for imine 80 a nitro group (strong EWG), positioned para to
the hydroxyl may increase the acidity of the latter by both inductive (-I) and mesomeric (-M) effects.
When the same group is placed meta with respect to the imine group, it exerts an inductive effect (-I)
only; however the basicity associated with the lone pair on nitrogen (located in the nodal plane of the π
system) is not substantially altered by mesomeric effects.
R
N
R
N
H
O
H
O+
-O
+
-H+
R
N
O
+
N
N
O-
O- 80
O
-O
+
N
O-
-
H+
R
N
R
+
N
H
O
H
O
-O
+
O
+
N
N
O-
O- 81
Scheme 3
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Although the nitro group at C-5 increases the acidity of both the OH of phenol form (80) and the NH of
OH
NH
NO
– σmetaNO
=
2 2
8
1, the first effect predominates as evidenced by the value σefNO
2
= σNO2 - σNO2 = σpara
0.81-0.71 = 0.10. Therefore, the preferential structure adopted in solution corresponds to enamine (34,
JCH,NH = 8.8 Hz, δC2 = 180.2 ppm). It is relevant to note that this result is not a consequence of how
OH
– σ
x
NH.
powerful the electronic effect of the substituent is, but rather of the difference σef = σ
x
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Therefore, the methoxycarbonyl group placed at the same position, even being more moderate attractor
than the nitro group, does actually exert the same effect, since the value of σef is essentially the same:
OH
NH
σ
CO2Me - σCO2Me = 0.44-0.35 = 0.09 (35, JCH,NH 9.2 Hz, δC2 176.7 ppm).
When the EWG is in the meta-position to the hydroxyl (82), its acidity increases by (–I) effect and
concomitantly decreases the basicity of the nitrogen by (–M) effect. The resulting effects are similar on
the enamine structure (83), the NH acidity increases while basicity of the carbonyl oxygen decreases
(Scheme 4).
R
N+
R
N
R
N:
H
O
H
O
-H+
O-
N
N
N
R
N+
-O + O-
O
+ O
-
-
O + O
82
O-
R
N-
-
N
-
R
R
N
O + O
+
N
H
O-
H
O
-H+
O
N
+
N
+
N
+
O-
O
O-
O-
O
O
83
Scheme 4
Again, the value of σef is going to dictate which effect predominates; now σefNO
= σNO2OH - σNO2NH
=
2
NO
– σparaNO = - (σparaNO – σmetaNO
) = 0.71-0.81= -0.10 and the equilibrium is shifted towards the
2 2 2 2
σ
meta
imine form (14/44, JCH,NH 5.6 Hz, δC2 168.6 ppm). In fact, the value of δC2 is very close to the value it
adopts when K = 1 (δC2 167.7 ppm, see later), which indicates a slight excess of the enamine form in
solution. The above examples emphasize that the effect exerted by a substituent in one position is
T
reversed by passing to the other, because it will always be true that (σpara – σmetaX) = - (σmeta – σparaX);
X
X
that is, σef5-X = - σef4-X.
An EDG with lone electron pairs on para-position relative to the hydroxyl will have a different effect to
the nitro group. The OH acidity will be decreasing by destabilizing the phenoxide ion (effect +M > -I),
while the basicity of the nitrogen decreases as well by inductive effect (-I). Both effects are opposed and
the former predominates over the second. Something similar happens for the enamine tautomer (Scheme
OH
NH
MeO
1
S). A clear-cut example is provided by the methoxy group, for which σefMeO = σMeO - σMeO = σpara
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
– σmetaMeO = - 0.28-0.10 = - 0.38 and the preferential structure of 12 in solution is iminic (JCH,NH 0.0 Hz,
δ
C2 156.6 ppm) (Figure 1).
Scheme 2S illustrates the remaining case when the EDG with lone pairs is placed at the meta-position to
the hydroxyl, as the latter increases its acidity (effect -I) and the substituent effect increases the basicity of
nitrogen too (+M effect). The effect is now reversed because σefMeO = σMeOOH - σMeONH = σmetaMeO
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeO
para
= 0.10-(-0.28) = 0.38; that is, σef4-X = - σef5-X, and the structure of 18 in solution is enamine (JCH,NH
σ
6
.0 Hz, δC2 174.2 ppm) (Fig. 1). Similar conclusions can be reached when EDG and EWG devoid of lone
pairs are present (e.g., methyl or trifluoromethyl, respectively), whose influences hinge on
hyperconjugation. Table 1 also collects the values of σ-OH = σ-5X and σ+NH = σ+4X, as well as the values of
±
±
σ
ef (= σ-OH - σ+NH). In most cases the absolute values of σef are greater than or equal to the absolute
values of σef (|σef±| ≥ |σef|). However, the results and conclusions reached remain unaffected.
Steric Effects on Tautomeric Equilibria. For substituents at C-3, position adjacent to the hydroxyl, the
corresponding σOH values are not usually tabulated because they are contaminated by steric effects. For
relatively small groups, such as oxygen-containing functions, the values of σOH at the para-position have
been taken; that is, it has been assumed that the effect exerted on C-3 is virtually identical to that exerted
on C-5. Similarly, the values for substituents at C-6, adjacent to the iminic group, have been equated to
those located at C-4. Bulkier groups such as Cl, Br or I can add significant alterations by approaching the
phenolic group to the imino group, thereby increasing the strength of the hydrogen bridge (as the distance
4
9
between oxygen and nitrogen atoms becomes shorter). As expected, substituents such as the nitro group
or the methoxycarbonyl would hinder their delocalization on the aromatic ring due to the lack of
coplanarity. Remarkably, predictions on the structure in solution for these compounds, reached by
equating the values σOH and σNH of substituents at C-3 and C-6 to those of C-5 and C-4, respectively, are
coincidental with the tautomers found experimentally. The use of the σortho constants reported by Barlin
and Perrin54 for ortho-substituents on phenols does not introduce any variation in the results obtained for
3
-substituted salicylidenimines (Table 2): σef ortho = σx orthoOH – σ metaNH. No σortho values have been
x
communicated for substituents contiguous to the imine group; we chose the use of σpara values for such
specific cases.
Table 2. Correlations of tautomeric preferences in solid state and solution with Hammett constants for 3-
substituted salicylidenimines.
Solid
structure
a
a
b
ortho c
ef
σ-OHd
σ+NHe
±f
Solutionf
Compound
X
σ
OH
σ
NH
σ
ef
σ
σ
ef
20
3-OEt
3-OMe
3-OH
-0.24
-0.28
-0.38
0.10
0.10
0.10
0.13
-0.28
-0.34
-0.38
-0.51
0.38
-0.10
-0.10
-0.51
0.38
-0.24
-0.28
-0.38
0.10
0.10
0.10
0.13
-0.78
OEt
-0.34
-0.38
-0.51
0.88
imine
imine
imine
enamine
d
enamine
2
2
2
1
2
3
enamine
enamine
enamine
6-OMe
aReference 53a. bσOH - σNH. cσefortho calculated with the values σortho (σorthoOMe = σortho = 0.0), reference 54. Reference 53b.
eReference 53c. fσ -OH – σ +NH. fIn DMSO-d
.
