Nucleophilic reactivities and Lewis basicities of 2-imidazolines and related N-heterocyclic compounds

Article abstract of DOI:10.1002/ejoc.201300213

The nucleophilicity parameters N and s_N, as defined by the linear free-energy equation log k(20 °C) = s_N(N + E), of the 2-imidazolines 1a-d and the related N-heterocyclic compounds 2-5 have been determined by studying the rates of their reactions with differently substituted benzhydrylium ions in dichloromethane at 20 °C by stopped-flow or laser flash photolysis techniques. It is demonstrated that the N and s_N parameters thus obtained can be used to reliably predict the rate constants for their reactions with Michael acceptors of known electrophilicity E. A comparison of the nucleophilicity parameters of the imidazoline derivatives 1 with other commonly used nucleophilic organocatalysts shows that they are 10 to 10 ³ times less nucleophilic than PPh₃, 1,8-diazabicyclo[5.4. 0]undec-7-ene, or 4-(dimethylamino)pyridine. The structure-reactivity relationships of these heterocycles are discussed. Rate and equilibrium constants for the reactions of 2-imidazolines and related N-heterocyclic compounds with diarylcarbenium ions have been measured in CH₂Cl ₂ at 20 °C. These data were employed to determine their nucleophilicities and Lewis basicities, which were compared with other nucleophilic organocatalysts. Copyright

Full text of DOI:10.1002/ejoc.201300213

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201300213
Nucleophilic Reactivities and Lewis Basicities of 2-Imidazolines and Related
N-Heterocyclic Compounds
Biplab Maji,[a] Mahiuddin Baidya,[a] Johannes Ammer,[a] Shinjiro Kobayashi,[a]
Peter Mayer,[a] Armin R. Ofial,[a] and Herbert Mayr*[a]
Keywords: Kinetics / Structure–reactivity relationships / Lewis basicities / Thermodynamics / Nucleophilic addition /
Organocatalysis
The nucleophilicity parameters N and sN, as defined by the
linear free-energy equation logk(20 °C)= sN(N+ E), of the 2-
imidazolines 1a–d and the related N-heterocyclic compounds
2–5 have been determined by studying the rates of their reac-
tions with differently substituted benzhydrylium ions in
rate constants for their reactions with Michael acceptors of
known electrophilicity E. A comparison of the nucleophilicity
parameters of the imidazoline derivatives 1 with other com-
monly used nucleophilic organocatalysts shows that they are
10 to 103 times less nucleophilic than PPh3, 1,8-diazabicy-
dichloromethane at 20 °C by stopped-flow or laser flash pho- clo[5.4.0]undec-7-ene, or 4-(dimethylamino)pyridine. The
tolysis techniques. It is demonstrated that the N and sN pa-
rameters thus obtained can be used to reliably predict the
structure–reactivity relationships of these heterocycles are
discussed.
imidazolines 1a–d, 2-methylthiazoline (2), and 2-methylox-
azoline (3), and to compare their reactivities with those of
the homologous tetrahydropyrimidines 4a,b, dihydropyrrole
5, and previously characterized nucleophilic organocata-
lysts (Scheme 1).[10]
Introduction
Imidazolines, oxazolines, and thiazolines are important
building blocks in natural products and pharmaceuti-
cals,[1,2] and are often used as ligands in coordination chem-
istry and homogeneous catalysis.[3] Chiral imidazolines have
been employed as organocatalysts[4] in asymmetric Diels–
Alder, Friedel–Crafts, and Michael reactions.[5] Recently,
Lectka and co-workers reported sulfonated analogues of
4,5-dihydro-1H-imidazole to be efficient nucleophilic cata-
lysts in diastereoselective Staudinger β-lactam synthesis by
activating in situ generated ketenes.[6] In 2006, Tan and co-
workers used chiral imidazolines as catalysts in asymmetric
Morita–Baylis–Hilman reactions.[7,8]
It has been reported in numerous publications that the
rate constants (logk) for the reactions of nucleophiles with
carbocations and Michael acceptors can be described by
the linear free-energy relationship (1),[9] in which electro-
philes are characterized by the solvent-independent electro-
philicity parameters E and nucleophiles are characterized
by two solvent-dependent parameters, the nucleophilicity
parameter N and the sensitivity parameter sN.
