Kinetics of Electrophilic Alkylations of Barbiturate and Thiobarbiturate Anions

Article abstract of DOI:10.1021/acs.joc.7b01223

Second-order rate constants (k₂) of the reactions of various barbiturate anions such as the parent barbiturate, 1,3-dimethylbarbiturate, 2-thiobarbiturate, and 1,3-diethyl-2-thiobarbiturate with diarylcarbenium ions and Michael acceptors have b

Full text of DOI:10.1021/acs.joc.7b01223

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Article
Kinetics of Electrophilic Alkylations of Barbiturate and Thiobarbiturate Anions
Alexander Schade, Ivan Tchernook, Mirko Bauer, Alexander
Oehlke, Martin Breugst, Joachim Friedrich, and Stefan Spange
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01223 • Publication Date (Web): 17 Jul 2017
Downloaded from http://pubs.acs.org on July 20, 2017
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Kinetics of Electrophilic Alkylations of Barbiturate and Thiobarbiturate Anions
‡
†
‡
‡
Alexander Schade , Ivan Tchernook *, Mirko Bauer , Alexander Oehlke , Martin
§
†
‡
Breugst , Joachim Friedrich and Stefan Spange *
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‡
Department of Polymer Chemistry, Technische Universität Chemnitz, Straße der
†
Nationen 62, 09107 Chemnitz, Germany, Department of Theoretical Chemistry, Technische
§
Universität Chemnitz, Straße der Nationen 62, 09107 Chemnitz, Germany and Department
für Chemie, Universität zu Köln, 50939 Köln, Germany.
stefan.spange@chemie.tuꢀchemnitz.de
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
2
Abstract: Secondꢀorder rate constants (k ) of the reactions of various barbiturate anions such
as the parent barbiturate, 1,3ꢀdimethylbarbiturate, 2ꢀthiobarbiturate, and 1,3ꢀdiethylꢀ2ꢀ
thiobarbiturate with diarylcarbenium ions and Michael acceptors have been determined in
o
dimethylsulfoxide solution at 20 C. The reactivity parameters N and s
N
of the barbiturate
anions were derived from the linear plots of log k
2
versus the electrophilicity parameters E of
o
these reference electrophiles, according to the linearꢀfreeꢀenergy relationship log k (20 C) =
2
N
s (E+N). Several reactions of these nucleophiles with benzylidenemalononitriles and quinone
methides proceeded with reversible formation of the new C–Cꢀbond followed by rateꢀ
determining proton shift. No evidence for initial attack of the electrophiles at the enolate
oxygens of these nucleophiles was found by the kinetic measurements, in line with quantum
chemical DFT calculations, which showed that in all cases Cꢀattack is kinetically and
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thermodynamically preferred over Oꢀattack. The nucleophilic reactivities of barbiturate
anions were compared with those of structurally related carbanions, e.g., Meldrum’s acid and
dimedone anions.
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Introduction
Barbituric acid (BA) derivatives are important for medical applications due to their
1
anxiolytic and hypnotic properties. Furthermore, certain barbiturate derivatives such as
2
murexide are analytically relevant complex ligands or suitable as NLO (nonꢀlinear optics)
3
ꢀ5
chromophores and solvatochromic dyes.
The parent BA is a CHꢀacidic compound which belongs to the class of malonic acid
6
derivatives. Accordingly, 5ꢀunsubstituted BA derivatives undergo Knoevenagel condensation
7
ꢀ10
11
reactions,
which give benzylidene derivatives with benzaldehydes. Structurally related
pushꢀpull dyes, with the BA moiety as electron acceptor substituent, are available by reactions
9
of BA anions with benzhydrylium cations followed by an oxidation reaction [Scheme 1 (a)].
Another type of barbituric acid dyes is available by nucleophilic aromatic substitution of
EWG (electron withdrawing group) paraꢀsubstituted aromatic fluoro compounds with
12
barbiturate anions [Scheme 1 (b)]. Such barbiturate dyes can switch between the ketoꢀ and
12,13
enolꢀform depending on the environment.
The enol formation is associated with a color
development because a pushꢀpull dye is generated with the barbiturate substituent as electron
1
2,13
donating group (EDG).
Accordingly, the BA moiety can serve either as EWG (a) or EDG
(b) as illustrated in Scheme 1.
Scheme 1. Two examples of reactions of barbiturate anions with organic electrophiles to produce solvatochromic
dyes. EDG = electron donating group; EWG = electron withdrawing group.
Therefore, barbiturate dyes are useful as switchable chromophores with fluctuating
1
2,13
hydrogen bonding pattern [Scheme 1 (b)].
This feature provides the BA moiety as
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valuable substituent for manifold applications in molecular recognition of nucleic bases and
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related compounds.
Usually, the BA moiety is introduced by the synthetic procedures
illustrated in Scheme 1, where the barbiturate anion undergoes a nucleophilic attack on the
electrophilic carbon atom of the substrate. A successful synthesis significantly depends on the
nucleophilic reactivity of Cꢀ5 of the barbiturate anion in conjunction with an appropriate
electrophilic reagent. However, competition between Cꢀ, Oꢀ, and Nꢀalkylation has to be
considered when BA anions undergo reactions with electrophiles (Scheme 2). For example,
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products arising from Cꢀattack were obtained in reactions with carbonyl compounds.
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Alkylations with dication ethers,
alkyl iodides, dimethyl sulfate or diazomethane
yield mixtures of Cꢀ, Oꢀ, and Nꢀalkylated products of BA. Nꢀalkylated products are solely
21,22
formed by reactions of 5,5ꢀdialkylsubstituted BA with triphenylmethylium ions.
H
H
O
O
H
H
O
O
H
N
O
N
N
N
N
O
O
O
N
OH
Cꢀalkylation
Oꢀalkylation
N
ꢀalkylation
Scheme 2. Examples of resonance structures and tautomerism of barbituric acid anion which demonstrate the
possible nucleophilic centers of those nucleophiles.
23ꢀ25
Whereas acid properties of BA derivatives were studied in water and DMSO,
quantitative data on nucleophilic reactivity of barbiturate anions are still not reported
26,27
compared to well characterized malonic acid and meldrum’s acid derivatives.
As the pK ꢀvalues of CHꢀacids correlate only poorly with the nucleophilicity of the
a
2
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corresponding carbanions, reactivity parameters of barbiturates must be attained by studying
their kinetics with reference electrophiles.
A methodology had been established to derive the nucleophilic reactivities of
carbanions from the secondꢀorder rate constants of their reactions with reference
electrophiles. It has been shown that the secondꢀorder rate constants (k ) can be calculated
2
N
from the nucleophilicity parameter N, the nucleophileꢀspecific susceptibility parameter s ,
2
8ꢀ38
and the electrophilicity parameter E (eq. 1).
log k (20 °C) = s (N + E)
2
N
(1)
This study aims to investigate the kinetics of barbituricꢀ and thiobarbituric acid salts as
well as their 1,3ꢀdialkylated derivatives (Scheme 3) with various electrophilic compounds in
order to obtain quantitative information about their nucleophilicity (N) according to eq. 1.
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Scheme 3. Barbiturate anions used in this work.
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Results
The nucleophilicities of barbiturate anions were determined by studying the kinetics of
their reactions with benzhydrylium ions 1c–g and Michael acceptors 2–6 (Table 1) as
reference electrophiles, which differ highly in reactivity whereas the steric shielding of the
3
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reaction center is not varied significantly.