6
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Newly owing to the different performance of substituent at different positions, the values of σef at C-3 and
C-5 are reversed by moving to positions C-4 and C-6, with consequent variation in the structure adopted
in solution. This is illustrated by the drastic effect caused by some substituents; for example, the methoxy
group at position C-5 (12) or C-3 (21) leads preferentially to imine structures, but at C-4 (18) or C-6 (23)
the enamine tautomer is generated (Figure 1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Electronic Effects on Polysubstituted Schiff Bases. The preceding Hammett-type analysis can be
extended to polysubstituted salicylaldehydes. Thus, for several substituents X, Y, ... one can write
equations [7-9]:
OH
NH) + ρ (σ
OH
NH) + ….. + c = ρ Σ(σ
OH
NH) + c
log K
log K
log K
T
T
T
= ρ (σ
x
- σ
x
y
– σ
y
i
– σ
i
[7]
[8]
[9]
x
y
i
T
= ρ σef + ρ σef + ….. + c = ρ Σσef + c = ρ σef + c
OH
NH) + c = ρ (Σσ
OH
– Σσ
i
NH) + c
= ρ Σ(σ
i
– σ
i
i
and equations [8] and [9] are transformed into [10]:
OH
NH) + c = ρ σef + c
T
log K
T
= ρ (Σσ
i
– Σσ
i
[10]
T
i
OH
NH
where now σef = Σσef = Σσ
i
– Σσ
i
and c is a constant.
OH
NH, then σef ≤ 0, K
>1 and the enamine tautomer is
Since c ≈ 0 for TRIS derivatives, if Σσ
x
≤ Σσ
≥ Σσ
NH, then σef ≥ 0, K
favored. Table 3 collects data for various polysubstituted compounds.
x
T
<1 and the imine structure
OH
predominates; on the other hand, if Σσ
x
x
T
Table 3. Correlations of tautomeric preferences in solid state and solution with Hammett constants for
polysubstituted TRIS-derived salicylimines.
Solid
state
ΣσOHa
ΣσNHa
b
ortho c
ef
Σσ-OHd
Σσ+NHe
± f
σ
ef
Solutiong
Comp.
X
σ
ef
σ
2
4
4-OH-6-Me
0.07
0.20
-0.25
0.30
0.48
0.52
1.62
-0.52
-0.56
-0.25
0.68
0.74
0.74
1.42
0.59
0.76
0.00
-0.38
-0.26
-0.22
0.20
0.07
0.20
-0.25
0.30
0.48
0.52
2.46
-1.23
-1.56
-0.79
0.68
0.74
0.74
1.42
1.30
1.76
0.54
-0.38
-0.26
-0.22
1.04
enamine
enamine
imine
enamine
25
4,6-(OMe)
2
2
2
2
2
6
7
8
9
3,4-(OH)
3,5-F
2
0.00
0.01
0.18
0.22
0.63
enamine
enamine
2
imine
3,5-Cl
3,5-Br
2
enamine
enamine
enamine
2
30
3,5-(NO
2 2
)
3
1
5-NO -3-OMe
2
0.53
-0.02
0.62
0.81
0.47
0.46
-0.28
-0.49
0.16
0.00
0.95
-0.02
0.62
0.81
0.47
-0.04
0.14
-0.49
0.66
enamine
imine
32
5-Br-3-OMe
3,5-Br -4-
OMe
-0.21
0.60
2
3
3
enamine
aReference 53a. bσOH - σNH. c ef calculated with the values σortho, reference 54. Reference 53b. Reference 53c. σ OH - σ+NH. gIn
d
e
f -
σ
6
DMSO-d .
±
For compounds 27-29 and 31, both σef and σef values are < 0, which points to imine structures. This
prediction, however, disagrees with the actual enamine structure in solution of dihaloderivatives 28 and
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
29, probably due to the steric effects created by bulky Cl and Br atoms at C-3. By employing the σortho
values of Barlin and Perrin,54 then σefortho > 0 (0.18 and 0.22, respectively), consistent with the formation
of enamine tautomers in solution. The values of σefortho ~ 0 shown by 27 and 31 prevent their predictive
structure in solution; in fact compound 27 is imine (σefortho ~ 0) whereas 31 is an enaminic derivative
ortho
(σ
ef
= 0.00).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Structural Predictions in Schiff Bases: Reliability, Scope and Limitations. In order to prove how
reliable the above treatment is to predict the structure of unknown and known Schiff bases in solution,
further explorations were undertaken. Thus, compounds 13 and 84-86 (Table 4) illustrate how the
arrangement of phenolic hydroxyls can dictate their preferred structure in solution. While 13 is imine (σef
= -0.51), 84 (σef = 0.51) and 86 (σef = 1.02) would be enamines. By moving the OH group from C-6 (86)
to C-5 in 85 (σef = 0), the tendency to form an enamine tautomer is virtually removed. Although 84 has
not yet been synthesized, its analogue 24 has enamine structure as predicted for 84 (the methyl group at
C-6 does not cause any appreciable alteration since its σef = 0.08). Predictions can be extended to external
factors capable of governing the tautomeric equilibrium such as the acidity or basicity. Transformation of
phenols 13, 22 or 84 into their conjugate bases 87-89 would still maintain the imine or enamine character
they already possess.
C(CH OH)3
N
C(CH OH)3
N
C(CH OH)3
N
C(CH2OH)3
N
C(CH OH)3
N
C(CH2OH)3
N
2
2
2
2
OH
OH
HO
OH
OH
OH
OH
-O
O-
HO
O-
OH
OH
OH
86
84
85
87
88
89
Table 4. Predicted structure in solution through substituent constants for polyhydroxylated Schiff bases.
Predicted
structure
a
a
b
σ-OHc
σ+NHd
± e
σ
ef
Comp.
X
σ
OH
σ
NH
σ
ef
8
4
4-OH
4,5-(OH)
4,6-(OH)
5-O-
0.13
-0.25
0.26
-0.38
-0.25
-0.76
-0.47
-0.47
-0.81
d
0.51
0.00
1.02
-0.34
-0.34
0.34
0.13
-0.25
0.26
-0.81
-0.81
-0.47
-
-0.38
-0.79
-1.84
-0.47
-0.47
-0.81
0.51
0.54
2.10
-0.34
-0.34
0.34
enamine
85
2
2
?
8
8
6
7
enamine
imine
-0.81
-0.81
-0.47
88
3-O-
imine
8
9
4-O-
enamine
aReference 53a. bσOH - σNH. Reference 53b. Reference 53c. σ OH - σ+NH
c
e
.
