Ene-diamine versus imine-amine isomeric preferences

Article abstract of DOI:10.1021/jo051102g

Cyanide-catalyzed aldimine coupling was employed to synthesize compounds with 1,2-ene-diamine and α-imine-amine structural motifs: 1,2,N,N′-tetraphenyletheylene-1,2-diamine (13) and (±)-2,3-di-(2- hydroxyphenyl)-1,2-dihydroquinoxaline (17), respectively. Single-crystal X-ray diffraction provided solid-state structures and density functional theory calculations were used to probe isomeric preferences within this and the related hydroxy-ketone/ene-diol system. The ene-diamine and imine-amine core structures were calculated (B3LYP/6-311++G(d,p)) to be essentially identical in energy (ΔG = 0.2 kcal/mol in favor of the imine-amine, within the error of the calculation). However, additional effects-such as π conjugation-in 13 render an ene-diamine structure that is slightly more stable than the imine-amine tautomer (14) (ΔG = 0.2-0.7 kcal/mol, within the error of the calculation). In contrast, the intramolecular hydrogen bonding present in 17 significantly favors the imine-amine isomer over the ene-diamine tautomer (18) (ΔG = 7.2-8.9 kcal/mol). For both 13 and 17, the optimized calculated structures (B3LYP/6-31+G(d′)) are identical to those observed by single-crystal X-ray diffraction.

Full text of DOI:10.1021/jo051102g

Ene-diamine versus Imine-amine Isomeric Preferences
B. Jesse E. Reich, Erin E. Greenwald, Aaron K. Justice, Brittany T. Beckstead,
Joseph H. Reibenspies, Simon W. North, and Stephen A. Miller*
Texas A&M University, College Station, Texas 77843-3255
samiller@mail.chem.tamu.edu
Received June 1, 2005
Cyanide-catalyzed aldimine coupling was employed to synthesize compounds with 1,2-ene-diamine
and R-imine-amine structural motifs: 1,2,N,N′-tetraphenyletheylene-1,2-diamine (13) and (()-2,3-
di-(2-hydroxyphenyl)-1,2-dihydroquinoxaline (17), respectively. Single-crystal X-ray diffraction
provided solid-state structures and density functional theory calculations were used to probe isomeric
preferences within this and the related hydroxy-ketone/ene-diol system. The ene-diamine and imine-
amine core structures were calculated (B3LYP/6-311++G(d,p)) to be essentially identical in energy
(∆G ) 0.2 kcal/mol in favor of the imine-amine, within the error of the calculation). However,
additional effectsssuch as π conjugationsin 13 render an ene-diamine structure that is slightly
more stable than the imine-amine tautomer (14) (∆G ) 0.2-0.7 kcal/mol, within the error of the
calculation). In contrast, the intramolecular hydrogen bonding present in 17 significantly favors
the imine-amine isomer over the ene-diamine tautomer (18) (∆G ) 7.2-8.9 kcal/mol). For both 13
and 17, the optimized calculated structures (B3LYP/6-31+G(d′)) are identical to those observed by
single-crystal X-ray diffraction.
SCHEME 1. The 1,2-Ene-diol Isomers 3-Z and 3-E
Are Not Observed in the Benzoin Condensation
Reaction
Introduction
Hydroxy-ketone vs Ene-diol Isomers. The cyanide-
catalyzed benzoin condensation reaction was apparently
first reported by Stange in 1824.1,2 The commonly ac-
cepted mechanism, generally attributed to Lapworth,3
produces the stable R-Hydroxy-ketone (2, benzoin), but
avoids the intermediacy of a 1,2-ene-diol structure such
as 3-Z or 3-E (Scheme 1).4
Ene-diol structures akin to 3-Z and 3-E have garnered
considerable interest over the past century in synthetic,
analytical, and theoretical chemistry (Scheme 2). Ene-
diolates such as 4-Na, 4-K, and 5 are stable and can be
(1) Stange, C. Repertorium fu¨r die Pharmacie 1824, 16, 80-107.
(2) The benzoin condensation is technically a dimerization since the
molecular weight of benzoin is twice that of benzaldehyde. Hence, the
term “coupling” is used here to avoid the misleading descriptor
“condensation” and is meant to apply generally to intermolecular and
intramolecular reactions.
prepared by reduction,5-7 but the ene-diol 6 is only stable
under neutral, anaerobic conditions when the aryl group
(3) (a) Lapworth, A. J. Chem. Soc. 1903, 83, 995-1005. (b) Lapworth,
A. J. Chem. Soc. 1904, 85, 1206-1213.
(5) Nef, J. V. Justus Liebigs Ann. Chem. 1899, 308, 264-334.
(6) Staudinger, H.; Binkert, A. Helv. Chim. Acta 1922, 17, 703-
710.
(4) Kuebrich, J. P.; Schowen, R. L.; Wang, M.; Lupes, M. E. J. Am.
Chem. Soc. 1971, 93, 1214-1220.
10.1021/jo051102g CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/09/2005
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Reich et al.