Scheme 1. Nitrogen-containing heterocycles 1–5 and DABCO and
DMAP.
logk(20 °C) = sN(N + E)
(1)
In this work we have used the benzhydrylium methodol-
ogy to characterize the nucleophilicity parameters of the 2-
Results and Discussion
[a] Department Chemie, Ludwig-Maximilians-Universität
München,
Butenandtstraße 5–13 (Haus F), 81377 München, Germany
Fax: +49-89-2180-77717
Reaction Products
E-mail: herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.lmu.de/oc/mayr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300213.
The addition of a dichloromethane solution of 1a or 1b
–
to an equimolar amount of (dma)2CH+BF4 in dichloro-
methane gave a mixture of monosubstituted 6a,b and disub-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
H. Mayr et al.
FULL PAPER
–
Scheme 2. Products obtained from the reaction of 1a,b with (dma)2CH+BF4 .
stituted products 7a,b in a ratio of around 1:3 as well as 1a-
H+ and 1b-H+ (Scheme 2; the abbreviations used to de-
scribe the benzhydrylium ions are defined in Table 1). The
formation of the disubstituted products 7a,b can be ex-
plained by the subsequent reactions of the deprotonated (by
a second molecule of 1a or 1b) monosubstituted products
–
6a,b with (dma)2CH+BF4 . Although we were unable to iso-
Scheme 3. Formation of 8 by the reaction of 4a with (dma)2-
–
CH+BF4 .
late the monosubstituted products, the disubstituted imid-
azolinium tetrafluoroborates 7a,b-BF4 were isolated by sub-
sequent aqueous work-up and crystallization. Crystals of
7b-BF4 suitable for single-crystal X-ray structure analysis
were grown by diffusion of n-pentane vapor into a dichloro-
methane/ethyl acetate solution (10:1) of 7b-BF4 (Fig-
ure 1).[11] For details of the experimental procedures and
characterization of the products, see the Supporting Infor-
mation.
Compounds 1c, 2, and 3 did not react with (dma)2-
–
CH+BF4 when an equimolar amount of the nucleophile
–
was mixed with (dma)2CH+BF4 in CH2Cl2 at room tem-
perature. However, mixing of 1c or 2 with an equimolar
amount of substituted benzhydryl chloride or bromide gave
the addition products 9–11 in yields greater than 90%, as
determined in situ by NMR spectroscopy (Scheme 4).
Scheme 4. Products obtained from the reactions of 1c and 2 with
benzhydryl derivatives.
Figure 1. Crystal structure of 7b-BF4. The ellipsoids are drawn at
the 50% probability level.[11]
Kinetics
The higher homologue of 1a, 2-methyl-1,4,5,6-tetra-
hydropyrimidine (4a), however, readily reacted with (dma)-
Most of the reactions of the nucleophiles 1–5 with benz-
–
CH+BF4 to give only the 1:1 adduct 8 in 92% yield hydrylium ions (Table 1) were investigated photometrically
(Scheme 3).
in CH2Cl2 at 20 °C by using stopped-flow techniques as
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
Nucleophilic Reactivities and Lewis Basicities of Imidazolines
–d[Ar2CH+]/dt = k2[Ar2CH+][Nu]
(2)
described previously.[9] The kinetics of the reactions of 4a
with benzhydrylium ions were also studied in CH3CN and
DMSO.
Table 1. Abbreviations and the electrophilicity parameters E for the
benzhydrylium ions used in this work.
Figure 2. a) Exponential decay of the absorbance A at 622 nm dur-
ing the reaction of 1b (1.28ϫ10–4 m) with (mpa)2CH+BF4
–
(1.00ϫ10–5 m) in CH2Cl2 at 20 °C (kobs = 10.7 s–1). b) Determi-
nation of the second-order rate constant k = 8.12ϫ104 m–1 s–1 from
the dependence of kobs on the concentration of 1b.
reference electrophiles Ar2CH+ were plotted against the em-
pirical electrophilicity parameters E of Ar2CH+ (Table 1),
[a] The electrophilicity parameters E for the benzhydrylium ions linear correlations were obtained, as shown for some repre-
are taken from refs.[9b,9g]
sentative examples in Figure 3 (see the Supporting Infor-
mation for all reaction series investigated). As described
above, the kinetics of the reactions of the nucleophiles 2 and
3 with benzhydrylium ions were measured by two different
techniques, the stopped-flow method and laser flash pho-
tolysis. Linear correlations (as shown for 2 in Figure 4) be-
tween the logarithms of the rate constants k measured by
the two methods and the electrophilicity parameters E re-
flect the consistency of our measurements.