Salicylimines derived from anilines also obey equation [5], although the constant term (c) can now be
different from zero (c  0). The enamine structure described for Schiff bases 66-79,26,40f is in agreement
with the positive value of σef calculated for compound 78 (Table 1). Also, imines derived from 2,3-
dihydroxybenzene-1,4-dicarbaldehyde (90) and 2,5-dihydroxybenzene-1,4-dicarbaldehyde (91) have in
solution imine structures, which correlate well with the magnitude of σef (< 0), while those from 2,4-
dihydroxybenzene-1,3-dicarbaldehyde (92) and 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde (93)
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exhibit on the contrary an enamine structure (σef > 0) (Table 5).28 The latter is clearly prone to form
enamines (96, 97, Scheme 5),28d,55 which agrees with the arrangement of the three hydroxyl groups, like
86.
CHO
CHO
CHO
CHO
CHO
CHO
OH
OH
OH
OH
HO
OH
OH
OH
OH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
CHO OHC
CHO OHC
OHC
CHO
CHO
OH
OH
OH
OH
90
91
92
93
94
95
Table 5. Predictions and reported tautomers for N-phenylamines derived from aldehydes 90-95.
Predicted
structure
Solid
state
Imines ofa
∑σOH
∑σNH
σ
ef
b
Solution
9
0
-0.03
-0.03
0.55
1.10
0.55
0.17
0.55
0.55
-0.58
-0.58
0.58
1.16
0.58
imine
imine
imine
imine
imine
91
9
9
2
3
-0.03
-0.06
-0.03
0.10
enamine
enamine
enamine
enamine
enamine enamine
enamine enamine
imine
94
9
5
0.07
imine
a
Referred to N-phenylimines. b For CH=NPh, σ
p
m
= 0.42 and σ = 0.35 (ref. 53a).
Ar
N
Ar
O
H
N
H
H
O
O
O
O
O
N
O
ArNH2
H
N
H
O
+
Ar
O
O
O
H
N
O
N
H
Ar
Ar
H
H
Ar
93
96
97
Scheme 5
A curious case involves the Schiff bases derived from 2,4-dihydroxybenzene-1,5-dicarbaldehyde (94) and
,3,4-trihydroxybenzene-1,5-dicarbaldehyde (95), as they show an imine structure in solution (98, 99).28e
2
While there is some ambiguity for the latter, because σef ~ 0, the former with σef = 0.58 should correspond
to the enaminic tautomer. However, in both cases the paradox is solved if one assumes that in order to
form a dienaminic structure, diradical species (100, 101), whose formation would otherwise be
energetically unfavorable, are required.
Ar
Ar
Ar
Ar
.
.
N
H
N
H
N
H
N
H
O
O
O
O
X
X
9
8 X=H
100 X=H
101 X=OH
99 X=OH
Previous theoretical calculations have been used to predict the structure of some Schiff bases, not yet
synthesized, derived from anilines and other polysubstituted salicylaldehydes like 102-10728c,28d. Results
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
fully agree with our predictions gathered in Table 6, even if some uncertainty occurs for the imines
derived from 103, 105 and 107, since σef = 0. For the two latter ones, the calculations suggest the imine
and enamine, respectively, to be the most stable tautomers. Like the cases of 98 and 99, the dienamine
structure of 106 would lead to a diradical species.
CHO
CHO
CHO
CHO
CHO
CHO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
OH HO
OH
OH
HO
CHO
OH
CHO
OH
OHC
HO
CHO
OH
HO
OH
OH
OHC
OH
OH
CHO
102
103
104
105
106
107
Table 6. Predictions and reported tautomers for N-phenylimines derived from aldehydes 102-108 and
12.
1
Predicted
structure
Predicted
structure
Imines ofa
∑σOH
∑σNH
σ
ef
b
c
1
1
02
03
0.13
-0.25
-0.03
-0.03
0.52
-0.38
-0.25
0.55
0.55
0.52
0.52
-0.26
-0.50
0.51
0.00
-0.58
-0.58
0.00
0.00
-0.60
0.35
enamine
?
104
imine
imine
imine
imine
imine
?
1
1
1
05
06
07
imine
0.52
enamine
1
08d
-0.86
-0.15
imine
enamine
112
a
b
c
d
t
Referred to N-phenylimines. At the B3LYP/6-31G* level, reference 28e. This work, based on σef. R = Bu.
Application to imine/enamine cavitands serve to illustrate the scope further. Thus, campestarenes, a
family of stable, novel shape-persistent conjugated Schiff base macrocycles with 5-fold symmetry
mediated by 3-center hydrogen bonding (109, R = alkyl),56 can be obtained from aminosalicylaldehydes
(
108). These compounds, like the macrocycle with 3-fold symmetry 110,28a,28b have an imine structure, as
t
the starting salicylaldehydes, such as 108 (R = Bu) and 90, have negative values of σef. In contrast,
primary aliphatic and aromatic imines of tetraformylresorcin[4]arenes exist exclusively as keto-enamine
2
9
tautomers (111, R = alkyl, aryl), in agreement with positive σef values for 102 and 112 (Tables 5 and 6).
It is known that many tautomerizations are strongly solvent-dependent. As an illustrative example, the
keto-enamine form of macrocycle 109 is favored in polar solvents, whereas non-polar solvents do favor
the imine tautomer.56
R
R
N
R
H
O
N
O
N
O
N
O
H
H
H
HO
N
H
CHO
OH
H
N
O
O
O
CHO
iBu iBu
HO
R
OH
N
HO
OH
O
H
H
N
O
H
R
OH
N
H
N
OH
N
iBu
iBu
N R
O
H
R
NH2
O
O
CH3
CH3
N
N
R
112
H
108
H
O
O
R
H
109
110
N
R
111
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The most important conclusion to be drawn from all of the above is that not only the electronic character
of the substituents is responsible for the imine or enamine structure of salicylidene derivatives (in the
gaseous phase or solution), but also, and equally important, the position they occupy with respect to the
tautomeric system. This predictive analysis appears to be general, only limited by the knowledge of σ
values for specific chemical groups. Clearly, the availability of σortho data introduces another limitation. It
is important to stress again that the rule hinges on the substituent at the imino nitrogen as well, and
variations are sensitive to the independent term (c) in equations [6] and [9]. As repeteadly mentioned, for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tris(hydroxymethyl)methyl, C(CH
aliphatic or aromatic substituent. Examples are provided by Schiff bases 113 (X = H, F, Cl, Br, NO
OCH CD solution (σef = -0.10) or 114 (σef = -0.20) and 115
, CN)30a, which exhibit imine structures in Cl
2
OH)
3
, c ≈ 0; but the rationale could in principle be applicable to either
2
, CH
3
,
3
3
(σ
ef = -0.13), both imines in isopentane at room temperature.21a
X
N
N
N
H
O
H
O
OH
OCH3
tBu
tBu
Cl
113
114
115
Finally, the inability to form unstable species such as diradicals derived from 98, 99 and 106 may also
invalidate predictions based on the magnitude of σef. Obviously, solid state structures, for which crystal’s
forces rather than electronic effects, play a dominant role, often deviate from this trend. Condensates
derived from TRIS have all an enamine structure in solid state. In solution, the favorable structure of
compounds 6-13, 20-22, 27 and 32 is largely the imine tautomer. However, adducts 4, 5, 14, 15, 18, 20,
2
1, 23-25, 28-33 showed JCH,NH ≠ 0 values indicating that, in general, an enamine structure may also be
the predominating form (34, 35, 44, 45, 48, 50, 51, 53-55, 58-63).