Table 1. Electrophilicity parameters (E) and UV/vis absorption maxima of benzhydrylium ions 1a–g and
Michael acceptors 2–6 employed as reference electrophiles in this study.
c)
b)
λ
max
cationic electrophiles
E
[
nm]
1
a)
1
a:
b:
c:
d:
R =
+3.63
‒7.02
–7.69
–8.22
469
613
620
618
1
a)
R =
1
R =
1
R =
1
e:
f:
R =
–8.76
–9.45
627
635
1
R =
1
g:
R =
–10.04
630
c)
neutral Michael
acceptor electrophiles
b)
λmax
[nm]
325
E
2
2
a:
b:
a:
R = H
–9.15
2
R = MeO
–10.28
–11.32
366
388
2
3
4
R = MeO
O
N
2
a:
R = Me
2
N
–12.76
480
N
R2
O
O
2
5
6
a:
b:
c:
R = H
–9.42
–10.80
–13.30
311
354
441
2
R = MeO
2
2
R = Me N
2
a:
b:
c:
R = MeO
–12.18
–13.39
–15.83
422
533
371
3
R = Ph
2
R = Me
2
N
3
R = Ph
2
R = Me;
3
t
R = Bu
a) electrophiles used only for product studies
1
1,40ꢀ45
b) electrophilicity parameters were taken from refs
1
1,28,41,42,44
c)
λmaxꢀvalues were taken from refs
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The barbiturate salts shown in Scheme 3 were generated by treating the corresponding
2 3
barbituric acids with aqueous solutions of stoichiometric amounts of K CO or tetraꢀnꢀ
butylammonium hydroxide. The potassium salts B and SB (Scheme 3) precipitated, were
separated by filtration, washed with cold water, and dried under reduced pressure. The
potassium salts MB and ESB were isolated by evaporation of water and subsequent
recrystallization of the crude products from ethanol. The tetraꢀnꢀbutylammonium salt
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(NBu MB) was isolated by removing water and recrystallization of the crude product from
diethyl ether.
NMRꢀproduct studies
One purpose of the various NMRꢀstudies was to prove whether Oꢀ, Cꢀ or Nꢀreactivity of the
barbiturate anions with the different types of electrophiles was kinetically observed.
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Therefore, according to previous studies,
the reaction of at least one nucleophile with
one example of each type of electrophiles, was directly monitored by NMRꢀexperiments in
d
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ꢀDMSO. Selected representative products were isolated for full product characterization.
Benzhydrylium ion 1a was chosen as electrophile for the product studies because a
potentially kinetically preferred Oꢀalkylation product would be expected due to the high
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electrophilicity of 1a according to ref. .
However, only Cꢀalkylation products were produced by reactions of both
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benzhydrylium cations (1a and 1b) with MB (Scheme 4). For details and spectroscopic data
see Experimental Section or Supporting Information page S20 – S29.
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Scheme 4. Reaction of NBu MB with 1a-OTf, directly monitored via H NMR experiments.
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The observed reaction cascade of MB with 2b, which course is similar to that of SB
with 4a, is illustrated in Scheme 5. The initial C−Cꢀbond formation is reversible for these
nucleophileꢀelectrophile combinations. Subsequently, the negatively charged intermediates
can undergo an intramolecular proton transfer (Scheme 5) and two different species are in
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⊖
equilibrium: an anion with the negative charge on the former electrophile part N–E and an
⊖
anion with the negative charge on the former nucleophile part N–E (Scheme 5). Together
⊖
⊖
with the equilibrium between N–E and N–E (Scheme 5), the formation of the anion of
Meldrum’s acid (MA) and 5ꢀ(4ꢀmethoxybenzylidene)ꢀ1,3ꢀdimethylbarbiturate (4b) are
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possible by C−Cꢀbond cleavage of the secondary product N–E.
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Scheme 5. Equilibria observed during reaction of MB and 2b as directly monitored by H NMRꢀexperiment in
DMSO.
Hence, not only the initially formed and assumed asymmetric adduct (MB2b) could be
observed during the reaction. Two symmetric products were also found (Scheme 6) due to
reactions of the additionally generated nucleophile (MA) and electrophile (4b). The products
were identified NMRꢀspectroscopically by three singlet signals for MB+2b at 5.07 ppm, 5.61
ppm and 6.12 ppm and for SB+4a at 5.96 ppm, 6.08 ppm and 6.20 ppm with statistically
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determined integrals of 0.25 : 0.50 : 0.25. Complete H NMRꢀspectroscopic data are given in
the Experimental Part.
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Scheme 6. Found product mixture in the HꢀNMRꢀexperiment of reaction of MB with 2b in DMSO.
For the reaction of 3a with MB, the back reaction is very slow, thereby the initially
formed asymmetric product could be identified. The formation of the symmetric byproducts
1
⊖
were detected in the HꢀNMR spectra after >48 hours. N–E seems to be stabilized by
tautomerization towards the enolicꢀform of the barbiturate moiety and formation of an
1
intramolecular hydrogen bond as illustrated for MB3a in Scheme 7 (results from H NMR
spectroscopy are given in the Experimental Section). A singlet at 5.61 ppm is detected in the
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H NMRꢀspectrum for the central CHꢀgroup which indicates the formation of MB3a (Scheme
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).
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Scheme 7. Reaction of MB with 3a as directly monitored by H NMRꢀexperiment in DMSO.
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H NMRꢀstudies of products formed from alkylidene malononitriles (5) with MB in
DMSO show two doublets at 4.68 and 6.20 ppm for MB5a and at 4.57 and 6.10 ppm for
MB5c (Scheme 8). This is an indication that these products do not form an intramolecular
⊖
hydrogen bond (Scheme 8). The initially formed adducts N–E were transferred into the
⊖
barbiturate anions N–E, as shown in Scheme 8. In case of the reaction of MB with 5a, the
product MB5aH could be isolated after treating the mixture with trifluoroacetic acid.
Analogous products have previously been observed for the reactions of
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benzylidenemalononitriles with carbanions of βꢀdiketones and of benzylidenebarbiturates
11
with malononitrile anions. However, the intermediate MB5c decomposes to portions of 5c
and 1,3ꢀdimethylbarbituric acid if trifluoroacetic acid is added.
1
Scheme 8. Suggested reaction cascade of MB with 5a and 5c as directly monitored by H NMRꢀexperiment in
DMSO. Product MB5aH could be isolated as solid in 76% yield (see experimental part).
The phenol intermediate (MB6c) was observed for the reaction of the quinonemethide
6
c with MB. The product formation is explainable by Cꢀalkylation with a subsequent proton
transfer reaction (Scheme 9). MB6cH could be isolated in 88 % yield after treating the
mixture with trifluoroacetic acid.
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Scheme 9. Suggested reaction cascade of MB with 6c as directly monitored by H NMRꢀexperiment in DMSO.
Product MB6aH could be isolated in 88% yield (see experimental part).
Because of the better solubility, MB was chosen as nucleophile for most of the product
1
characterizations. To study the influence of Nꢀalkylation, an H NMR experiment of B with
6
6c in d ꢀDMSO was performed. A singlet at 5.21 ppm was detected, which is characteristic
for the central CHꢀgroup, occurring after C−Cꢀbond formation (see Experimental Section). Nꢀ
alkylation is therefore not observed for the unalkylated barbituric acid anions B and SB.
Altogether, only products resulting from Cꢀalkylation were found for all nucleophileꢀ
1
electrophile combinations as proven by H NMR spectroscopy. Spectroscopic data are given
in the experimental part.
It could be concluded from the product studies that the initially formed intermediates
⊖
⊖
N–E may undergo a proton shift to form N–E (ketoꢀ or enolꢀstructure) (Scheme 10). The
relative concentrations of these types of adducts were controlled by the acidꢀbase equilibrium
48
constant KPT (Scheme 10).
⊖
Scheme 10. Suggested scenario for the reactions of the barbiturate anion (N ) with neutral Michael acceptors
E).
(
Generally, the scenario suggested in Scheme 10 applies to all barbiturate anion/Michael
acceptor combinations which have to be considered by interpreting the kinetic data.
Kinetic investigations
The kinetics of the reactions of barbiturate anions (Scheme 3) with reference
electrophiles (Table 1) were studied in DMSO solution at 20 °C by monitoring the UV/vis
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absorptions of the electrophiles by means of conventional or stoppedꢀflow techniques. To
simplify the evaluation of the kinetic experiments, the barbiturate anions were used in large
excess (> 10 equiv.). Thus their concentrations remained almost constant throughout the
reactions, and pseudoꢀfirstꢀorder rate constants were obtained in all runs. The observed firstꢀ
orderꢀrate constants (kobs) were derived by least squares fitting of the exponential function A
t
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=
A0 × exp( – kobs × t) + C to the time dependent absorbances A of the electrophiles (Figure
t
1). Secondꢀorderꢀrate constants (k
2
) were obtained as the slopes of linear correlations of kobs
with the concentrations of the nucleophiles (Figure 1) The axis interception is the sum of all
side reactions, including the back reaction k−1 as shown in Figure 2. All data are listed in
Table 2.