For the fast reactions (k Ͼ 106 m–1 s–1), the benz-
hydrylium ions were generated by laser flash photolysis
(7 ns pulse, 266 nm) of substituted benzhydryltri-
phenylphosphonium tetrafluoroborates in the presence of 2
and 3, as described previously.[12] In all cases, an excess of
the heterocyclic nucleophiles (more than 10 equiv.) over the
electrophiles was used to achieve pseudo-first-order condi-
tions. The pseudo-first-order rate constants kobs were ob-
According to Equation (1), the slopes of the correlation
tained by a least-squares fit of the exponential decay of the
lines give the nucleophile-specific sensitivity parameters sN
absorbances of Ar2CH+ to the expression A= A0e–kobst + C.
and the intercepts on the abscissa give the nucleophilicity
The plots of kobs against nucleophile concentration were lin-
ear with negligible intercepts, as shown in Figure 2b, which
parameters N for 1–5; these values are listed in Table 2.[9]
indicates a second-order rate law [Equation (2)]. The slopes
of these correlation lines yielded the second-order rate con-
Relationship between Structures and Nucleophilicities
stants k, which are presented in Table 2.
The similarities of the slopes of the correlation lines in
Figure 3 (and Figure 4), which are numerically expressed by
the sensitivity parameters sN in Table 2, indicate that the
Nucleophilicity Parameters
When the logarithms of the second-order rate constants relative nucleophilicities of the N-heterocycles 1–5 depend
(Table 2) for the reactions of the nucleophiles 1–5 with the only slightly on the nature of the electrophiles.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
H. Mayr et al.
FULL PAPER
Table 2. Second-order rate constants for the reactions of benzhy-
drylium ions (Ar2CH+) with the nucleophiles 1–5 in dichlorometh-
ane at 20 °C.
Figure 3. Plots of logk for the reactions of the N-heterocyclic com-
pounds 1a–d and 4a,b with benzhydrylium ions versus their electro-
philicity parameters E in CH2Cl2 at 20 °C.
Figure 4. Plots of logk for the reactions of 2 with benzhydrylium
ions versus their electrophilicity parameters E in CH2Cl2 at 20 °C.
Scheme 5. Relative nucleophilic reactivities of the nucleophiles 1a–
d and 4a,b towards (pyr)2CH+ in CH2Cl2. [a] k for the reaction of
1c with (pyr)2CH+ was calculated by using Equation (1), the N and
sN values from Table 2, and the electrophilicity E from Table 1.
Scheme 5 shows that the tetrahydropyrimidine deriva-
tives 4a and 4b are 16 and 30 times more nucleophilic than
the imidazolines 1a and 1b, respectively. This ring size effect
[a] Nucleophilicity parameters N and sN derived from Equation (1).
[b] For abbreviations, see Table 1. [c] SF = stopped-flow. LFP =
laser-flash photolysis.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
Nucleophilic Reactivities and Lewis Basicities of Imidazolines
parallels the previously observed reactivities of cyclic guan- Table 3. Comparison of the calculated and experimental second-
order rate constants k [m–1 s–1]for the reactions of the nucleophiles
1a,d and 4 with the Michael acceptors 12a–d in dichloromethane
at 20 °C.
idines[10g] and isothioureas,[10f] that is, amidines in six-mem-
bered rings are generally one order of magnitude more nu-
cleophilic than the corresponding amidines in five-mem-
bered rings.[10e–10g]
Replacement of the 2-methyl group in 1a or 4a by the
phenyl group in 1b or 4b reduces the reactivity by a factor
of 3 and 1.7, respectively. Although the replacement of the
NH proton of 1a by the electron-withdrawing acetyl group
(1aǞ1c) decreases the reactivity by a factor of 183, the
replacement of the NH proton of 1b by the electron-donat-
ing benzyl group (1bǞ1d) increases the reactivity by a fac-
tor of 8.7.
Scheme 6 illustrates the effect of heteroatoms at the 3-
position of 2-methylpyrroline (5). The replacement of
“CH2” by “O” (5Ǟ3) reduces the reactivity by a factor of
102. Because electrophilic attack takes place at the sp2 lone
pair of nitrogen, which resides in the plane of the ring, the
reduction of nucleophilicity can be explained by the induc-
tive effect of “O”, which overcompensates the mesomeric
effect. The replacement of “O” by “S” (3Ǟ2) does not have
a significant influence on the nucleophilic reactivities of the
N-heterocycles. The lower electronegativity and weaker +M
effect of “S” relative to “O” clearly compensate each other.