Electronic Effects of Substituents on Chemical Shifts. As customary in assessing the electronic
influence of substituents in delocalized systems by NMR spectroscopy, correlations between the chemical
shift of the azomethine carbon with both Hammett and Taft substituent parameters allow to elucidate the
mode of transmission of the electronic effect, as well as the influence of substitution on the conformation
and polarity of the C=N bond.37,38,50,57
As pointed out in previous remarks, the basicity of the oxygen and nitrogen atoms involved in the
tautomeric equilibrium depends on the electron density of each atom, which is collectively well
understood by shift of the proton, the nitrogen atom, and the imino and phenolic carbons. Table 3S
summarizes the NMR data for the carbon of iminic Schiff bases bearing substituents at C-3 and C-5 (6-9,
1
1-13, 20-22, 27 and 32), which lead to a poor linear plot with σNH (regression coefficient, r = 0.798; Fig.
S). The low correlation is largely due to the influence of steric effects that contaminate the σNH values at
1
the positions adjacent to the phenolic hydroxyl. In fact, by removing such points, a good relationship is
obtained (r = 0.966; Fig. 2).
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6
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1
65.2
64.8
64.4
y = -1.9036x + 164.76
r = 0.966
164.0
163.6
0
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
0.1
0.0
0.1
0.2
0.3
0.4
σNH
Figure 2. Linear relationship between carbon resonances of iminic signals (C=N) and NH values (ortho-
substituents were deliberately omitted).
On the other hand, Hammett's representation for the enamines lacking steric effects, i.e. without
substituents at C-3 and C-6: 4, 5, 14-19, and 78 is linear, fitting well both the values of σNH and those of
+
σ
NH (Table 4S, Fig. 3).
(a)
(b)
1
1
67.0
66.0
167.0
166.0
165.0
164.0
163.0
162.0
161.0
160.0
y = 3.4777x + 163.5
r = 0.928
y = 2.1252x + 164.24
r = 0.950
165.0
164.0
1
1
1
1
63.0
62.0
61.0
60.0
-
1.0
-0.5
0.0
σ
0.5
1.0
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
+
NH
σ
NH
Figure 3. Linear relationship between iminic chemical shifts (C=N) and NH (a) and +NH parameters for
compounds 4, 5, 14-19, and 78.
Also, data for enamines 26, 28-31 and 33, substituted at C-3, position contiguous to the phenolic
+
hydroxyl, lead to fairly good linear plots with both σ (r = 0.957) and σ (r = 0.940), although the fit is
better against the former (Table 4S, Fig. 2S). When the representation is carried out for imines as function
of σef, a pretty good linear relationship is obtained again (if one omits the divergent case of compound 11)
(Fig. 4).
1
1
1
1
1
65.1
64.7
64.3
63.9
63.5
y = -1.6977x + 163.84
r = 0.922
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
σef
Figure 4. Linear relationship between chemical shifts (C=N) and ef for iminic structures.
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For plots against OH, only a modest correlation could be obtained for the chemical shifts at C-2 for
imines 6-13, which becomes acceptable (r = 0.935) by removing the deviation caused by 6 (Table 5S,
Fig. 5).
4
2
.0
.0
y = 16.715x - 2.882
r = 0.935
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.0
-2.0
-4.0
-
-
6.0
8.0
-
-
10.0
12.0
-
0.5
-0.4
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
σOH
Figure 5. Linear relationship between chemical shifts (CO) and OH for 7-13.
Finally, the representation of the chemical shifts for phenolic or NH protons leads to a linear graph, with
both imines (r = 0.952) and enamines (r = 0.950) (Table 6S, Fig. 3S). In fact, the chemical shifts of the
phenolic proton of imines and the NH proton of enamines (5-19 and 78) can be plotted at the same time,
although the fit is a little worse (r = 0.944) (Fig 6). As shown, the O–H/N–H shifts increase as σOH
increases. This trend demonstrates that the H-bond becomes stronger as we move from electron-donating
to electron-withdrawing groups.
0
0
.9
.4
y = 1.4614x - 0.2845
r = 0.944
-0.1
-
-
0.6
1.1
-
0.4
-0.2
0.0
0.2
0.4
0.6
0.8
σOH
Figure 6. Hammett-type correlation between the OH/NH chemical shifts and OH for 5-19 and 78.
Overall, these results prove that both carbons, iminic and phenolic, and OH/NH of the tautomeric system
are subject to the same effects and support the hypothesis that this system responds globally to the effect
of the substituents, thus justifying the approximation ρOH ≈ ρNH ≈ ρ to derive equations [6] and [10].
Electronic Effect of the Substituents on the Tautomeric Equilibrium. Some research teams have used
13C chemical shifts to estimate K
37,43
T,
although it has been noted that the corresponding 15N shifts of the
iminic nitrogen lead to more accurate results, because their variation between imine and enamine
1
3
structures is ten times greater than that shown by the corresponding C atoms. The values of the coupling
constants 15N-H, 13C- C and C- N have also been used for identical purposes.
13
13
15
37,47,58,59
We have
attempted to quantify the influence of the substituents on the tautomeric equilibrium using 13C chemical
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
shifts. Equations [11] and [12] can be used to calculate the populations of each tautomer, provided that we
i e i e
have adequate δ /δ and J /J values:
n
i
= (δ
e
- δexp)/(δ
e
– δ
i
) = (J
e
– Jexp)/(J
e
– J
i
)
[11]
[12]
[13]
and analogously,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n
e
= (δexp – δ
i
)/(δ
e
– δ
i
) = (Jexp – J
i
)/(J
e
– J
i
)
For the imine-enamine balance, the equilibrium constant K
T
= n
e
/n
i
is expressed by:
T e i i e i e
K = n /n = (δexp – δ )/(δ - δexp) = (Jexp – J )/(J – Jexp)
T
The tautomerization constants (K ) of 4-33 have been calculated on the basis of equation [13]. The values
δ
i
= 154.45 ppm from imine 13 and δ
e
= 180.18 ppm from enamine 34 were arbitrarily chosen, because
they are the lowest and highest ones, respectively, and could then reflect "pure" imine and enamine
tautomers. The final equation [14] is similar to the one obtained by other authors,43 and the resulting data
are shown in Table 7S. Such results can be employed for a Hammett plot by representing the logarithmic
expression [15], which affords rather modest free-energy relationships (LFER) with both σef (r = 0.789)
±
and σef (r = 0.781) values (Fig. 4S).