0.7
70
60
50
40
k
obs = 28564
✕ [MB] + 1.16
r² = 0.999
0.6
0.5
0.4
0.3
2
ꢀ k = 2.86—10
4 L—mol−1—s−1
3
0
20
1
0
0
0.0000
0.0005
0.0010
0.0015
0.0020
0.0025
−
1
0.2
[MB] [molL ]
0.1
0.0
0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 0.20
t [s]
–
5
–1
Figure 1. Plot of the UV/vis absorbance of 3a (c = 4.45 × 10 molL ) versus time for its reaction with MB
(c = 1.27 × 10–3 molL–1) in DMSO at 20 °C; inset: correlation of the pseudoꢀfirstꢀorder rate constants (kobs
versus concentration of MB.
)
Figure 2 illustrates the incomplete reaction of the barbituric acid based Michael acceptor 4a
with MB. The obtained kobs values increase linearly with the nucleophile concentration with a
slope corresponding to the secondꢀorder rate constant of the forward reaction and an intercept,
which indicates the incomplete conversion for combinations of MB+3a, SB+3a, ESB+3a,
4
9
B+4a, MB+4a, SB+4a and ESB+4a (see SI page S9−S11). Also negative intercepts were
found, which could be related to a partial decomposition of the nucleophile during dissolution
50
as suggested in the literature. However, selfꢀaggregation or strong solvation of the
barbiturate anions by DMSO may also possible because of their high dipolarity. But, these
negative intercepts are small and, because of the good correlation of log k2 versus
electrophilicity (E) of these data, they were further used for the determination of the
nucleophilicity (N) of barbiturate anions.
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1
1
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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4
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5
5
5
5
5
5
6
k
obs = 2538
✕ [MB] + 5.34
r² = 0.999
[
MB]
9.64
.61
2.25
.89
3.53
[MB]/[4a] conversion
ꢀ
04
03
03
03
03
1.4
1.2
1.0
✕
10
11.5
19.1
26.8
34.5
42.1
28.5 %
42.0 %
50.3 %
56.6 %
62.5 %
ꢀ
ꢀ
ꢀ
ꢀ
14
12
k2 = 2.54 ✕
10³ Lmolꢀ1sꢀ1
1
✕
10
ꢀ
✕
10
2
✕
10
10
✕
1
0
8
6
4
2
0
0.8
0.6
0.4
0.2
0.0
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
0.1
0.2
0.3
0.4
0.5
t [s]
0.6
0.7
0.8
0.9
1.0
0.000
0.001
0.002
0.003
0.004
−
1
[MB] [molL
]
Figure 2. left: Plot of the UV/vis absorbances of 4a versus time for five different concentrations of MB in
DMSO at 20 °C; right: plot of the obtained pseudoꢀfirstꢀorder rate constants (kobs) versus the nucleophile
concentration.
Altogether, reactions of barbiturate anions with electrophiles 3a and 4a show
incomplete conversions. The degree of conversion increases in the order from oxoꢀ to
thiobarbiturates (B < SB and MB < ESB) and from alkylated to nonalkylated barbiturates
(MB < B and ESB < SB) as measured by UV/vis spectroscopy (see SI page S9 – S11).
The equilibrium constants (K) are identified by titration experiments according to
Figure 2 left, by measuring the incomplete conversions of the electrophile at the equilibrium
state for reactions of B, MB, SB and ESB with the electrophiles 3a and 4a (see Table S1).
Reaction rate constant of the back reaction (k−1) from ordinary intercept are determined to
check the magnitude of the Kꢀvalue (Scheme 11). Data and discussion see supporting
information page S1 – S2.
The interpretation of the observed secondꢀorderꢀrate constants (k2,obs) is unambiguous in
cases where the initial C–Cꢀbondꢀforming step immediately yields the final product. The
situation is more complex, when the observable product is formed through a proton transfer
following the C–Cꢀbondꢀforming step which may play a role according to the product studies
observed for the electrophiles of the 5- and 6ꢀtype.
If the Bodenstein approximation (steady state of the initially formed adduct) can be
applied for the reaction sequence in Scheme 11, the rate of disappearance of the electrophile
5
1ꢀ53
is given by eq. 3.
For a detailed mathematic derivation of eq. 3 see Supporting
Information page S16. Scheme 11 does not consider the additional ketoꢀenol equilibria for
simplification.
⊖
Scheme 11. General reaction scheme of an anionic nucleophile N with a neutral electrophile E.
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dꢀEꢁ
dꢂ
ꢇPT
ꢆ
=
ꢃ−ꢄꢅꢃ
×
ꢃꢀEꢁꢃꢀN ꢁꢃ
×
ꢃꢇ
1ꢃ
(3)
PTꢈꢃꢇ
–
Let us now consider two extremes for the relative magnitudes of the reverse reaction
(k
–1) and the proton transfer kPT (eq. 4 and 5)
dꢀEꢁ
ꢃꢀEꢁꢃꢀNꢆꢁꢃ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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45
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49
50
51
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54
55
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57
58
59
60
forꢃꢄ ꢃ≫ ꢄ ꢃ⇒ꢃ
=ꢃ−ꢄꢅꢃ
=ꢃ−ꢄꢅꢃ
×
×
(fast proton transfer)
(4)
PT
–1
dꢂ
dꢀEꢁ
dꢂ
ꢇPT
ꢆ
forꢃꢄ ꢃ≪ ꢄ ꢃ⇒ꢃ
ꢃꢀEꢁꢃꢀN ꢁꢃ
×
ꢃ
ꢇ–1ꢃ (very slow proton transfer) (5)
PT
–1
ꢇ
dꢀEꢁ
ꢊꢃ
ꢆ
ꢃꢃwithꢃꢉ =ꢃꢇ ꢃ⇒ꢃ dꢂ =ꢃ−ꢄPTꢃ
×
ꢃKꢃꢃ
×
ꢃ
ꢀEꢁꢃꢀN ꢁꢃꢃ
(6)
–1
In both cases one would observe a monoexponential decay of the electrophile UV/visꢀ
absorbance if one works under pseudoꢀfirstꢀorder conditions, and kinetic methods do not
allow to differentiate whether the secondꢀorderꢀrate constants k2,obs listed in Table 3
correspond to k (eq. 1) or k K (eq. 6). The product of k K can be assumed as an apparent
2
PT
PT
rate constant kapp
.
However, analysis by eq. 1 enables one to differentiate between the both cases. When
the log k2,obsꢀvalues of Table 3 are plotted against the Eꢀparameters of the electrophiles, one
finds that all rate constants for the reactions of MB and ESB with the electrophiles 1–4, are
on the correlation lines, indicating that eq. 1 holds for these reactions (Figure 3b). As the rate
constants for the reactions with 5 and 6 are below the correlation lines, one can assume that
these rate constants reflect kPTK.
Analogously, all rate constants for the reactions of B and SB with 1–4 follow the
correlation as expected from eq. 1 (Figure 3a). In contrast to the behavior of MB and ESB,
also the reactions with the quinone methides 6 are on the correlation lines, suggesting that k
2
is measured. In Figure 3a only the k2,obsꢀvalues of the reactions with the benzylidene
malodinitriles 5 deviate from the linear correlation, indicating that k K is rateꢀdetermining in
PT
reactions of B and SB with 5.
1
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6
a)
b)
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2
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0
1
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1
c
1f
1e
1e
f
7
6
1
2
b
1
2
b
3a
5
4a
3a
4
1d
1
d
4a
2a
5a
3
2a
a
g
1g
2
6
c
0
1
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3
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9
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5
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0
1
2
3
4
5
6
7
8
9
0
5b
1
5
6a
0
6a
5b
6b
ꢀ
ꢀ
ꢀ1
ꢀ2
ꢀ3
6
c
6b
ꢀ3
ꢀ
16
ꢀ15
ꢀ14
ꢀ13
ꢀ12
ꢀ11
ꢀ10
ꢀ9
ꢀ8
ꢀ7
ꢀ16
ꢀ15
ꢀ14
ꢀ13
ꢀ12
ꢀ11
ꢀ10
ꢀ9
ꢀ8
ꢀ7
E
E
Figure 3. Plots of log k2,obs for the reaction of barbiturate anions with reference electrophiles versus the
corresponding electrophilicity parameters E.