SCHEME 2. Stable (4, 5, 7, 9) and Metastable (3, 6)
Molecules Bearing the Ene-diolate or Ene-diol
Motif
SCHEME 3. Intermolecular Aldimine Coupling:
Dimerization
isomers,10-12,15 thermodynamic details are relatively sparse.
The experimentally determined equilibrium constant
between E-stilbenediol (3-E) and Z-stilbenediol (3-Z)s
measured via electrochemical reduction of benzilswas
found to favor the E isomer by 1.7 kcal/mol at pH 7.16
Additionally, quantum chemical calculations suggest that
benzoin (2) is 7.6 kcal/mol lower in energy than Z-
stilbenediol (3-Z).17 This result implies that the hydroxy-
ketone core structure has significantly stronger inherent
bonding than the ene-diol core structure.
Ene-diamine vs Imine-amine Isomers. The cyanide-
catalyzed aldimine coupling reaction (AIC) is analogous
to the benzoin reaction and likely proceeds through a
similar mechanism.18,19 The proposed mechanism for
intermolecular AIC involves cyanide attack at an aldi-
mine and tautomerization to form a carbanion; this
nucleophile attacks a second aldimine and the subse-
quent tautomerization is followed by elimination of
cyanide (Scheme 3). The proposed mechanism for in-
tramolecular AIC cyclization is similar except that the
nucleophilic attack proceeds intramolecularly (Scheme
4).20 Aerobic conditions for either reaction generally afford
R-diimines, but anaerobic or phase-transfer conditions
can prevent the final oxidation step, in which case an
ene-diamine or imine-amine should result.
Despite the number of accounts describing isomerism
in the hydroxy-ketone/ene-diol system, relatively little
has been reported for the ene-diamine/imine-amine sys-
tem. Strain recognized the existence of multiple isomers
for dimerized N-benzylideneaniline in an early manu-
script,21 but did not recognize all possible isomers. For
the prototypical dimerization of N-benzylideneaniline
(11), the product could exist as six possible isomers:
is highly substituted (Ar ) 2,4,6-trimethylphenyl, 2,4,6-
triethylphenyl, or 2,6-diethylphenyl).8,9 The electrochemi-
cal reduction of benzil leads to ephemeral ene-diols.10,11
It was shown that 3-E tautomerizes to benzoin somewhat
faster than does 3-Z.12 The 1,2-ene-diol motif is known
to exist in a stable form in a limited number of molecules.
For example, trans-1,2-di-(2-pyridyl)-ethylene-1,2-diol (7,
R-pyridoin)13 and L-ascorbic acid (9, vitamin C)14 both
exist as ene-diols. Notably, 7 and 9 are stabilized by
intramolecular hydrogen bonding in the solid state.
While several accounts describe the kinetic details
of interconversion among hydroxy-ketone/ene-diol
(7) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1927, 49,
2584-2592.
(8) (a) Fuson, R. C.; Corse, J. J. Am. Chem. Soc. 1939, 61, 975. (b)
Fuson, R. C.; Corse, J.; McKeever, C. H. J. Am. Chem. Soc. 1939, 61,
2010-2012. (c) Fuson, R. C.; Scott, S. L.; Horning, E. C.; McKeever,
C. H. J. Am. Chem. Soc. 1940, 62, 2091-2094.
(9) Thompson, R. B. J. Am. Chem. Soc. 1939, 61, 1281-1283.
(10) (a) Pasternak, R. Helv. Chim. Acta 1947, 30, 1984-1999. (b)
Pasternak, R. Helv. Chim. Acta 1948, 31, 753-776.
(11) Vincenz-Chodkowska, A.; Grabowski, Z. R. Electrochim. Acta
1964, 9, 789-801.
(15) (a) Dominguez, M.; Roldan, E.; Carbajo, J.; Calvente, J.;
Gonzalez-Arjona, D.; Andreu, R. J. Electroanal. Chem. 1991, 316, 133-
142. (b) Johnson, D. C.; Gaines, P. R. Anal. Chem. 1973, 45, 1670-
1675.
(16) Meunier-Prest, R.; Laviron, E.; Gaspard, C.; Raveau, S. Elec-
trochim. Acta 2001, 46, 1847-1861.
(17) Pawelka, Z.; Kryachko, E. S.; Zeegers-Huyskens, T. Chem. Phys.
2003, 287, 143-153.
(18) Strain, H. H. J. Am. Chem. Soc. 1928, 50, 2218-2223.
(19) Correia, J. J. Org. Chem. 1983, 48, 3343-3344.
(20) Reich, B. J. E.; Justice, A. K.; Beckstead, B. T.; Reibenspies, J.
H.; Miller, S. A. J. Org. Chem. 2004, 69, 1357-1359.
(21) Strain, H. H. J. Am. Chem. Soc. 1929, 51, 269-273.
(12) (a) Stapelfeldt, H. E.; Perone, S. P. Anal. Chem. 1968, 40, 815-
818. (b) Stapelfeldt, H. E.; Perone, S. P. Anal. Chem. 1969, 41, 623-
627.