K
T
= (δC2 – 154.45)/(180.18 – δC2
)
[14]
[15]
log K
T
= log [(δC2 – 154.45)/(180.18 – δC2)] = ρ σef + c
Figure 7 shows the same representations for derivatives substituted at C-4 and C-5 positions only, in
order to avoid the influence of steric effects at C-3 and C-6. The regression coefficients are improved,
especially when the deviations caused by 18 and 19 (gray line) are not taken into account.
1
.50
(b)
1.00
(a)
y = 1.8451x - 0.0892
r = 0.909
y = 2.7282x + 0.0741
r = 0.876
1.00
0.50
0
0
.50
.00
0.00
y = 1.7731x - 0.0211
r = 0.814
-
-
0.50
1.00
y = 0.7346x - 0.1208
r = 0.716
-0.50
-1.00
-1.50
-1.50
-
0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
-0.5
0.0
0.5
1.0
1.5
2.0
±
σ
ef
σ
ef
±
Figure 7. Representations of log K vs ef (a) and ef (b).
T
Finally, a plot of log K
T
for the TRIS-salicylimines 4-33 versus the corresponding δC2 values yields an
excelent linear relationship between these two variables (Fig. 5S):
log K
T
= 0.0845 x δC2 – 14.143 (r = 0.988)
[16]
The calculation of K
those of δ or δ : when δC2 → δ
and log K → -∞. In other words, for values of δC2 close to δ
T
through equation [14] has a serious drawback when the values of δC2 approach
(180.18) then K and log K → ∞ and when δC2 → δ (154.45) then K
and δ , small experimental errors in the
e
i
e
T
T
i
T
→
0
T
e
i
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determination of δC2 are magnified. Equation [16] can be used to calculate the values of K
T
and log K
T
in
the extreme zones. Thus, for 12 and 34 the values of 0.08 and 12.1 are obtained for K
T
, respectively,
which indicate that the imine form of 12 and enamine of 34 are either prevalent or exclusive in solution
and are more realistic than those obtained by equation [14].
In addition, when the proportions of the imine and enamine tautomers are equal, K
C2 becomes 167.4 ppm (almost coincidental with the arithmetic mean of δ and δ , 167.6 ppm). Since δC2
is actually an experimental average between δ and δ + n , with n + n = 1), δC2 values lower
T T
= 1 and log K = 0,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ
e
i
e
i
(δexp = n
i
δ
i
e
δ
e
i
e
than the latter indicate a predominance of the imine form, whereas at higher ones the enamine tautomer
predominates. Therefore, the carbon shift of 167.5 ppm can be used as an approximate boundary to define
the predominance of one form or another in solution. On applying this conclusion to the δC2 values shown
in Table 2S, it is found that compounds 20, 21 and 32, even though they have δC2 values less than 167.5
ppm, show significant JNH,CH couplings. In addition, compounds 28 and 29, with values almost identical
to 167.5 ppm, possess high values of JNH,CH (11.6 Hz), very close to those shown by compounds with a
clear predominance of the enamine structure (e.g., 64, 179.8 ppm, JNH,CH =12.4 Hz).
Although the issue of quasi-aromaticity will be treated later, in the present context it should also be
+
mentioned that new σ
p
constants can be obtained from the regression of the aromaticity descriptors
HOMA (geometry-based, σ+p(H)) and magnetic index NICS (σ p(N)) (Table 8S). When these new values
60
+
+
of σ
p
are plotted against log K
T
, fine correlations could be obtained as shown in Figure 8. Likewise, good
correlations with the chemical shifts at C-2 are depicted in Fig. 9.
0
.00
(a)
(b)
0
.00
-
-
0.20
0.40
-
-
-
0.20
0.40
0.60
y = 1.0117x - 0.1415
r = 0.998
y = 1.3048x + 0.0088
r = 0.995
-0.60
-
-
-
0.80
1.00
1.20
-0.80
1.00
-1.20
-1.00
-
-
1.00
-0.80
-0.60
-0.40
-0.20
0.00
-0.80
-0.60
-0.40
-0.20
0.00
σ+p(H)
σ+p(N)
+
Figure 8. Linear relationships of log K
T
vs σ
p
constants calculated from HOMA (a) and NICS (b)
indexes.
2
0.00
15.00
0.00
20.00
(b)
(a)
15.00
10.00
5.00
y = 17.45x + 4.0149
r = 0.947
y = 16.137x + 2.688
r = 0.992
1
5
0
.00
.00
0.00
-5.00
10.00
15.00
-5.00
10.00
15.00
-
-
-
-
-
1.00
-0.50
0.00
0.50
1.00
-1.00
-0.50
0.00
σ+p(H)
0.50
1.00
σ+p(N)
+
Figure 9. Linear representations of δC-2 vs σ
p
constants derived from HOMA (a) and NICS (b) indexes.
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6
Analysis of Substituent Effects on Examples Drawn from Literature. It is obvious that either thumb
rule claiming generality should not only have predictive capability, but also justify results from previous
literature. As preliminary examples we chose the salicylamines derived from methylamine (116-126)
described by Hansen et al.45d, for which we calculated the tautomerization equilibrium constants using
equation [14], with δ
respectively. These imines are not included in the representation because their log K
overcome this limitation, the values δ = 180.18 (from enamine 34) and δ = 152.00 (from imines derived
e
= 176.71 and δ
i
= 152.19, which are the extreme values of 126 and 120,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
T
are unknown. To
e
i
from 4-methoxysalicylaldehyde and 4-methoxyaniline)60 were employed, which correspond to the
maximum and minimum shifts reported for salicilimines. Results are shown in Table 10S.
CH3
N
H
O
X
116 X = H
122 X = 3,5-Br2
1
1
17 X = 5-Br
18 X = 5-Me
123 X = 3,4,5,6-Cl4
1
1
24 X = 5-OMe
25 X = 4-OMe
119 X = 5-Cl
1
1
20 X = 3-OMe
21 X = 3,5-Cl2
126 X = 4,6-(OMe)2
T
The representation of log K versus σef gives rise to good fits (Figure 10). The correlation of Fig. 10b
improves by removing structure 120 (r = 0.9550).
1.00
1.50
.00
(a)
(b)
1
0
0
.50
.00
0.50
0.00
y = 1.3152x - 0.1942
r = 0.874
y = 1.7771x - 0.3691
r = 0.821
-0.50
-1.00
-1.50
-
-
0.50
1.00
-
2.00
-2.50
-
0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
σ
ef
σ
ef
Figure 10. Linear representations of log K
T
vs σef data for structures 116-126: a) equation [13]: δ
= 180.18 ppm, δ = 152.00 ppm.
e
=
1
76.71 ppm, δ = 152.19 ppm; b) equation [13]: δ
i
e
i
Moreover, the linear relationships improve further by removing structures with substituents at C-3 and C-
6
, which include steric effects not contemplated in the values of σ. Thus, using the data for only 116-119,
24, and 125, an excellent correlation could be obtained with log K (r = 0.960) (Figure 11).