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Table 2. Secondꢀorderꢀrate constants k2,obs for the reactions of barbiturate anions with electrophiles 1–6, and the
a)
resulting nucleophileꢀspecific parameters N and s for the barbiturate anions in DMSO at 20 °C.
N
–
1 –1
Nucleophile
N
s
N
Electrophile
k
2,obs [Lmol s ]
5
1
d
e
f
5.90 × 10
2.33 × 10
1.26 × 10
5.28 × 10
1.01 × 10
1.93 × 10
2.69 × 10
1.05 × 10
2.31 × 10
1.14 × 10
1.18 × 10
7.59 × 10
2.32 × 10
1.91 × 10
1.57 × 10
2.86 × 10
2.54 × 10
2.36 × 10
1.04 × 10
3.48 × 10
1.54 × 10
6.81 × 10
7.01 × 10
1.34 × 10
1.41 × 10
1.76 × 10
1.82 × 10
3.77 × 10
6.43 × 10
2.08 × 10
6.16 × 10
3.42 × 10
1.25 × 10
2.60 × 10
5.43 × 10
5.05 × 10
6.68 × 10
4.48 × 10
15.59
0.80
5
5
4
5
4
3
2
2
0
6
5
5
5
5
4
3
5
5
4
4
3
3
3
3
2
1
1
0
5
4
4
4
4
3
3
2
1
1
1
1
2a
2b
3
4
6
6
1e
1f
1
2
2
3
4
1
g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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49
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59
60
a
a
a
c
1
1
7.46
4.24
0.72
0.82
g
b
b
a
a
c
1d
1e
1
1
2
2
2
f
g
a
b
b
3a
4a
6a
6b
1d
1e
1f
1
4.90
0.80
1g
2a
2
2
3
4
5
5b
5c
b
b
a
a
0
a
3.38 × 10
7.82 × 10
c)
‒
1
6
5
5
5
6
6
6c
5a
5
b
a
b
c
a
b
b)
‒
1
2
4.32 × 10
2.62 × 10
c)
1.62 × 10
1.38 × 10
6.46 × 10
1.14 × 10
1.47 × 10
‒
3
1
–
‒
‒
3
1
2
b
5c
c)
‒2
‒3
5
5
5c
6a
a
b
6.62 × 10
5.60 × 10
c)
0
6.15 × 10
1.86 × 10
‒1
6
b
a) The kinetic results of reactions of barbiturate anions with malononitriles 5 and several quinone methide
electrophiles 6 are presented separately at the end of the table, because these data were not used for
N
determination of N and s . b) no evaluation, because of bisexponential curves; c) no evaluation, because of too
slow reaction (τ1/2 > 48 h)
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5
6
Quantum chemical calculations
Although no evidence for the formation of Oꢀalkylation products has been found
experimentally, quantum chemical calculations have been performed to examine whether
initial Oꢀattack can account for the deviation of some rate constants from the correlations in
Figure 3. The solvent effects for DMSO are included by the COSMO solvation model with
ε = 48.
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
From the quantum chemical investigation, some general features can be derived. The
calculated energies and the resulting Gibbsꢀreaction profiles are exemplarily shown in Figure
4
for the alkylation of MB with the neutral electrophiles 2a, 4a, 5a, and 6a. Obviously for all
investigated electrophiles the attack at C(5) is favored over the alkylation at the enolate
oxygen (Figure 4). The Gibbs energies of Oꢀalkylated products are not only higher than those
of the Cꢀalkylated products, but also higher than those of the reactants (endergonic reactions).
As the transition states for Cꢀalkylation are also energetically lower than those for Oꢀ
alkylation (Figure 4), the formation of the Cꢀalkylated products is thermodynamically as well
as kinetically favored. This result is in accordance with the product studies where only Cꢀ
alkylated products were observed. Therefore, Oꢀattack at the barbiturate anion cannot be the
reason for the deviations of some reactions from the correlations in Figure 3.
Electrophilicity (E)
Figure 4. Reaction profiles for the reactions of MB at Cꢀ or at Oꢀatom with the electrophiles 2a, 5a, 6a, and 4a. The
⊖
⊖
transition states for Cꢀ and Oꢀattack as well as the corresponding products are denoted with TS/TS and N-E /N -E
O
O
respectively. The reaction profiles are ordered according to the order of the electrophilicity of the investigated
electrophiles. The lowest dispersion complex is set to zero and the energy profiles are given for PW6B95ꢀD3/def2ꢀ
TZVPP/COSMO singleꢀpoint calculations (ZPVE: BP86ꢀD3/TZVP).
1
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As shown in Figure 5, the quantum chemically calculated Gibbsꢀactivation energies for
‡
the reactions of B and MB (ꢁG , open symbols) with neutral electrophiles also correlate
linearly with the electrophilicities E. This correlation also includes the reactions with
electrophiles 5a−c and 6a,b, where the experimentally determined rate constants deviate from
the linear correlations shown in Figure 3, i.e., the reactivity order indicated by the Eꢀ
parameters is in full agreement with the quantum chemical calculations of the transition
states. This observation provides further evidence for our earlier conclusion (see above) that
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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47
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49
50
51
52
53
54
55
56
57
58
59
60
2
the deviations from the log k vs. electrophilicity E correlations in Figure 3 are due to a
change of the rateꢀdetermining step.
‡
The lower ꢁG ꢀvalues calculated for the reactions of MB compared to B are in accord
with the experimentally observed faster reactions of MB (Figure 5). Using the Eyringꢀ
equation, the measured secondꢀorderꢀrate constants can be converted into Gibbsꢀactivation
‡
energies ꢁG , which are shown by filled symbols in Figure 5, for the reactions with rateꢀ
determining C−Cꢀbond formation.
–1
However, the calculated activation free energies were found to be 15–20 kJmol
smaller than those derived from the experimentally determined rate constants. This can be
attributed to the simplified model in the computational studies (reactant complex as reference
point, modeling the solvent environment, etc.). However, as both computational and
experimental activation free energies correlate linearly with each other, we can assume that
any effects found in the computational study can be transferred to the experimental
conditions.
75
70
4
a
65
60
55
50
6
c
3a
1g
6b
1
f
1
e
1d
45
40
5
c
ꢀ
35
‡
‡
‡
‡
3
0
5
ꢀ
G
G
G
G
(MB)
exp
6
a
2
5b
ꢀ
ꢀ
ꢀ
calc (MB)
20
15
(B)
exp
2b
5a
(B)
calc
1
0
5
0
2
a
ꢀ8
ꢀ9
ꢀ10
ꢀ11 ꢀ12 ꢀ13 ꢀ14 ꢀ15 ꢀ16
ꢀ17 ꢀ18
Electrophilicity (E)
‡
–1
Figure 5. Gibbsꢀactivation energies ꢁG (in kJmol ) derived from the theoretical and the experimental
investigation of the reactions of barbiturate anions with reference electrophiles as function of the corresponding
electrophilicity parameters E.
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1
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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
Discussion
The relative Gibbs energies of the proton transfer products are calculated and compared
with the corresponding Cꢀalkylated products for the alkylation of MB with 2a, 4a, 5a, and 6a
⊖
(
Figure 6). As shown in Figure 6, the secondary products N-E, which results after the
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
alkylation of MB with electrophile 5a or 6a and the subsequent proton transfer, are
⊖
energetically favored compared to the initially formed Cꢀalkylation product N-E . Otherwise,
⊖
alkylation products N-E for the alkylation of 2a and 4a are more stable than the secondary
⊖
products ( N-E) which would develop after the proton transfer (Figure 6).
⊖
Figure 6. Gibbsꢀreaction energies ꢁG for the Cꢀalkylation to the product N-E and the subsequent proton
⊖
transfer (PT) resulting in N-E are given for the reaction of MB with 2a, 4a, 5a, and 6a. The energy values are
given for PW6B95ꢀD3/def2ꢀTZVPP/COSMO singleꢀpoint calculations (ZPVE: BP86ꢀD3/TZVP/COSMO).