Compensation of the opposing inductive and resonance ef-
fects also explains why the introduction of the “NH” group
in place of “CH2” (5Ǟ1a) causes only a marginal increase
in the nucleophilicity.
[a] Electrophilicity parameters E are taken from ref.[13] [b] Calcu-
lated by using Equation (1), the N and sN values are from Table 2,
and the E values from Table 3. [c] Highly reversible.
Comparison of the experimental rate constants kexp with
the rate constants kcalc calculated by using Equation (1) and
the N and sN parameters in Table 2 and the E values from
ref.[13] shows agreement within factors of 3 to 11. In view
of the simplicity of the three-parameter Equation (1), we
consider these deviations acceptable because the electrophi-
licities of the Michael acceptors 12 were determined from
their reactions with carbanions in DMSO and the nucleo-
philicity parameters of 1 and 4 are derived from their reac-
tions with benzhydrylium ions in CH2Cl2 (Table 2). We
therefore conclude that the rates of the reactions of the nu-
cleophiles 1 and 4 with electrophiles with known electrophi-
licity parameters E can be predicted by using Equation (1)
and the N and sN parameters reported in Table 2.
Scheme 6. Relative nucleophilic reactivities of the nucleophiles 1a,
2, 3, and 5 towards (mor)2CH+ in CH2Cl2. [a] k was calculated by
using Equation (1), the N and sN values are from Table 2, and the
electrophilicity E from Table 1.
Equilibrium Constants and Intrinsic Barriers
As the reactions of the nucleophiles 1–5 with the colored
benzhydrylium ions give colorless products, equilibrium
constants for these reactions were also measured photomet-
rically. Because of the proportionality between the concen-
trations and absorbances of the colored benzhydrylium
Reactions with Michael Acceptors
To examine the applicability of the nucleophilicity pa-
rameters N and sN in Table 2 to the reactions with other
types of electrophiles, we studied the rates of the reactions
of the cyclic amidines 1a,d and 4a with the Michael ac-
ceptors 12a–d, the electrophilicity parameters of which have
previously been determined.[13]
The rates of the reactions of 1a,d and 4a with 12a–d were
measured by the same photometric method as described
above for their reactions with benzhydrylium ions, that is,
by following the decay of the absorbances of 12a–d at or
close to their absorption maxima at 20 °C in CH2Cl2. The
resulting second-order rate constants are listed in Table 3.
Although 1d is 2.7 times more nucleophilic than 1a, it does
not react with any of the Michael acceptors studied because
of the high reversibility of these reactions.
(3)
(4)
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
H. Mayr et al.
FULL PAPER
Table 4. Equilibrium constants K, reaction free energies ΔG°, acti-
vation free energies ΔG϶, and intrinsic barriers ΔG0 for the reac-
϶
tions of nucleophiles 1–3 with benzhydrylium ions Ar2CH+ in
CH2Cl2 at 20 °C.
Scheme 7. Comparison of the rate and equilibrium constants for
the reactions of (ind)2CH+ with 1d, DABCO, DMAP, and PPh3 in
CH2Cl2. [a] In CH3CN from ref.[10h] [b] From ref.[10a,d]
϶
Marcus Equation (5)[14] yields the intrinsic barriers ΔG0
for these reactions, which are listed in Table 4.
϶
϶
ΔG϶ = ΔG0 + 0.5ΔG° + [(ΔG°)2/16ΔG0
]
(5)
Table 4 shows that the intrinsic barrier ΔG0϶ for the reac-
tion of the benzhydrylium ion (mor)2CH+ with 2 is
2 kJmol–1 smaller than that for the reaction with 3, and
4 kJmol–1 smaller than that for the reaction with 1c. From
the data for the series SϽ OϽ NAc, one can conclude that
the product stabilizing mesomeric effect of O and, even
more so, of NAc is only partially developed in the transition
states of the reactions with benzhydrylium ions.[15]
[a] Calculated by using the equilibrium constants K in this table
(ΔG° = –RTlnK). [b] Calculated by using the rate constants in
Table 2, determined by using the Eyring equation. [c] Calculated
by using Equation (5). [d] Calculated by using Equation (1), N and
sN values from Table 2 and E values from Table 1.
ions, the equilibrium constants K for the reaction in Equa-
tion (3), which are listed in Table 4, were calculated by using
Equation (4), in which A0 and A are the absorbances of
Ar2CH+ before and after the addition of nucleophiles,
respectively.