1
T
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9
0.20
.00
0
-
-
-
0.20
0.40
0.60
y = 1.1804x - 0.3483
r = 0.960
-0.80
1.00
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
-
0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
σef
Figure 11. Linear representations of log K
T
vs σef data for structures 116-119, 124, and 125 (equation
= 152.00 ppm).
[
13]: δ = 180.18 ppm, δ
e
i
In addition, the plot of chemical shifts C2 versus σef generates good fitting (r = 0.954, Figure 12a), further
improved if substitutions at C-3 and C-5 are not taken into account (r = 0.983, Figure 12b).
1
1
1
1
1
1
1
80.00
75.00
70.00
65.00
60.00
55.00
50.00
168.00
(a)
(b)
1
1
1
1
66.00
64.00
62.00
60.00
y = 18.725x + 162.03
r = 0.954
y = 15.007x + 161.14
r = 0.983
158.00
156.00
154.00
-
0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
σ
ef
σ
ef
Figure 12. Linear correlations of C2 vs σef data for structures 116-126.
1
5
A similar analysis has been performed by using N chemical shifts for compounds 119-122 and 124-126,
4
8b
and in solid state48a, plotted against different σ parameters (Tables 7
measured by Schilf et al. in CDCl
and 11S, Figures 8S-13S). Although such δ15
temperatures, good linear relationships could be obtained nevertheless.
3
N
measurements (CDCl ) were recorded at several
3
Table 7. Hammett correlations of iminic nitrogen chemical shift of 119-122 and 124-126.a
Hammett equationa
= -101.25σef -131.61
= -118.84σef -141.36
r
T (K)
266
 15
 15
 15
N
N
N
N
N
N
N
N
N
N
N
N
N
N
0.925
0.947
0.926
0.876
0.899
0.923
0.949
0.962
0.936
0.965
0.980
0.968
0.675
0.142
217
= -117.97σef -147.43
205.5
266
 15
= -95.71σefortho -120.63
 15
 15
 15
 15
 15
 15
 15
 15
= -112.60σefortho -128.45
= -117.43σefortho -134.16
217
205.5
266
±
= -54.88σef -118.33
±
= -63.82σef -125.88
217
±
= -63.04σef -132.12
205.5
266
= -57.48σef±ortho -114.08
= -66.91σef±ortho -120.92
217
= -67.18σef±ortho -126.96
205.5
297
 15
 15
= -109.76σef -173.16b
= -14.92σOHortho -125.22
266
a
b
In CDCl
3
at 50.68 MHz. In solid state at 50.68 MHz.
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6
However, δ15
values measured in the solid state led to representations with worse regression coefficients
N
(Figure 14S), thereby evidencing the dominant role of intermolecular interactions in the crystalline lattice
as prime factor in tautomer’s stability.22
Good representations were also obtained not only for δOH and δ15
N
, but also for δOD and δOT of the
respective deuterated and tritiated forms of 124-12647b (Tables 8 and 12S, Figures 15S-23S).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
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1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH3
CH3
CH3
N
Y
N
Y
N
Y
O
O
MeO
O
MeO
OMe
125 Y=H,D,T
OMe
126 Y=H,D,T
124 Y=H,D,T
Table 8. Hammett correlations for NMR data of 124-126.a
Hammett equationa
r
T (K)
303
303
303
303
303
303
303
303
303
298
298
298
298
298
298
223
223
223

OH = 1.11σef +13.30
OD = 0.87σef +12.98
0.983
0.970
0.931
0.999
0.994
0.873
0.963
0.945
0.959
0.968
0.956
0.993
0.987
0.942
0.927
0.983
0.949
0.995

 15
= -98.56σef -116.62
N

OH = 2.57σOH +13.56
OD = 2.04σOH +13.18

 15
N
= -211.94σOH -140.17
±

OH = 0.58σef +13.14
±

 15
OD = 0.46σef +12.85
±
N
= -54.82σef -100.29






 15
 15
 15
OH = 1.03σef +13.39
OT = 0.79σef +12.92
OH = 2.41σOH +13.63
OT = 1.87σOH +13.11
±
OH = 0.54σef +13.24
±
OT = 0.41σef +12.81
N
N
N
= -129.33σef -134.41
= -286.32σOH -165.26
±
= -70.67σef -113.93
aIn CDCl
at 500.13 ( H) and 50.68 ( N) MHz.
1
15
3
Our analysis can be successfully extended to another family of structurally related substances, namely N-
benzylsalicylimines 127-13047d (Table 9 with linear regressions gathered in Figures 24S-26S), as well as
1
31-134 (Tables 10 and 13S, Figures 27S-29S).
N
H
N
OH
N
H
O
H
O
O
X
X
X
127 X = H
131 X = H
135 X = 5-Cl
128 X = 5-NO2
132 X = 5-NO2
133 X = 5-OMe
134 X = 5-Br
136 X = 5-OH
129 X = 5-OMe
30 X = 5-Br
1
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Table 9. Hammett correlations for NMR data of 127-130.a
Hammett equationa
OH = 3.00σef +13.84
r
T (K)
266
266
266
266
266


0.881
0.841
0.666
0.984
0.990
0.922
C2 = 36.43σef +166.58
 15
= -127.16σef -114.52
N
±

OH = 1.84σef +13.54
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
±

C2 = 23.54σef +162.85
 15
= -96.54σef -101.40
±
N
266
15
aIn DMSO-d
at 500.13 ( H), 125.77 ( C) and 50.68 ( N) MHz.
1
13
6
Table 10. Hammett correlations for NMR data of 131-134.a
Hammett equationa
r
T (K)
266
266
266
266
266

OH = 4.30σef +14.42
0.838
0.833
0.675
0.984
0.988
0.926

 15
C2 = 39.83σef +167.76
N
= -156.95σef -125.73
±

OH = 2.77σef +13.98
±

 15
C2 = 25.90σef +163.68
±
N
= -118.21σef -109.54
266
15
aIn DMSO-d
at 500.13 ( H), 125.77 ( C) and 50.68 ( N) MHz.
1
13
6
Besides, like in above-mentioned correlations, good fitting could be established between the electronic
5
1
effect of the substituents and the pK
a
values of Schiff bases 127-130, 135 and 136 , as shown in Tables
1
1 and 14S, and Figures 30S and 31S.
of 127-130, 135, and 136.a
a
Table 11. Hammett correlations for pK
Hammett equationa
r
T (K)
pK
a
pK
a
pK
a
pK
a
= -2.43σef +8.28
0.896
0.915
0.895
0.878
296.15
296.15
296.15
296.15
±
= -1.60σef +8.54
= -1.30σOH +8.84
-
= -0.95σOH +8.87
aIn CD
OD at 296.15 ± 1 K.