The interpretation of the product formation for electrophile/barbiturate anion
⊖
a
combinations is also possible if the pK ꢀvalues of the parent acids of the intermediates N-E
⊖
and N-E are taken into account (see Table 3). The appropriate scenario is like we illustrated
in Scheme 4. The reaction of the electrophile with the barbiturate anion immediately
⊖
generates N-E which basicity can be reflected by the pK
a
of the corresponding parent acids,
⊖
which were used for discussion, because the actual pK
a
ꢀvalues of N-E are not directly
⊖
available (Column 3 of Table 3). The structural discrepancy between N-E and the anions of
a
the parent acids seems insignificant for the discussion. The order of pK : 6 >> 5 > 4 > 3 > 2 of
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⊖
the N-E ꢀseries should not be influenced if consistent functionalization at the electrophilic
⊖
carbon atom took place, i.e. by reactions with the barbiturate anions N .
Now, it can be estimated whether the proton transfer reaction should be of relevance as
indicated in Column 4 of Table 3. Obviously, the reactions of electrophiles 5 and 6 with
10
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⊖
barbiturate anions generate an N-E whose pK
a
is greater than that of the barbituric acid
⊖
itself. That argument readily explains that N-E is actually the more thermodynamically
⊖
stable product compared to N-E when 5 or 6 reacts with a barbiturate anion. As
consequence, the consecutive proton transfer reaction can have an effect on the kinetics for
those electrophile/nucleophile combinations. Electrophile/nucleophile combinations, which
2
deviate from the linear plot log k as function of E (Figure 3), are specified in the right column
of Table 3 for comparison.
a
Table 3 Parent Brønstedꢀacid compounds of the Michael acceptor electrophiles 2, 3, 4, 5, and 6, pK ꢀvalues in
DMSO, theoretically expected scenario when the specific electrophile type reacts with barbiturate anion
according to Scheme 10 and indication of electrophile/nucleophile combinations which deviate from the linear
plot log k2,obs as function of E.
combinations which show
deviating kinetics according
to Figure 3
electrophile
type
expected scenario
according to Scheme 10
parent acid
pK
a
(DMSO)
O
O
O
O
5
4
2
3
Meldrum’s Acid
7.3
7.8
none
none
none
no subsequent proton
transfer
O
55
K
PT << 1
Indandione
DMSO/H
2
O
(90:10)
O
O
an equilibrium state is
suggested
HN
HN
NC
NC
5
4
4
5
O
Barbituric Acid
Malononitrile
8.4
K
PT ~ 1
O
54
B, MB, SB, and ESB with
5a, 5b, and 5c
11.0
16.8
subsequent proton
transfer
KPT >> 1
2
,6ꢀDiꢀtertꢀ
54
MB with 6a, 6b, and 6c;
ESB with 6a, and 6b
6
OH
butylphenol
⊖
⊖
K
PT = [ NꢀE] / [NꢀE ]
It is striking that only such electrophile/nucleophile combinations deviate from the
⊖
linear plot of log k
2
versus E where N-E is the thermodynamically more stable product
⊖
compared to N-E (Figure 6). Notwithstanding, it is difficult to decide whether k−1 or kPT is
responsible for the deviating values of k2, according to eq. 6.
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
4
4
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4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
N
However, due to the clear kinetics of the electrophiles 1, 2, 3 and 4, Nꢀ and s ꢀ
parameters of the barbiturate anions can be accurately determined according to eq. 1.
Figure 7 shows that the 1,3ꢀdialkylated barbiturates are more nucleophilic than the
nonalkylated ones (MB > B and ESB > SB). This fact can be explained by the electronꢀ
donating effect of the alkyl groups as well as by ground state stabilization of the anions with
0
1
2
3
4
5
6
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8
9
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1
2
3
4
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7
8
9
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1
2
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5
6
7
8
9
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1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
56
NHꢀgroups through hydrogenꢀbonding.
The thiobarbiturates show slightly lower Nꢀvalues than the oxobarbiturates
SB < B, ESB < MB), which may be explained by the stronger electron withdrawing effect of
(
the thiocarbonyl group, as indicated by the relative magnitudes of the Hammettꢀconstants of
57
2 5 p 2 5 p
–NHꢀCOꢀNHꢀC H (σ = –0.26) compared to –NHꢀCSꢀNHꢀC H (σ = 0.07).
In accordance with the weaker electronꢀaccepting effect of an amidocarbonyl group
compared to an alkoxycarbonyl group, the barbituric acid anion B (N = 15.59) is considerably
more nucleophilic than the anion derived from Meldrum’s acid (N = 13.91), which is
comparable to the thiobarbiturate anion SB (N = 14.24).
Secondꢀorderꢀrate constants of alkylation reactions of 5ꢀmethylꢀMeldrum’s acid and
1,3ꢀdimethylbarbituric acid anions with ethyl iodide in methanol/acetonitrile were determined
58
by Kondo et al. They showed that 1,3ꢀdimethylbarbiturate anion is slightly more
nucleophilic than 5ꢀmethylꢀMeldrum`s acid anion which is substantially in line with our
results.
Furthermore, Figure 7 shows that the dimedone anion (N = 16.27), where the urea
fragment of barbituric acid is replaced by an alkyl group, has a nucleophilicity between B
and MB.
A fair correlation of N with pKaH is shown in Figure 8, which includes carbanions of
malonic acid derivatives, 1,3ꢀdicarbonyl compounds, and the barbiturate anion B. The
deviation of cyanoꢀsubstituted carbanions from this correlation due to the lower
28
reorganization energies has previously been discussed.
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7
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O
O
N
O
O
2
0.22 / 0.65
20
19
18
NC
NC
19.36 / 0.67
18.82 / 0.69
O
O
O
N
O
O
O
MB
17.64 / 0.73
1
7.46 / 0.72
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
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O
O
1
1
1
7
6
5
O
O
NH
NH
O
S
S
B
1
6.27 / 0.77
O
O
O
O
15.59 / 0.80
4.90 / 0.80
14.24 / 0.82
N
N
1
5.24 / 0.74
ESB
SB
O
1
O
O
2
O N
O
O
NH
NH
O
O
14
1
3.91 / 0.86
O
N
Figure 7. Ranking of the nucleophilicity parameters N/s for B, MB, SB, and ESB compared to established
carbanionic nucleophiles.
5
9
Figure 8. Correlation of the nucleophilicity parameter (N) of carbanions with the pK ꢀvalues of the conjugate
a
acids in DMSO. Sqaures are nucleophilicitie values and acidities of structurally related anions from the
literature. The empty squares are cyanoꢀsubstituted carbanions, which deviate from the linear correlation. The
star is the barbituric acid anion (B) which nucleophilicity parameter (N) was newly determined.
The discussion of the newly determined nucleophilicity parameters clearly shows that
N
Nꢀ and s ꢀparameters for barbiturate anions are scientifically sound. Therefore, these data are
3
7
used according to the methodology already demonstrated in ref. for the thorough discussion
of deviantꢀsecondꢀorderꢀrate constants. Now, k2,calcd of the elementary C−Cꢀbond formation
step (see Scheme 10 and 11) were calculated from eq. 1 for those electrophile/barbiturate
anion combinations for which k is not directly experimentally available using the Eꢀ
2
parameters from Table 2 and the just determined Nꢀ and s
N
ꢀparameters of the barbiturate
anions from Table 3. That approach is justified because of the excellent linear correlation of
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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
‡
the electrophilicity parameter E with the quantumꢀchemically calculated ꢁG ꢀvalues (Figure
).
5
Calculated k2,calcdꢀvalue are compiled in Table 4. According to eq. 5 and eq. 6, the desired
value of kPT/k−1 is the quotient of k2,obs/k2,calcd (Table 4) assuming that kPT ≪ꢃ
−1
k .
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
Table 4 Calculated (k2,calcd from eq. 1) and observed (k2,obs from Table 2) secondꢀorderꢀrate constants of
electrophile 5 and 6 with barbiturate anion. k /k ꢀvalues of Column 4 are charged directly from k2,obs/k2,calcd
.