Table 4 shows that the 2-methylimidazoline derivative 1c
is a 50 times stronger Lewis base than 2-methylthiazoline
[2, reference (mor)2CH+] and an eight times stronger Lewis
base than 2-methyloxazoline [3, reference (mor)2CH+]. Al-
though a direct comparison of the equilibrium constants is
not possible, the data in Table 4 demonstrate that N-benzyl-
ated 2-methylimidazoline (1d) is a much stronger Lewis
base than 1c, 2, and 3 because it gives adducts even with
the weakly Lewis acidic benzhydrylium ions (lil)2CH+,
(jul)2CH+, and (ind)2CH+.
According to Scheme 7, the reaction of (ind)2CH+ with
the imidazoline derivative 1d has a much higher intrinsic
϶
barrier (ΔΔG0 = 6 kJmol–1) than the corresponding reac-
tions with DMAP and PPh3. Although 1d is a 102 times
stronger Lewis base than PPh3, both 1d and PPh3 attack
electrophiles with similar rates. On the other hand, despite
the similar Lewis basicities of 1d and DMAP, imidazole 1d
reacts 10 times more slowly than DMAP because of the
higher reorganization energy needed for the formation of a
resonance stabilized amidinium ion from 1d. In comparison
with 1d, the higher nucleophilicity (Ͼ103 times) of the
weaker Lewis base DABCO (Ͼ102 times) can analogously
϶
be explained by the lower intrinsic barriers (ΔΔG0
=
20 kJmol–1) of its reactions with electrophiles.
Comparison of the rate and equilibrium constants for
the reactions of benzhydrylium ions with the imidazoline
derivative 1d and other commonly used nucleophilic organ-
ocatalysts (Scheme 7) illustrates that 1d reacts with electro-
philes at a rate similar to PPh3, but 10 and 2.5ϫ103 times
more slowly than 4-(dimethylamino)pyridine (DMAP) and
1,4-diazabicyclo[2.2.2]octane (DABCO), respectively. How-
ever, 1d is a 200–300 times stronger Lewis base than PPh3
and DABCO, comparable to the Lewis basicity of
DMAP.[10] This breakdown of the rate–equilibrium rela-
tionship indicates that these reactions have different Marcus
intrinsic barriers ΔG0϶, the barriers of the corresponding
reactions without any thermodynamic driving force (ΔG° =
0).[14]
Nucleofugalities
Equation (6), which is formally analogous to Equa-
tion (1), has recently been suggested as a basis for a nucleo-
fugality scale, allowing calculation of the rate constants of
heterolytic cleavage kǟ (at 25 °C) from the electrofugality
parameters Ef of the electrofuges, the nucleofugality param-
eter Nf, and the nucleofuge-specific sensitivity parameters
sf.[16]
logkǟ(25 °C) = sf(Ef + Nf)
(6)
In analogy to the procedure used to determine the nu-
cleophile-specific parameters N and sN, the Nf and sf pa-
Substitution of the activation free energies ΔG϶ (derived rameters were obtained from linear plots of logkǟ(25 °C)
from the rate constants in Table 2 by using the Eyring equa- versus the electrofugality parameters (Ef) of the benzhy-
tion) and Gibbs free energies ΔG° (= –RTlnK) into the drylium ions reported in ref.[16] However, as the number
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
Nucleophilic Reactivities and Lewis Basicities of Imidazolines
of kǟ values in Table 5 that are available for each of the ions follow the linear free-energy relationship (1), which al-
nucleofuges is not sufficient to derive reliable values for sf, lowed us to determine the nucleophilicity parameters N and
we followed the previously recommended procedure[10f,16] sN for 1–5 and to compare them with those of commonly
and assumed sf = 1.0 to calculate the nucleofugality param- used nucleophilic organocatalysts (Figure 6). The N values
eters of the N-heterocycles in Table 5, which are compared in Figure 6 show that the imidazoline derivatives 1 are mod-
with the previously characterized nucleofuges in Figure 5.
erately reactive N-nucleophiles. Although they are 10 to 103
times less nucleophilic than DHPB, DBU, DBN, or DMAP,
the imidazolines 1 are 10 to 102 times more nucleophilic
than imidazoles and benzimidazoles. On the other hand,
the tetrahydropyrimidine derivatives 4 have nucleophilicities
similar to THTP, DBU, and DBN.
Table 5. Reverse rate constants kǟ for the reactions of nucleophiles
1–3 with benzhydrylium ions (Ar2CH+) in CH2Cl2 at 20 °C.
[a] kǟ = k/K. [b] Calculated by using Equation (6) and neglecting
the small difference in temperature. [c] Calculated by using Equa-
tion (1) to calculate k.