3
In summary, the quality of all linear correlations allow us to demonstrate the utility and broad scope of
this analysis to quantify the electronic effects of the substituents involved in the tautomeric equilibrium of
salicylimine derivatives.
6
Imine/Enamine-Oxazolidine Equilibria. When DMSO-d solutions of the Schiff bases derived from
TRIS are kept at room temperature, partial isomerization (~5%) to a cyclic oxazolidine occurs (see SI).
Imine-Enamine Tautomerizations. The experimentally-measured C=O and C-N bond lengths for 18
42
(dC=O 1.288 Å, dC-N 1.306 Å) and 23 (dC=O 1.310 Å, dC-N 1.300 Å) are midway between the calculated at
M06-2X/6-311G++(d,p) level for the structures of imine (~1.335 and ~1.282 Å for C-O and C=N,
respectively) and enamine (~1.255 and 1.322 Å for C=O and C-N, respectively) tautomers (48 and 53).
These results suggest the coexistence of imine and enamine structures in a fast equilibrium within the
crystal lattice (see SI for the calculation methodology).
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5
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To investigate further the feasibility of such imine-enamine transformations, DFT calculations at the
aforementioned level were undertaken, both in gas phase and with bulk solvation using the SMD method.
The mono-substituted derivatives 34, 36-38, 40, 42-48, 51, 53, 84 and other disubstituted ones, namely
5
4, 57, 60 and 61, all of which exhibit enamine structures in solid state, were chosen as models, albeit 36-
8, 40, 42, 43, 46, 47, 51 and 57 adopt a predominant imine structure in solution. The relative stability of
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
imine (138) and enamine (140) forms, and the corresponding transition state (139) were calculated in the
gas phase (Scheme 6), with data gathered in Table 15S. Results indicate that the imine form is more
stable than the enaminic one, which contrasts with the situation encountered in the solid state favoring the
formation of enamine tautomers (140). It is obvious that the strong divergence between gas phase and
solid state structures should reasonably be ascribed to the intermolecular interactions generated in the
crystal lattice.22
C(CH OH)3
C(CH OH)
C(CH OH)
C(CH OH)
2
2
3
2
3
2
3
N
N
H
N
H
N
H
O
H
O
O
O
X
X
X
X
137
138
139
140
Scheme 6
As this transformation takes place intramolecularly without the participation of solvent’s molecules, one
should assume that the energies calculated in gas phase for the transition structures will be similar to
those present in the solid. The activation energy for the interconversion imine→enamine is sufficiently
‡
‡
low, so that it proceeds easily at room temperature (ΔG
energies are, in general, negative for the enamine→imine transformation (-1.5 ≤ ΔG
1.4 kcal/mol) (Calculations made on 124-126 lead to similar results, see table 16S).
i
= ΔGTS - ΔGimine ≤ 7.5 kcal/mol). The activation
‡
‡
e
= ΔGTS - ΔGenamine
<
Analogous results were obtained by including solvent effects (DMSO, Table 17S), although solvation
‡
i
decreases the tautomerization barriers; for imine→enamine: ΔG ≤ 5.2 kcal/mol and for enamine→imine:
‡
-1.0 ≤ ΔG
e
< 0.9 kcal/mol. The corresponding transition structures are not only characterized by a low
-1
energy barrier but also by their high imaginary frequency (~800-1000 cm ), the latter listed in Tables
5S-17S for all imines studied. This behavior has been recently found in mono- and di-azaderivatives of
1
malondialdehydes13,62 and in heterocyclic hydrazones of gossypol,63 featuring strong intramolecular H-
bonding as well.
Table 17S shows that in solution the enaminic forms 60 and 61 are more stable than their iminic
counterparts 30 and 31, unlike the rest of Schiff bases. Interestingly, in the first case the activation energy
‡
is negative for imine→enamine tautomerization (ΔG
i
= -1.0 kcal/mol) and positive for enamine→imine
‡
‡, ΔG
‡
tautomerization (ΔG
e
~1.5 kcal/mol), while in the second both are positive (ΔG
i
e
< 1.0 kcal/mol).
A plot of the electronic energy profiles extracted from Tables 15S and 17S is shown in Figure 13a, and
reveals the lack of symmetry in the tautomerization of salicylidene derivatives from TRIS. The saddle
points show an almost identical energy to the enaminic tautomers 140, and therefore their structure must
be similar. Figure 13b shows a similar picture for the intramolecular hydrogen transfer between tautomers
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‡
138 and 140 based on the ΔG values, which might suggest a more complex reaction path involving at
least another relative local minimum and an additional saddle point sandwiched between the transition
structure drawn and tautomer 140.
C(CH OH)
N
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
O
(a)
(b)
2
C(CH OH)3
N
H
X
O
139
140
1.5
<
< 1.4
X
<
8
2
C(CH OH)3
2
C(CH OH)3
139
N
N
140
H
O
H
< 7.5
2
C(CH OH)
2
3
O
N
H
C(CH OH)3
O
N
X
H
O
X
138
138
X
X
Reaction coordinate
Reaction coordinate
Figure 13. Schematic diagram showing the relative energy profiles for the tautomerization of 138 and
40; (a) electronic energies; (b) free energies.
1
Furthermore, the internal reaction coordinate (IRC) for the transition structure TS10/40 in DMSO,
corresponding to the tautomerization of simpler Schiff bases (10 into 40) was calculated (Table 18S). The
IRC obtained evidenced that TS10/40 (Figs. 33S and 34S) is actually the true saddle point. This prototropy
-1
is characterized by a low energy barrier (< 6 kcal/mol) and a high imaginary frecuency ~1000 cm , which
cause a sharp drop in the zero point energy (ZPE) as shown in Figure 14 using thermochemical data for
each structure along the reaction path (Table 19S).
5
.00
4.00
3
2
.00
.00
ΔE
ΔH
ΔG
1.00
.00
1.00
0
-
0
10
20
30
40
50
IRC step
Figure 14. Variations of enthalpy (ΔH), electronic (ΔE) and free energy (ΔG) calculated at 298.15 K (in
kcal/mol) near the saddle point for 10/40.