PT −1
N + Eꢀ
k2,obs (from Table 3) k2,calcd (from eq. 1) kPT / k−1
−1 −1 −1 −1
combination [Lmol s ]
B + 5a
[Lmol s ]
0
4
−5
−7
−5
−6
−4
−7
−5
−6
−1
−2
−2
−2
−4
3.4 × 10
4.3 × 10
1.1 × 10
6.6 × 10
7.8 × 10
2.6 × 10
1.5 × 10
5.6 × 10
1.6 × 10
6.2 × 10
1.4 × 10
1.9 × 10
6.5 × 10
8.6 × 10
3.9 × 10
7.0 × 10
1.3 × 10
2.7 × 10
1.2 × 10
4.2 × 10
2.2 × 10
2.9 × 10
2.6 × 10
4.1 × 10
1.6 × 10
1.2 × 10
4.3 × 10
−
−
−
−
1
1
2
1
5
MB + 5a
SB + 5a
ESB + 5a
B + 5b
MB + 5b
SB + 5b
ESB + 5b
MB + 6a
ESB + 6a
MB + 6b
ESB + 6b
MB + 6c
6.2 × 10
3
9.0 × 10
4
2.4 × 10
3
6.8 × 10
−2
−2
−3
3
4
6.2 × 10
2
6.6 × 10
3
1.9 × 10
3
6.3 × 10
0
2
1.5 × 10
1
2
8.5 × 10
−
1
3
1
1.6 × 10
−
1
1.5 × 10
Now, the deviation of the kinetics will be explained more profoundly from data of Table
4
. Altogether, kPT/k−1 ratios are << 1 of those nucleophileꢀelectrophileꢀreactions which deviate
from the linear plot in Figure 3. This observation clearly confirms that the proton transfer
reaction is the rate determining step and not the C−Cꢀbond formation for reactions of
electrophile 5 with barbituric anions.
For the electrophiles of type 6 there are differences as function of the structure of the
barbiturate anion. Unalkylated barbiturate anions (B, SB) show a good consistency between
k
2,obs and k2,calcd (Figure 3b). Only Nꢀalkylated barbiturate anions (MB, ESB) show kPT/k−1ꢀ
ratios smaller than 1 (Table 4) and those rate constants deviate from the linear correlations in
Figure 3a. However, these kPT/k−1ꢀratios are not as small as found for electrophiles of 5ꢀtype.
A reasonable explanation for that behavior is, that the initially formed intermediates N-
⊖
E undergo proton transfer more rapidly, if unalkylated barbiturate anions (B, SB) were used.
Tautomerism of the CO–NH moiety might account for this behavior. In case of the Nꢀ
alkylated barbiturate anions (MB, ESB) the proton transfer is slower and thereby rate
determing.
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Reasonably, the assumption of the apparentꢀreactionꢀrate constant kapp = k2,obs = kPT
K
(
eq. 6) for the alkylation with electrophiles of 5ꢀ and some of 6ꢀtype is emphatically
substantiated by the considerations in Table 4.
10
11
12
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60
Conclusion
The nucleophilicity parameter N, and the corresponding nucleophileꢀspecific
susceptibility parameter s
N
for the parent barbiturate B (N = 15.59; s
N
= 0.80), 1,3ꢀ
= 0.82),
dimethylbarbiturate MB (N = 17.46; s
N
= 0.72), 2ꢀthiobarbiturate SB (N = 14.24; s
N
and 1,3ꢀdiethylꢀ2ꢀthiobarbiturate ESB (N = 14.90; s = 0.80) have been determined from the
N
secondꢀorderꢀrate constants of their reactions with benzhydrylium cations and Michael
acceptors. The Nꢀvalues of the barbiturate anions are in good relationship with the
nucleophilicity parameters of related carbanions. In addition, a correlation of N of BA as
function of the pKaHꢀvalues of the corresponding acids shows the eligibility of the determined
nucleophilicity parameters.
The k ꢀvalues for reactions of barbiturate anions with electrophiles of types 1–4
2
correlated linearly with the electrophilicities E. The corresponding reactions of MB and ESB
with the electrophiles 5 and 6 and of B and SB with electrophiles 5 were slower than derived
from the correlations because the rateꢀdetermining step was not the C−Cꢀbond formation but
the subsequent proton transfer.
Quantumꢀchemical calculations show that the product formation during these
nucleophileꢀelectrophileꢀreactions is thermodynamically determined. All calculated activation
‡
barriers (ꢁG ) for the C−Cꢀbondꢀforming step correlate well with the electrophilicity
‡
parameters E. This correlation includes also those reactions for which ꢁG could not be
measured, because C−Cꢀbond formation was not rateꢀdetermining. This is the first time that a
quantum chemical verification of the empirical Eꢀparameters of electrophiles has been
achieved apart from benzhydrylium ions. That approach allows calculation of secondꢀorderꢀ
2
rate constants k for such electrophile/barbiturate anion combinations for which only kapp is
experimentally accessible.
Especially noteworthy is the quantum chemical calculations showed, that Oꢀalkylation
is kinetically and thermodynamically not favored for the investigated electrophiles. These
results are completely in line with the product studies. Nevertheless, Oꢀalkylations of BA with
18
60
alkylhalides or Oꢀsilylations with hexamethyldisilazane were sometimes reported in the
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6
literature. These examples could be explained by the oxophilicity of the silicon atom or by
sterical demanding electrophiles.
Experimental Section
Product studies:
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0
Reaction of MB with 1a:
To a solution of bis(4ꢀtolyl)methylium bromide (74.0 mg 0.269 mmol) in dry DCM,
silver triflate (70.0 mg, 0.272 mmol) was added at –80 °C. The solution changes his color to
intensive yellow, indicating the formation of the benzhydrylium cation (1a). The tetraꢀnꢀbutyl
4
ammonium salt of 1,3ꢀdimethylbarbituric acid (NBu MB) (100 mg, 0.25 mmol) was
dissolved in 20 ml DCM and the yellowish solution of bisꢀtolyl methylium triflate (1a) was
added under cooling to –80 °C. The reaction was stirred 1 h under cooling, gives 5ꢀ(bisꢀpꢀ
tolylmethyl)ꢀ1,3ꢀdimethylbarbituric acid (MB1a). The reaction product was not isolated,
1
because solely Cꢀalkylation products were found in the H NMRꢀspectrum of the crude
product. Characteristic signals for Oꢀalkylation products were not found.
1
3
H NMR (d
6
ꢀDMSO): δ 2.24 (s, 6H, CH
3
), 2.94 (s, 6H, CH
3
), 4.44 (d, JHH = 4.5 Hz,
3
1
H, CH), 4.74 (d, JHH = 4.5 Hz, 1H, CH), 7.05–7.15 (m, 8H, ArH)
Reaction of MB with 1b:
9
1
The reaction is already reported in the literature. The directly monitored H NMRꢀ
9
experiments confirm the NMRꢀdata from the literature.
1
3
H NMR (d
6
ꢀDMSO): δ 2.89 (s, 12H, CH
3
), 2.94 (s, 6H, CH
3
), 4.33 (d, JHH = 4.5 Hz,
3
3
3
1
H, CH), 4.61 (d, JHH = 4.5 Hz, 1H, CH), 6.74 (d, JHH = 7.9 Hz, 4H, ArH), 7.07 (d, JHH
=
7.9 Hz, 4H, ArH)
Reaction of MB with 2b.
Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (5.0 mg 0.026 mmol) and 2ꢀ(4ꢀ
methoxybenzylidene) meldrum’s acid (2b) (6.8 mg 0.026 mmol) was dissolved in 1 ml
1
d ꢀDMSO. H NMRꢀspectra of the solution shows nearly full conversion after few minutes, to
6
give
5ꢀ((6ꢀhydroxyꢀ1,3ꢀdimethylꢀ2,4ꢀdioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀyl)(4ꢀ
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methoxyphenyl)ꢀmethyl)ꢀ2,2ꢀdimethylꢀ4ꢀoxoꢀ4Hꢀ1,3ꢀdioxineꢀ6ꢀolate (MB2b) as expected
product, as well as two symmetric side products, which were formed by post reactions as
described in the resultsꢀpart. Due to the dynamic equilibria, individual products could not be
purely isolated.