(13) Ashida, T.; Hirokawa, S.; Okaya, Y. Acta Crystallogr. 1965, 18,
122-127.
(14) (a) Hvoslef, J. Acta Crystallogr. 1968, B24, 23-35. (b) Hvoslef,
J. Acta Crystallogr. 1968, B24, 1431-1440.
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Ene-diamine vs Imine-amine Isomeric Preferences
SCHEME 4. Intramolecular Aldimine Coupling:
Cyclization
SCHEME 5. Population Distributions at 35 °C in
CDCl3 for Imine-amines and Ene-diamines25
aromatic imine-amines and aliphatic imine-amines at 35
°C in CDCl3 (Scheme 5).25 In the aromatic cases (R′′ )
Ph), both tautomeric forms were observed. However in
the aliphatic cases (R′′ ) n-alkyl), the ene-diamine
tautomer was not detected.
In the hydroxy-ketone/ene-diol system, there seems to
be a strong preference to populate the hydroxy-ketone
tautomer. However, there is no consistent tautomeric
preference in the ene-diamine/imine-amine system; these
structures are apparently similar in energy. Our contin-
ued investigation of the cyanide-catalyzed aldimine
coupling reaction has revealed new synthetic routes to
ene-diamine/imine-amine structures, allowing charac-
terization of such compounds with unprecedented detail.
Herein, we seek to combine this newfound experimental
accessibility with theoretical calculations to disentangle
the bonding energetics that are responsible for the
aforementioned isomeric and tautomeric preferences.
E-1,2,N,N′-tetraphenylethylene-1,2-diamine (13-E); Z-1,2,-
N,N′-tetraphenylethylene-1,2-diamine (13-Z); (S)-E-phenyl-
(2-phenylimino-1,2-diphenylethyl)-amine (14-S-E); (R)-
E-phenyl-(2-phenylimino-1,2-diphenylethyl)-amine (14-
R-E); (R)-Z-phenyl-(2-phenylimino-1,2-diphenylethyl)-
amine (14-R-Z); and (S)-Z-phenyl-(2-phenylimino-1,2-
diphenylethyl)-amine (14-S-Z) (Figure 1).
Results and Discussion
X-ray Crystallography. To resolve structural claims
and to examine the relevant isomeric preferences, we
have structurally characterized two exemplary products
of aldimine coupling by single-crystal X-ray diffraction.
The solid-state structures of the products arising from
the dimerization of N-benzylideneaniline (11) and the
cyclization of salophen (16)20 have been elucidated (Scheme
6). Straightforward examination of the geometry and
substitution at carbon reveals that ene-diamine 13-E is
the preferred form of the N-benzylideneaniline dimer,
while cyclized salophen exists as the imine-amine isomer
17a. Note that the latter is stabilized by intramolecular
hydrogen bonding.
1
NMR Investigations. H NMR and 13C NMR room-
FIGURE 1. Six possible isomeric products of the cyanide-
catalyzed aldimine coupling of N-benzylideneaniline (11).
temperature solution spectra of cyclized salophen (17a)
are essentially consistent with the C1-symmetric solid-
state structure. Twenty distinct carbon peaks exist as
well as four distinct nonaromatic proton peaks, corre-
sponding to the hydrogens on the lone sp3 carbon, the
amine nitrogen, and the two different oxygens. In con-
Among the existing reports, there is disagreement over
the preferred isomeric form of the N-benzylideneaniline
dimer, which has not been conclusively established.
Strain originally invoked an imine-amine isomer (14)
because hydrolysis afforded the R-hydroxy-imine.21 Later,
Becker cited NMR evidence for the prevalence of an
imine-amine isomer (14),22 but subsequently suggested
that an extensively conjugated 1,2-ene-diamine (13-E or
13-Z) is more consistent with UV-visible absorption
spectra.23 Cariou also suggested this structural assign-
ment, but only fully N-alkylated products, bearing no
acidic hydrogens, were characterized.24
1
trast, the H NMR spectrum of E-1,2,N,N′-tetraphenyl-
ethylene-1,2-diamine (13-E) consists of broad peaks with
several resonances unaccounted for by the solid-state
structure. This finding suggests the possibility of multiple
equilibrating isomers in solution.
To address the question of equilibrating isomers,
crystals of 13-E were dissolved in CDCl3 and multiple
The sole experimental investigation that elaborated on
the isomerization between ene-diamines and imine-
amines involved the 1H NMR spectra of a series of
(24) Several compounds of the type PhMeN(Ar)CdC(Ar)NMePh
were synthesized, separated by column chromatography, and assigned
as E or Z based on λmax in the UV-visible spectrum, NMR evidence,
and melting points. Cariou, M.; Carlier, R.; Simonet, J. Bull. Soc. Chim.
Fr. 1986, 5, 781-792.
(25) Duhamel, P.; Duhamel, L.; Legal, J.-C. C. R. Acad. Sci. Ser. C:
Sci. Chim. 1970, 271, 156-158.
(22) Becker, H.-D. J. Org. Chem. 1964, 29, 2891-2894.