Addition of thermal corrections, including the ZPE correction, to the electronic energy does justify a
marked decrease in the internal energy and hence, of the enthalpy and free energy at the saddle point, thus
‡
‡
leading to negative values for H and G . This particular behavior is responsible for a variational effect
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2
2
2
2
2
2
2
2
3
3
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6
‡
‡
that displaces the maximum values of ΔH and ΔG with respect to the saddle point. The necessary
correction could then be formulated in terms of the Marcus theory.64
Hydrogen Bonding Analysis. The OH/NH group forms an intramolecular hydrogen bond, almost
coplanar with the aromatic ring. As pointed out earlier, the strong hydrogen bond between O-H and N or
N-H and O atoms, is evidenced by the observation of a large downfield shift of the proton peak for 4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
1
2
3
4
5
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7
8
9
0
3
3/34-63 in DMSO-d
6
(Table 2S). Their hydrogen bonding energy (EHB in kcal/mol) can be calculated by
65
means of the Schaefer’s correlation: Δδ = (−0.4 ± 0.2) - EHB, where Δδ is given in ppm for the chemical
shift difference between the O-H signal of 4-33/34-63 (δexp) and that in phenol (δ 4.29). Since Δδ = δexp
–
4.29, equation [17] can be employed here:
E
HB = - δexp + 3.89 ± 0.2
[17]
The hydrogen-bonding energy is collected in Table 2S and estimated to be -11.5 to -9.5 kcal/mol for 4-
. These values are expected for a strong hydrogen bond. Emsley66 defined a weak
3/34-63 in DMSO-d
3
6
or normal hydrogen bond as one whose strength is less than 50 kJ/mol (12 kcal/mol). Current figures
suggest a weak hydrogen bond shows a strength of 4 kcal/mol at most, one strong 4-15 kcal/mol, and one
very strong 15-40 kcal/mol.1c,4a,67
However, Kleinpeter et al.68 have shown that ring current effects on resonance-assisted and
intramolecularly bridged hydrogen bond protons contribute significantly to the chemical shift of the latter,
making it questionable to use δ(OH)/ppm for estimating intramolecular hydrogen bond strength (the
difference is usually less than 1 ppm). Thus, for imine structures the strength of the hydrogen bridge can
be estimated by DFT calculations as the difference in stability between the open (137) and closed (138)
forms (Scheme 6). To this end, a rotation of 180º around the C-OH bond was carried out with further
optimization of 137. The energy difference between the initial and final structures can be regarded as
r
measurement of the hydrogen bond strength (ΔΔG = -EHB) (Tables 15S and 17S). The value found for
imines in DMSO [M06-2X/6-311++G(d,p)] lies in general in the range from -11.6 to -9.0 kcal/mol, in
total agreement with that determined by equation [17]. This protocol is not applicable to enamines, and
the hydrogen bonding energy (EHB in kcal/mol) in 34, 36-38, 40, 42-48, 51, 53, 54, 57, 60, 61, and 84 was
estimated by another empirical relationship, equation [18],69 developed for intramolecular hydrogen
bonding in enol-aldehydes and enol-imines derived from malonaldehyde and salicylaldehyde.
5
E
HB (kcal/mol) = -5.554 x10 exp(-4.12dD…A
)
[18]
where dD…A denotes either an experimentally measured or theoretically calculated distance (in Å)
between donor (D) and acceptor (A) atoms involved in that non-covalent interaction. In general, in the
gas phase the apparent hydrogen bond energy (EHB) lie within -14 to -10 kcal/mol for imines (Table 20S)
and 16.5-13 kcal/mol for enamines (Table 21S), slightly higher than those obtained by previous
calculations. However, in presence of DMSO the H-bonding energies are -13 to -12 kcal/mol for imines
(
Table 22S) and -11 to -10 kcal/mol for enamines (Table 23S), which points to a leveling effect of the
strength between both tautomers caused by solvation. It is also noteworthy that electron-withdrawing
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groups (NO
2
) lead to the strongest hydrogen bonds in imine structures (~ 14 kcal/mol for 4 and 31, ~ 17
kcal/mol for 30) and the weakest in enamine tautomers (~ 10 kcal/mol for 34 and 61, ~ 9 kcal/mol for 60).
Pseudo-Aromaticity in H-bonded Tautomeric Salicylimines. The intramolecular hydrogen bonding in
Schiff bases derived from salicylaldehydes, for which the concept of resonance-assisted hydrogen bonds
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
1
2
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4
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1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
RAHB) can be invoked,5-7 and despite the cautionary elements formulated by other authors, invites
8
(
clearly to explore whether or not there is some delocalization of the π-electrons through single and double
bonds. If true, such strong hydrogen bonds may have a significant covalent character beyond their
5
electrostatic nature. This delocalization can be evaluated for pseudo-heterocyclic tautomers of Schiff
bases derived from salicylaldehydes in terms of geometrical considerations.10,70,71 These include a series
of well-established aromaticity indexes such as the Harmonic Oscillator Model of Aromaticity
(HOMA).71,72 The calculated HOMA values of pseudo-heterocyclic and carbocyclic rings for tautomers
1
38 and 140, and their transition structures 139 (Scheme 6), corresponding to the intramolecular proton
transfer in gas phase of salicylimines substituted at C-4 and C-5, are collected in Tables 12 and 32S
see also Tables 24S-31S).
(
Table 12. HOMA values for pseudo-heterocyclic rings.a
b
X
5-NO
5-F
137
0.11
0.06
0.08
0.08
0.03
0.04
0.10
0.08
0.13
0.12
0.12
0.14
0.15
138
0.36
0.32
0.34
0.34
0.29
0.30
0.35
0.33
0.38
0.37
0.36
0.38
0.40
139
0.66
0.74
0.73
0.73
0.74
0.75
0.73
0.71
0.71
0.73
0.73
0.69
0.70
140
0.62
0.69
0.69
0.69
0.72
0.72
0.68
0.70
0.64
0.67
0.68
0.64
0.62
Σ
HOMA
0.98
1.01
1.03
1.03
1.01
1.02
1.03
1.03
1.02
1.04
1.04
1.02
1.02
2
5-Cl
5-Br
5
-OMe
5
-OH
H
4
-NO
-F
2
4
4
-Cl
4
-Br
4
-OMe
-OH
4
aAt M06-2X/6-311G(d,p) level in gas phase. bΣHOMA = HOMA(138) + HOMA(140).
Data in Table 12 show a significant increase of the electronic delocalization in pseudo-heterocyclic rings
from imine (~0.3-0.4) to enamine (~0.6-0.7) tautomers. The hydrogen bond is essential for this
delocalization to occur, because in open imines lacking hydrogen bridge the HOMA value is practically
zero (~0.1). The HOMA indices for enamines are only slightly lower than those reached in the transition
state. Moreover, the sum of the HOMAs of the cyclic imine and its tautomeric enamine remains
essentially constant (ca. 1.0, eq. [19]) for all cases studied (Table 12, last column).
Σ
HOMA pseudoheterocycle = HOMAclosed im (138) + HOMAenam (140) = 1.0
[19]
This finding is appealing indeed, as it proves the inter-relationship between imine and enamine structures,
or in other words, the aromaticity lost by the imine is concomitantly gained, at the same extent, by the
enamine form irrespective of the electronic character of the substituent.
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