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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32
33
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43
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60
6 3 3
H NMR (d ꢀDMSO – Enol): δ 1.57 (s, 6H, CH ), 3.15 (s, 6H, CH ), 3.67, 3,69 (s, 3H,
CH ), [5.07 (s, 0.19H), 5.61 (s, 0.39H), 6.12 (s, 0.29H) Σ = 1H, CH], 6.72 (m, 2H, CH), [6.92
3
3
3
3
(
d, JHH = 8.50 Hz, 0.69H), 7.01 (d, JHH = 8.0 Hz, 0.91H), 7.11 (d, JHH = 8.5 Hz, 0.51H) Σ =
2H, CH]
The solution was acidified with trifluoroacetic acid to obtain the neutral compound 6ꢀ
hydroxyꢀ5ꢀ((6ꢀhydroxyꢀ2,2ꢀdimethylꢀ4ꢀoxoꢀ4Hꢀ1,3ꢀdioxineꢀ5ꢀyl)(4ꢀmethoxyphenyl)methyl)ꢀ
1,3ꢀdimethylpyrimidineꢀ2,4(1H,3H)ꢀdione. However, also weak signals of the electrophiles
2b and 4b are observed as discussed in the chapter product studies.
1
H NMR (d
6
ꢀDMSO – Enol): δ 1.56 (s, 6H, CH
3
3 3
), 3.16 (s, 6H, CH ), 3.68 (s, 3H, CH ),
3
3
6.12 (s, 1H, CH), 6.71 (d, JHH = 7.3 Hz, 2H, ArH), 6.93 (d, JHH = 8.3 Hz, 2H, ArH)
Reaction of MB with 3a.
Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (5.0 mg 0.026 mmol) and 2ꢀ(4ꢀ
methoxybenzylidene)indeneꢀ1,3ꢀdione (3a) (6.8 mg 0.26 mmol) were dissolved in 1 ml
1
d
6
ꢀDMSO. The HꢀNMR spectrum of the reactants solution shows nearly complete
conversion after few minutes and 2ꢀ((1,3ꢀdimethylꢀ2,4,6ꢀtrioxohexahydropyrimidineꢀ5ꢀyl)(4ꢀ
methoxyphenyl)methyl)ꢀ1,3ꢀdioxoꢀ2,3ꢀdihydroꢀ1Hꢀindeneꢀ2ꢀide (MB3a) is monitored.
However, acidification of MB3a solution induces a decomposition and formation of 3a
together with 1,3ꢀdimethylbarbituric acid is observed.
1
H NMR (d
6
3 3
ꢀDMSO – Enol): δ 3.12 (s, 6H, CH ), 3.66 (s, 3H, CH ), 5.61 (s, 1H, CH), 6.69
3
3
(
d, JHH = 8.5 Hz, 2H, ArH), 6.98 (d, JHH = 8.3 Hz, 2H, ArH), 7.20–7.31 (m, 4H, ArH);
1
3
C NMR (d ꢀDMSO – Enol): δ 27.7, 28.0, 30.1, 54.9, 91.6, 110.9, 111.9, 113.0, 113.2, 127.8,
6
135.9, 136.9, 138.2, 151.4, 151.9, 156.7, 163.1
Reaction of SB with 4a.
Potassium salt of 2ꢀthiobarbituric acid (SB) (0.663 mg, 0.004 mmol) was dissolved in
1
6
ml d ꢀDMSO. 5ꢀ(4ꢀdimethylamino)benzylideneꢀ1,3ꢀdimethylbarbituric acid (4a) (1.023 mg,
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1
1
1
1
1
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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
1
0.004 mmol) dissolved in 1 ml d
shows about 60
6
ꢀDMSO was added. The H NMRꢀspectrum of the solution
%
conversion of the reactants after few minutes. 5ꢀ(4ꢀ
dimethylamino)phenyl)(2ꢀthiobarbiturate)methyl)ꢀ1,3ꢀdimethylbarbiturate (SB4a) is observed
as expected product, as well as two side products, which were formed by post reactions as
described in the chapter products studies. Due to the dynamic equilibria, individual products
could not be purely isolated as subsequently demonstrated.
0
1
2
3
4
5
6
7
8
9
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1
2
3
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7
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2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
H NMR (d
6
ꢀDMSO – Enol): δ 2.79 (s, 6H, CH
3
), 2.99 (s, 6H, CH
3
), [5.86 (s, 0.12H), 5.98 (s,
3
3
0.44H), 6.09 (s, 0.40H) Σ 1H, CH], 6.55 (d, JHH = 8.8 Hz, 2H, ArH), 6.82 (d, JHH = 9.0 Hz,
2H, ArH), [11.40 (s), 11.52 (s), 11.53 (s) Σ 2H, NH]
The solution was acidified with trifluoroacetic acid to obtain the neutral compound 5ꢀ
(
(4ꢀ(dimethylamino)phenyl)(6ꢀhydroxyꢀ4ꢀoxoꢀ2ꢀthioꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
yl)methyl)ꢀ6ꢀhydroxyꢀ1,3ꢀdimethylpyrimidineꢀ2,4(1H,3H)ꢀdione. Additionally,
5ꢀ(4ꢀ
dimethylamino)benzylideneꢀ1,3ꢀdimethylbarbituric acid (4a) as well as 5ꢀ(4ꢀ
dimethylamino)benzylideneꢀ2ꢀthioxobarbituric acid was obtained.
1
H NMR (d ꢀDMSO – Enol): δ 3.10 (s, 6H, CH ), 3.12 (s, 6H, CH ), 5.99 (s, 1H, CH),
6
3
3
3
3
7
.19 (d, JHH = 7.8 Hz, 2H, ArH), 7.50 (d, JHH = 8.8 Hz, 2H, ArH), 11.71 (m, 2H, NH).
Reaction of MB with 5a:
Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (76.2 mg, 0.392 mmol) was
dissolved in 5 ml DMSO under slight heating. Benzylidenemalononitrile (5a) (60.5 mg,
0
2
5
.392 mmol), also dissolved in 5 ml DMSO, was added and stirred at room temperature for
1
h. The H NMRꢀspectrum of the combined solutions shows nearly complete conversion to
ꢀ(2,2ꢀdicyanoꢀ1ꢀphenylethyl)ꢀ1,3ꢀdimethylbarbiturate (MB5a) as intermediate product.
1
3
H NMR (d
6
ꢀDMSO): δ 3.07 (s, 6H, CH
3
), 4.69 (d, JHH = 12.3 Hz, 1H, CH), 6.20 (d,
3
3
J
HH = 12.3 Hz, 1H, CH), 7.18–7.28 (m, 3H, ArH), 7.52 (d, JHH = 7.0 Hz, 2H, ArH);
1
3
C NMR (d ꢀDMSO): δ 25.7, 26.8, 43.7, 83.4, 115.0, 115.3, 126.6, 127.8, 127.9, 141.8,
6
152.6, 161.8
After acidification with trifluoroacetic acid, the DMSO solution was poured into 50 ml
water and extracted twice with 30 ml DCM. The combined organic phases were dried over
MgSO and the solvent was evaporated The obtained solid was 7ꢀaminoꢀ1,3ꢀdimethylꢀ2,4ꢀ
4
11,61
dioxoꢀ5ꢀphenylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrano[2,3ꢀd]pyrimidineꢀ6ꢀcarbonitrile (MB5aH)
with one equivalent DMSO (116 mg, 0.299 mmol, 76 %)
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melting point: 230−233 °C; H NMR (d
6
ꢀDMSO): δ 3.08 (s, 3H, CH
3
), 3.36 (s, 3H,
1
3
CH
3
), 4.33 (s, 1H, CH), 7.20−7.33 (m, 7H, ArH, NH
2
); C NMR (d
6
ꢀDMSO): δ 27.7, 29.2,
3
6.6, 58.7, 88.9, 119.1, 126.8, 127.4, 128.3, 144.2, 150.1, 151.2, 157.7, 160.5
10
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59
60
Reaction of MB with 5c.
Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (97.0 mg, 0.499 mmol) was
dissolved in 5 ml DMSO under slight heating. 4ꢀDimethylaminoꢀbenzylidene malononitrile
(5c) (99.0 mg, 0.502 mmol), also dissolved in 5 ml DMSO, was added and stirred at room
1
temperature for 30 h. The H NMRꢀspectrum of the combined solutions shows about 50 %
conversion of the reactants. Therefore, the solution was heated up to 100 °C for 8 h and
stirred 24 h at room temperature to produce 5ꢀ(2,2ꢀdicyanoꢀ1ꢀ(4ꢀdimethylaminophenyl)ethyl)ꢀ
1
1
,3ꢀdimethylbarbiturate (MB5c) in sufficient amount for a clear H NMRꢀanalysis. However,
acidification of MB5c leads to a decomposition and the formation of 5c together with 1,3ꢀ
dimethylbarbituric acid.