(23) Becker, H.-D. J. Org. Chem. 1970, 35, 2099-2102.
J. Org. Chem, Vol. 70, No. 21, 2005 8411

Reich et al.
SCHEME 6. Dimerization of 11 Affords the
Ene-diamine 13-E, whereas the Cyclization of 16
Yields the Imine-amine 17aa
FIGURE 3. Variable temperature 1H NMR spectra of the
N-H region from -60 to 60 °C of dimerized N-benzylidene-
toluidine (13-Me2) in CDCl3.
(14) is discounted because each should introduce 18 new
peaks; these are not observed.
We can estimate the rate of exchange at the coales-
cence temperature (ca. 50 °C) as k ) 27 s-1, which
corresponds to a ∆Gq(50°C) for E to Z isomerization of 16.8
kcal/mol (based on a 12.3 Hz peak separation at -60
°C).26 This is much lower than the 41-46 kcal/mol energy
barrier for E/Z isomerization in stilbene,27 presumably
because of the energetically accessible imine-amine in-
termediate 14. To further validate our claims, we have
synthesized the dimer of N-benzylidenetoluidine (13-Me2)
and see similar effects for the amine (Figure 3) and
methyl protons, as well as an increase in the number of
13C NMR peaks at low temperature (a 2-fold increase is
not fully realized using a 300 MHz instrument because
the 13C NMR peaks are in a 9:1 E:Z ratio and the smaller
ones are not all clearly apparent).
After demonstrating equilibration among dimerized
N-benzylideneaniline isomers, we investigated a similar
phenomenon in cyclized salophen (17). Because of hy-
drogen bonding available to 17, we anticipated the imine-
amine to be favored. We also expected thatsat least at
high temperaturesstautomerization would allow the
facile exchange of the hydrogen bond between the two
N/O pairs in the molecule, resulting in a time-averaged
species with an apparent increase in symmetry. However,
upon heating to 130 °C, the 1H NMR spectrum of 17 (in
Cl2DCCDCl2) showed flattening of the already broad
amine peak, but no other peaks changed significantly.
Also, the number of peaks in the 13C NMR spectrum did
not halve at high temperatures, further suggesting there
is not rapid equilibration between the two degenerate
imine-amines at 130 °C (Figure 4). This observation
implies the persistence of C1-symmetry, a relatively high
barrier to tautomerization, and unusually strong hydro-
gen bonding in 17. This additional bonding, not available
in 13, readily explains the energetic preference of the
imine-amine tautomer over the ene-diamine tautomer.
Energetics. According to average bond dissociation
energies obtained from a standard physical organic
chemistry textbook, the generally prevailing hydroxy-
a
X-ray structures are depicted with 50% ellipsoids.
FIGURE 2. Variable temperature 1H NMR spectra of the
N-H region from -60 to 60 °C of dimerized N-benzylidene-
aniline 13 in CDCl3.
1H NMR and 13C NMR spectra were taken between -60
and 60 °C. The H NMR spectra depict amine proton
1
peaks that coalesce at high temperature, but are fully
resolved with approximately equal intensity at -25 °C
(Figure 2). The resolved peaks (5.79 and 5.75 ppm) are
attributed to the static structures of 13-E and 13-Z. The
13C NMR data corroborate this assignment, as there are
18 peaks in the 13C NMR spectrum at low temperatures,
corresponding to 9 peaks arising from 13-E and 9 peaks
arising from 13-Z. The presence of imine-amine isomers
(26) Kegley, S. E.; Pinhas, A. R. Problems and Solutions in Orga-
nometallic Chemistry; University Science Books: Mill Valley, CA, 1986;
pp 20-26.
(27) (a) Santoro, A. V.; Barrett, E. J.; Hoyer, H. W. J. Am. Chem.
Soc. 1967, 89, 4545-4546. (b) Meier, H. Angew. Chem., Int. Ed. Engl.
1992, 31, 1399-1420. (c) Han, W.-G.; Lovell, T.; Liu, T.; Noodleman,
L. Chemphyschem 2002, 3, 167-178.
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Ene-diamine vs Imine-amine Isomeric Preferences
FIGURE 4. Variable temperature 1H NMR of cyclized salophen
(17) in Cl2DCCDCl2 at 30 °C and 130 °C.
ketone structure is 11 kcal/mol more stable than the ene-
diol structure.28 Similar calculations predict that the
imine-amine motif is more stable than the ene-diamine
motif by 19 kcal/mol. This latter calculation is contrary
to the solid-state structure of dimerized N-benzylidene-
aniline, which exists as the E-ene-diamine isomer 13-E,
but is congruent with the solid-state structure of cyclized
salophen, which exists as the imine-amine isomer 17.
Because simple average bond dissociation energies can-
not explain the observed isomeric preferences, quantum
chemical calculations were pursued.
FIGURE 5. DFT optimized structures and relative gas-phase
Gibbs free energies (298.15 K) of benzoin isomers 2, 3-Z, and
3-E.
is the most stable.32 Among compounds 17-18, the imine-
amine 17a is the most stable. These theoretical results
are in agreement with the aforementioned single-crystal
X-ray diffraction studies. For compounds 13-14, three
different isomers are calculated to be within 0.7 kcal/mol
of one another. The difference between the two most
stable isomers in 17-18 (17a and 17b) is 1.7 kcal/mol,
and the difference between the least favorable isomer 18c
and the most favorable isomer 17a is 15.9 kcal/mol, which
is the largest energy difference seen among the presented
models.
DFT Small Model Calculations. Geometry optimi-
zations and frequency calculations for 19, 20, 21, and 22
were performed using B3LYP/6-311++G(d,p) with pure
d orbitals and all energies include zero-point energy.
DFT calculations were performed on several isomers
and rotamers of ethylene-1,2-diamine, a model substrate
with reduced size for computational tractability (Figure
7). The Z-ene-diamine (19-Z) is the most stable isomer,
with an energy of 2.2 kcal/mol below that of the next
closest isomer 20a-E. The stabilizing energy of the
intramolecular hydrogen bond in 20a-E can be estimated
by taking the energy difference between 20a-E and 20b-
E, which is 1.0 kcal/mol. The stabilizing energy of the
intramolecular hydrogen bonding in 19-Z is difficult to
estimate because each rotamer has a hydrogen bond or
a lone pair/lone pair interaction. Neither imine-amine
20b-E nor ene-diamine 19-E is stabilized by intramo-
lecular hydrogen bonding. Hence, the inherent energetic
difference between these two tautomeric structures is
approximately 0.2 kcal/mol, with a slight preference for
the imine-amine.32 This sharply contrasts with the
energetic difference between the corresponding oxygen
analogues, s-trans-hydroxy-acetaldehyde (21) and E-eth-
DFT Calculations. Geometry optimizations and fre-
quency calculations for 2, 3, 13, 14, 17, and 18 were
performed using B3LYP/6-31+G(d′) with pure d orbitals
and all energies include zero-point energy.29
Among the benzoin isomers 2, 3-Z, and 3-E (Figure 5),
the hydroxy-ketone 2 is predicted by average bond
dissociation energies, NMR evidence, and the solid-state
structure to be the most stable isomer.30 A calculated
energy difference of 12.1 kcal/mol between 2 and 3-Z is
larger than the 7.6 kcal/mol (B3LYP/6-31+G(d,p)) re-
ported by Pawelka et al.17 A calculated energy difference
of 2.6 kcal/mol in favor of 3-Z over 3-E is contradicted by
Benson additivities31swhich generally favor E-alkenes
by 1.1 kcal/molsand is also contradicted by cyclic volta-
mmetry experiments,16 which showed 3-Z to be higher
in energy than 3-E by 1.7 kcal/mol in aqueous solution.
We suspect that the energetic discrepancy is largely
related to intramolecular hydrogen-bonding stabilization
of 3-Z in the gas phase, which becomes less important
in aqueous solution when intermolecular hydrogen bond-
ing is prevalent.
DFT calculations were performed for isomers of 13-E,
13-Z, 14-E, 14-Z, 17a, 17b, 18a, 18b, and 18c (Figure
6). Among compounds 13-14, the E-ene-diamine 13-E
(28) Values from: Lowry, T. H.; Richardson, K. S. Mechanism and
Theory in Organic Chemistry, 3rd ed.; HarperCollinsPublishers: New
York, 1987; pp 161-162. See the Supporting Information.
(29) The present electronic structure calculations are limited to the
gas phase and detailed solvent models are beyond the scope of this
paper. The calculations would likely be improved by employing
continuum solvent models (like polarizable continuum (PCM) or
conductor-like-screening (COSMOS)), although these consider general
solvent molecules and would not capture specific hydrogen bonding
with a particular type of solvent. Correcting the calculated gas-phase
entropies for solvent effects may also offer some improvement on the
present calculated Gibbs free energies. However, such corrections
would not likely offer insight that greatly affects the present conclu-
sions and these effects have, therefore, been neglected.
(30) Haisa, M.; Kashino, S.; Morimoto, M. Acta Crystallogr. 1980,
B36, 2832-2834.
(31) Cohen, N.; Benson, S. W. Chem. Rev. 1993, 93, 2419-2438.
(32) Note that the uncertainty of these theoretical calculations is
1-3 kcal/mol. Accordingly, the energetic ordering of structures within
this range cannot be made with unqualified certitude.
J. Org. Chem, Vol. 70, No. 21, 2005 8413

Reich et al.
FIGURE 6. DFT optimized structures and relative gas-phase Gibbs free energies (298.15 K) for various isomers 13-14 and
17-18.
FIGURE 7. DFT optimized structures and relative gas-phase Gibbs free energies (298.15 K) for 19-20, 21, and 22.
ylene-1,2-diol (22); the hydroxy-aldehyde structure (cf.
benzoin) is calculated to be more stable than the ene-
diol structure by 10.1 kcal/mol (Figure 7).