1
3
H NMR (d ꢀDMSO): δ 2.83 (s, 6H, CH ), 3.07 (s, 6H, CH ), 4.57 (d, J = 12.3 Hz,
6
3
3
HH
3
3
3
1H, CH), 6.11 (d, JHH = 12.0 Hz, 1H, CH), 6.60 (d, JHH = 8.8 Hz, 2H, ArH), 7.33 (d, JHH
=
13
8
.8 Hz, 2H, ArH); C NMR (d
6
ꢀDMSO): δ 26.2, 26.9, 40.3, 43.2, 84.0, 112.1, 115.3, 115.6,
1
28.5, 129.7, 149.4, 152.7, 161.8
Reaction of B with 6c.
Potassium salt of barbituric acid (B) (0.5 mg 0.003 mmol) and 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ(4ꢀ
methylbenzylidene)ꢀcyclohexaꢀ2,5ꢀdienone (6c) (0.8 mg 0.003 mmol) were dissolved in 1 ml
1
d
6
ꢀDMSO. The H NMRꢀspectrum of the solution shows nearly complete conversion of the
reactants after few minutes and 5ꢀ((3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)(4ꢀtolyl)methyl)ꢀ
barbiturate (B6c) is monitored.
1
H NMR (d ꢀDMSO): δ 1.30 (s, 18H, CH ), 2.22 (s, 3H, CH ), 5.21 (s, 1H, CH), 6.88
6
3
3
3
3
(
d, JHH = 8.3 Hz, 2H, ArH), 7.05 (d, JHH = 8.0 Hz, 2H, ArH), 7.15 (s, 2H, ArH), 8.62 (s, 2H,
NH)
Reaction of MB with 6c.
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Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (5.0 mg 0.026 mmol) and 2,6ꢀdiꢀ
tertꢀbutylꢀ4ꢀ(4ꢀmethylbenzylidene)ꢀcyclohexaꢀ2,5ꢀdienone (6c) (7.9 mg 0.026 mmol) were
1
dissolved in 1 ml d
6
ꢀDMSO. The H NMRꢀspectrum of the solution shows nearly complete
conversion of the reactants after few minutes and 5ꢀ((3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)(4ꢀ
tolyl)methyl)ꢀ1,3ꢀdimethylbarbiturate (MB6c) is monitored.
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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2
3
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5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H NMR (d ꢀDMSO): δ 1.30 (s, 18H, CH ), 2.20 (s, 3H, CH ), 3.01 (s, 6H, CH ), 5.34
6
3
3
3
3
3
(
s, 1H, CH), 6.42 (s, 1H, OH), 6.88 (d, JHH = 7.8 Hz, 2H, ArH), 7.04 (d, JHH = 7.8 Hz, 2H,
13
ArH), 7.14 (s, 2H, ArH); C NMR (d
6
ꢀDMSO): δ 20.7, 27.0, 30.7, 34.4, 46.0, 88.9, 125.6,
1
27.4, 137.1, 137.5, 144.7, 128.6, 132.3, 150.8, 153.1, 161.8
Potassium salt of 1,3ꢀdimethylbarbituric acid (MB) (97.0 mg 0.499 mmol) and 2,6ꢀdiꢀ
tertꢀbutylꢀ4ꢀ(4ꢀmethylbenzylidene)ꢀcyclohexaꢀ2,5ꢀdienone (6c) (150.0 mg 0.486 mmol) were
dissolved in 3 ml DMSO. The reaction was stirred for 2 h at room temperature. Then, 10 ml
1 M HCl was added and a yellow solid precipitates. The solid was filtered off, washed with
water and dried under reduced pressure. As product 0.210 g (0.452 mmol, 93 %) of 5ꢀ((3,5ꢀdiꢀ
tertꢀbutylꢀ4ꢀhydroxyphenyl)(4ꢀtolyl)methyl)ꢀ1,3ꢀdimethylbarbituric acid (MB6cH) was
obtained as pale yellow powder.
1
melting point: 157−159 °C; H NMR (d
6
ꢀDMSO): δ 1.29 (s, 18H, CH
3
), 2.27 (s, 3H,
3
3
CH
3
), 2.83 (s, 3H, CH
3
), 2.97 (s, 3H, CH
3
), 4.29 (d, JHH = 2.5 Hz, 1H, CH
3
), 4.63 (d, JHH
=
3
3
2
.5 Hz, 1H, CH
3
), 6.82 (s, 2H, ArH), 7.11 (d, JHH = 8.0 Hz, 2H, ArH), 7.29 (d, JHH = 8.0 Hz,
1
3
2H, ArH); C NMR (d
6
ꢀDMSO): δ 20.6, 27.8, 28.0, 30.2, 34.4, 40.0, 54.4, 124.7, 128.3,
1
7
28.6, 129.8, 135.6, 137.8, 138.9, 151.0, 152.9, 167.9, 169.0; Anal. Calcd for C28 : C:
36 2 4
H N O
2.39; H: 7.81; N: 6.03. Found: C: 72.34; H: 7.69; N: 6.02.
Kinetics:
The studied barbiturate anions were used as potassium salts, all kinetics were measured
in dry DMSO (Acros, H O < 0.005%) at 20 °C and monitored by UV/vis spectroscopy. The
2
used UV/vis absorption maxima are given in Table 1. The addition of 1.3 equivalents of 18ꢀ
crownꢀ6 did not change the obtained k2,obsꢀvalues, indicating that the corresponding cations
have no influence on the kinetics.
Fast reactions with τ1/2 < 100 s were investigated with stopped flow technique, slower
reactions were measured with standard UV/vis equipment.
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Instruments and Materials:
1
13
NMRꢀspectra were measured on a 250 MHz ( H) and 62.9 MHz ( C) device. Chemical
4
7,62
shifts are given in ppm and refer to TMS (δ
H
= 0.00 ppm). Electrophiles 1a and 1b,
b, 3a, 4a, as well as 5a, 5b, and 5c for product studies were prepared according to the
literature. The used barbiturate anions were prepared by treatment of the barbituric acids with
K CO or tetraꢀnꢀbutylammonium hydroxide in water and recrystallization.
2a and
63
41
64
65
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2
3
Computational Details:
All quantum chemical calculations were performed using the TURBOMOLE 6.5
6
6
quantum chemistry program package. The potential energy surface (PES) for each reaction
67ꢀ70
was explored using the density functional theory (DFT). We used BP86
functional with
7
1
72ꢀ74
Grimme's dispersion correction (D3) and TZVP
basis. The equilibrium structures and
7
5
the transition state structures were confirmed by normalꢀmode analysis. For the BP86ꢀ
D3/TZVP geometry optimized structures singleꢀpoint energies were calculated more
67,76ꢀ78
67,76,78,79
accurately. Therefore, several common functionals like PBE0,
TPSS,
basis set were
6
7,76,78ꢀ80
81
82,83
TPSSH
and PW6B95 with D3 correction and def2ꢀTZVPP
employed (see SI page S29 – S77). The results obtained by the sophisticated PW6B95
functional were chosen for a detailed discussion. Solvent effects were included by applying
84
the COSMO solvation model with ꢋꢃ= 48 (for DMSO as solvent). The Gibbs energies were
calculated by freeh module as implemented in TURBOMOLE 6.5 (see SI page S29 – S77).
‡
The reported relative Gibbs energies (
Δ
G) and the activation barriers (
Δ
G ) are given in
1
‒
kJ mol .
Acknowledgement
The authors thank Prof. Herbert Mayr for the opportunity measuring the reaction kinetic
at his devices at the LMU in Munich and the intense discussions and support writing this
paper. The DFG (Deutsche Forschungsgemeinschaft SP 392/26ꢀ1 and 26ꢀ3) is gratefully
acknowledged for financial support. Furthermore, we thank the Technische Universität
Chemnitz for providing computing time on the computation cluster CHiC. Joachim Friedrich
also thanks the Fonds der Chemischen Industrie for financial support due to the Material Cost
Allowances program.
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Supporting Information Available
All kinetic data, NMR spectra and data from DFT calculations are summarized in the
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
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(
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