These computational results are in approximate agree-
ment with quantum chemical calculations by Lien and
Chuang carried out at three different levels of theory.33
Their calculations indicate that E-ethylene-1,2-diamine
(19-E) is 4.33 (HF/6-31G**), 1.96 (B3LYP/6-31G**), or
2.15 (G2) kcal/mol higher in energy than 2-imino-ethyl-
amine (20b-E). Our calculated value of 0.2 kcal/mol for
the 19-E/20b-E energetic difference involves a consider-
ably larger basis set (triple-ú split-valence polarized basis
set with additional diffuse functions as opposed to a
double-ú split-valence polarized basis set) than the cor-
(33) Chuang, C.-H.; Lien, M.-H. Eur. J. Org. Chem. 2004, 2004,
1432-1443.
8414 J. Org. Chem., Vol. 70, No. 21, 2005

Ene-diamine vs Imine-amine Isomeric Preferences
pure d orbitals, and are gas-phase Gibbs free energies derived
from the equation ∆G ) ∆H - T∆S using the calculated ∆H
and ∆S terms at T ) 298.15 K.
responding B3LYP calculation that yielded 1.96 kcal/mol.
The increased basis set size generally provides a more
accurate result, presuming the methodology offers a
reasonable description of the electronic structure.34-36
Also indicated by Lien and Chuang is that 22 is 14.27
(HF/6-31G**), 9.75 (B3LYP/6-31G**), or 10.23 (G2) kcal/
mol higher in energy than 21. These latter two determi-
nations are in accord with our calculated value of 10.1
kcal/mol.
Despite the fact that the computationally investigated
nitrogen-containing compounds (13-14, 17-18, 19-20)
preferred three different lowest energy isomers, a unify-
ing theme appeared: unlike analogous products of the
benzoin condensation, the E-ene-diamine, Z-ene-diamine,
and imine-amine core structures are energetically similar.
In the hydroxy-ketone/ene-diol system, the difference in
energy between the two core structures is large, and
interactions such as steric hindrance, π electron effects
(conjugation), or hydrogen bonding do little to change
isomeric preference. In the ene-diamine/imine-amine
system, core structure energy differences are small and
thus, steric hindrance, π electron effects, and hydrogen
bonding are the determining factors for isomeric prefer-
ence.
Preparation of Aldimine Substrates. The following
method20 was utilized to synthesize the aldimine substrates,
which are known compounds. A total of 200 mmol of an
aldehyde was dissolved in 80-200 mL of methanol. To this,
100 mmol of liquid diamine was added and the reaction was
shaken for 16 h. In the case of solid formation (salophen), the
solid was isolated by filtration, washed with 100-200 mL of
methanol, and dried in vacuo. If no solid formed (N-benzylide-
neaniline and N-benzylidenetoluidine), the solution was con-
centrated by rotary evaporation. A dichloromethane extraction
was performed and the organic layer was dried over magne-
sium sulfate. The slurry was filtered and the filtrate concen-
trated by rotary evaporation. This yellow-orange oil can be
used or higher purity aldimines can be prepared by short path
distillation of the aldimine near 130-140 °C under high
vacuum.
N-Benzylideneaniline (11).18 90% yield. 1H NMR
(CDCl3): δ 7.25 (m, 3H), 7.42 (m, 2H), 7.49 (m, 3H), 7.92 (m,
2H), 8.47 (s, 1H). 13C NMR: δ 121.1, 126.2, 129.0, 129.1, 129.4,
131.7, 136.4, 152.3, 160.7. MS (ESI): m/z ) 182 [M + H]+.
C13H11N (181.09).
1
N-Benzylidenetoluidine (11-Me).18 98% yield. H NMR
(CDCl3): 2.45 (s, 3H), 7.25 (m, 4H), 7.55 (m, 3H), 7.98 (m, 2H),
8.54 (s, 1H). 13C NMR: δ 21.3, 121.1, 129.0, 129.1, 130.1, 131.5,
136.1, 136.7, 149.8, 159.9. MS (ESI): m/z ) 196 [M + H]+.
C14H13N (195.10).
Conclusions
N,N′-Bis(salicylidene)-o-phenylenediamine (16, salo-
1
phen).42 95% yield. H NMR (CDCl3): δ -1.90 (s, 2H), 6.94
Energetically, the hydroxy-ketone/ene-diol system is
quite different from the structurally analogous ene-
diamine/imine-amine system. Theoretical investigations
into isomeric preferences for products of the benzoin
condensation show that the hydroxy-ketone motif is
favored by 10-15 kcal/mol over the ene-diol tautomers.
In contrast, experimental and theoretical investigations
into isomeric preferences for products of aldimine cou-
pling show that the three core structures (E-ene-diamine,
Z-ene-diamine, and imine-amine) have similar energetics
(range ) 3 kcal/mol); quantum chemical calculations
suggest that isomeric preference is determined by factors
other than inherent bonding such as steric hindrance, π
electron effects, and hydrogen bonding. Among these,
hydrogen bonding is most important (see 17a) and
structures that lack hydrogen bonding are likely to
assume the isomer that best minimizes steric interactions
and maximizes conjugation (see 13-E). The single-crystal
X-ray structures of 13-E and 17a match those optimized
at the B3LYP/6-31+G(d′) level, suggesting that this level
of theory is appropriate and suitable for investigating
ene-diamine and imine-amine isomeric preferences.
3
3
(t, 2H, JHH ) 7.5 Hz), 7.07 (d, 2H, JHH ) 7.5 Hz), 7.24 (m,
2H), 7.35 (m, 2H), 7.40 (m, 4H), 8.64 (s, 2H). 13C NMR: δ 117.6,
119.1, 119.4, 119.8, 127.9, 132.5, 133.5, 142.6, 161.5, 163.8.
MS (ESI): m/z ) 317 [M + H]+. C20H16N2O2 (316.35).
1,2,N,N′-Tetraphenylethylene-1,2-diamine (13).18 A flask
was charged with 18.12 g (100 mmol) of N-benzylideneaniline,
0.125 g (2.6 mmol) of NaCN, and 50 mL of N,N-dimethylform-
amide. The mixture was sparged with N2 for 20 min and sealed
with a rubber septum. The reaction was stirred for 24 h and
then 100 mL of methanol was added. The solution was cooled
to 0 °C. The resulting yellow solid was isolated by filtration.
High vacuum-drying provided 13.0 g (71.8%) of a neon yellow-
green solid. The product can be recrystallized from dichloro-
methane affording E-1,2,N,N′-tetraphenylethylene-1,2-di-
1
amine. The H NMR (CDCl3) spectrum at -50 °C indicates a
(37) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P.
Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03, revision C.02; Gaussian, Inc.:
Wallingford, CT, 2004.
Experimental Section
Theoretical Methods. All calculations were performed
using the Gaussian 0337 suite of programs. Optimized structure
and frequency calculations were performed using density
functional theory (DFT) employing the Becke’s three-param-
eter hybrid functional (B3)38 with the correlation functional
of Lee, Yang, and Parr (LYP),39,40 and the Pople style basis
sets, 6-31+G(d′) and 6-311++G(d,p).41 Restricted calculations
were performed, as all relevant species were closed shell
molecules. All reported energies include zero-point energy, use
(38) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(39) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789.
(40) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett.
1989, 157, 200-206.
(41) 6-31G: Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257-2261. 6-31G**: Hariharan, P. C.; Pople, J. A. Theor.
Chim. Acta 1973, 28, 213-222. 6-311G**: Krishnan, R.; Binkley, J.
S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650-654. Diffuse
Functions: Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys.
1984, 80, 3265-3269.
(34) Davidson, E. R.; Feller, D. Chem. Rev. 1986, 86, 681-696.
(35) Bauschlicher, C. W., Jr.; Partridge, H. Chem. Phys. Lett. 1995,
240, 533-540.
(42) Pfeiffer, P.; Hesse, T.; Pfitzner, H.; Scholl, W.; Thielert, H. J.
Prakt. Chem. 1937, 149, 217-296.
(36) Swart, M.; Snijders, J. G. Theor. Chem. Acc. 2003, 110, 34-41.
J. Org. Chem, Vol. 70, No. 21, 2005 8415

Reich et al.
nearly even mixture of E and Z isomers: δ 5.73 (s, 1H), 5.77
(s, 1H), 6.56 (m, 4H), 6.77 (m, 2H), 7.10-7.34 (m, 12H), 7.56
(d, 2H, 3JHH ) 8.4 Hz). The 13C NMR (CDCl3) spectrum at -50
°C indicates a nearly even mixture of E and Z isomers: δ 116.0,
116.1, 119.0, 119.1, 126.8, 127.3, 128.0, 128.2, 128.5, 128.7,
129.2, 129.4, 129.5, 130.5, 136.6, 136.8, 143.8, 145.6 MS
(ESI): m/z ) 363 [M + H]+. C26H22N2 (362.47). X-ray crystal-
lography (SM18): Green plates were grown by slow evapora-
tion of a dichloromethane solution. Crystal data: monoclinic,
P21/c, a ) 11.091(7) Å, b ) 8.924(5) Å, c ) 19.781(12) Å, R )
90°, â ) 101.359(11)°, γ ) 90°, V ) 1919.4(19) Å3, Z ) 4, T )
a toluene or acetone solution. 1H NMR (acetone-d6, RT): δ
-0.22 (s, 1H), 2.88 (s, 1H), 6.12 (broad s, 1H), 6.34 (m, 1H),
6.17 (m, 4H), 6.97 (m, 4H), 7.30 (m, 2H), 7.46 (m, 1H), 9.12
(broad s, 1H), 13C NMR (acetone-d6, RT): δ 46.9, 114.5, 114.6,
115.8, 117.8, 117.9, 118.2, 118.6, 120.2, 126.1, 126.2, 128.01,
128.04, 128.2, 139.2, 129.7, 132.66, 132.71, 153.3, 162.7. 1H
NMR (Cl2DCCDCl2, 130 °C): δ 3.50 (s, 1H), 7.55 (s, 1H), 7.89
3
(d, 1H, JHH ) 9.0 Hz), 8.11 (m, 4H), 8.37 (m, 4H), 8.65 (m,
3H), 9.13 (broad s, 1H), 9.39 (broad s, 1H). 13C NMR (Cl2-
DCCDCl2, 130 °C): δ 49.8, 116.6, 117.7, 119.7, 119.9, 120.0,
120.8, 121.1, 123.1, 127.9, 129.3, 130.4, 130.5, 131.1, 132.3,
133.0, 133.5, 134.2, 137.0, 164.1. MS (ESI): m/z ) 317 [M +
H]+. C20H16N2O2 (316.35). X-ray crystallography (SM11): Or-
ange-red blocks were grown by slow evaporation of a toluene
solution. Crystal data: monoclinic, P21/n, a ) 9.708(2) Å, b )
15.970(4) Å, c ) 11.254(3) Å, R ) 90°, â ) 115.496(3)°, γ )
90°. V ) 1574.9(6) Å3, Z ) 4, T ) 110(2) K, R1 (on F0) ) 0.0557,
2
110(2) K, R1 (on F0) ) 0.0574, wR2 (on F0 ) ) 0.1340, GOF )
1.008 for 225 parameters and 3333 unique data.
1,2,-Diphenyl-N,N′-di-(p-methylphenyl)-ethylene-1,2-
diamine (13-Me2).18 A flask was charged with 20.0 g (102.5
mmol) of N-benzylidenetoluidine, 1.0 g (20.4 mmol) of NaCN,
and 50 mL of N,N-dimethylformamide. The mixture was
sparged with N2 for 20 min and sealed with a rubber septum.
This was stirred for 24 h and then 100 mL of methanol was
added. The solution was cooled to 0 °C. The resulting yellow
slurry was filtered. High vacuum-drying provided 13.4 g
(67.0%) of a neon yellow solid. The product can be recrystal-
lized from dichloromethane affording E-1,2-diphenyl-N,N′-di-
(p-methylphenyl)-ethylene-1,2-diamine. The 1H NMR (CDCl3)
spectrum at -60 °C indicates a 90:10 mixture of E and Z
isomers. Major isomer: δ 2.22 (m, 6H), 5.71 (m, 2H), 6.47 (d,
2
wR2 (on F0 ) ) 0.1015, GOF ) 1.056 for 229 parameters and
3553 unique data. A second crystal from a separate prepara-
tion was grown by slow evaporation of an acetone solution.
An essentially identical X-ray structure was determined.
Acknowledgment. The authors thank the Robert
A. Welch Foundation (no. A-1537) and the donors of the
Petroleum Research Fund (no. 39671-G1), administered
by the American Chemical Society, for support of this
research. We thank the staff at the supercomputing
facilities and the Laboratory for Molecular Simulations
at Texas A&M University for quantum chemical calcu-
lation support. Lisa M. Pe´rez and Chad Beddie are
thanked for their valuable quantum chemical calcula-
tion insights. A.K.J. gratefully acknowledges the NSF-
REU program for a 2003 undergraduate summer fel-
lowship.
3
4H, JHH ) 5.1 Hz), 6.95 (m, 4H), 7.26 (m, 6H), 7.55 (d, 4H,
3JHH ) 7.5 Hz). 13C NMR (CDCl3, -60 °C): δ 20.6, 115.6, 127.1,
127.5, 127.8, 128.0, 128.8, 129.4, 136.1, 142.5. MS (ESI): m/z
) 391 [M + H]+. C28H26N2 (390.21). X-ray crystallography
(SM81): Neon yellow needles were grown by slow evaporation
of a dichloromethane solution. Crystal data: orthorhombic,
Fdd2, a ) 16.5867(17) Å, b ) 44.319(6) Å, c ) 5.7826(6) Å, R
) 90°, â ) 90°, γ ) 90°, V ) 4250.8(8) Å3, Z ) 8, T ) 110(2) K,
2
R1 (on F0) ) 0.0430, wR2 (on F0 ) ) 0.1024, GOF ) 1.046 for
138 parameters and 1534 unique data.
(()-2,3-Di-(2-hydroxyphenyl)-1,2-dihydroquinox-
aline (17).20 A flask was charged with 11.60 g (36.7 mmol) of
N,N′-bis(salicylidene)-o-phenylenediamine, 2.00 g (40.8 mmol)
of sodium cyanide, 1.50 g (4.06 mmol) of tetra-n-butylammo-
nium iodide, 100 mL of dichloromethane, and 100 mL of water.
The reaction mixture was refluxed for 64 h. The solid that
formed at the interface of the two phases was isolated by
suction filtration and dried in vacuo to yield 6.50 g (56.0%) of
product. Single crystals can be grown by slow evaporation of
Supporting Information Available: Compound charac-
terization data, including NMR spectra, X-ray crystallographic
data (13-E, 13-Me2-E, and 17a), DFT zero-point energies, and
Cartesian coordinates for all relevant computationally studied
species. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051102G
8416 J. Org. Chem., Vol. 70, No. 21, 2005