Figure 6. Comparison of the nucleophilicities N of the nucleophiles
1–5 with those of other nucleophilic organocatalysts (solvent is
CH2Cl2 unless otherwise stated, N from Table 2 and ref.[9h]).
Because the electrophiles attack the lone pair in the plane
of the N-heterocycles, the nucleophilic reactivity order
3≈2Ͻ 1a≈5 can be rationalized by the interplay of induc-
tive and mesomeric effects of the heteroatoms at the 3-posi-
tion of the ring.
Figure 5. Comparison of the nucleofugalities Nf of the heterocycles
1–3 with those of other organocatalysts (solvent is CH2Cl2 unless
otherwise stated, Nf from Table 5 and refs.[10f,16]).
Substitution of the rate and equilibrium constants into
the Marcus Equation (5) yielded the intrinsic barriers
ΔG0϶, which show that the reactions of electrophiles with
the imidazoline 1d require more reorganization energy than
the corresponding reactions with PPh3, DMAP, or
Conclusions
We have found that the rate constants for the reactions DABCO. As a result, 1d is a weaker nucleophile than
of the N-heterocyclic compounds 1–5 with benzhydrylium DMAP, which has a similar Lewis basicity.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
H. Mayr et al.
FULL PAPER
mar, M. K. Tse, M. Klawonn, C. Döbler, B. Bitterlich, A. Grot-
evendt, M. Beller, Org. Lett. 2005, 7, 3393–3396; h) G. Desi-
moni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106, 3561–
3651; i) C. A. Busacca, J. C. Lorenz, N. Grinberg, N. Haddad,
H. Lee, Z. Li, M. Liang, D. Reeves, A. Saha, R. Varsolona,
C. H. Senanayake, Org. Lett. 2007, 9, 341–344; j) H. Liua, D.-
M. Du, Adv. Synth. Catal. 2009, 351, 489–519.
a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296; b) Y.
Huang, A. K. Unni, A. N. Thadani, V. H. Rawal, Nature 2003,
424, 146; c) P. M. Pihko, Angew. Chem. 2004, 116, 2110; Angew.
Chem. Int. Ed. 2004, 43, 2062–2064; d) D. Uraguchi, M. Ter-
ada, J. Am. Chem. Soc. 2004, 126, 5356–5357; e) D. Nakash-
ima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 9626–9627;
f) G. Lelais, D. W. C. MacMillan, Aldrichim. Acta 2006, 39, 79–
87; g) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; h) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758;
i) A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416–5470; j) B. List, Chem. Rev. 2007, 107, 5413–5415; k)
C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130,
9246–9247; l) D. Enders, C. Wang, J. X. Liebich, Chem. Eur. J.
2009, 15, 11058–11076; m) K. L. Jensen, G. Dickmeiss, H. Ji-
ang, Ł. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45,
248–264.
Experimental Section
General: CH2Cl2 was freshly distilled from CaH2 prior to use. Com-
mercially available acetonitrile (VWR, Prolabo, HPLC-gradient
grade) and DMSO (Acros, 99.9%, Extra Dry, AcroSeal) were used
as received. Compounds 1a (ABCR), 1b (Aldrich), 2 (Aldrich), and
3 (ABCR) were purchased and used without further purification.
Compound 5 was purchased (Aldrich) and distilled prior to use.
Compounds 1c,[17a] 1d,[17b] 4a,[17c] and 4b[17c] were synthesized ac-
cording to the procedures in the quoted references. Benzhydrylium
tetrafluoroborates,[9b] phosphonium salts,[12c] and Michael ac-
ceptors[13] were prepared as described previously.
[4]
Kinetics: The reactions of the nucleophiles 1–5 with the benzhy-
drylium ions Ar2CH+ and Michael acceptors 12 were followed pho-
tometrically at or close to the absorption maxima of Ar2CH+ and
12 by stopped-flow UV/Vis spectroscopy or laser flash photolysis.
The pseudo-first-order rate constants kobs (s–1) were obtained by
least-squares fitting of the absorbances to the monoexponential
function At = A0exp(–kobst)+ C. The second-order rate constants k
(m–1 s–1) were obtained from the slopes of the linear plots of kobs
against the nucleophile concentrations. For details, see the Support-
ing Information.
[5]
a) S. B. Tsogoeva, G. Dürner, M. Bolte, M. W. Göbel, Eur. J.
Org. Chem. 2003, 1661–1664; b) D. Akalay, G. Dürner, J. W.
Bats, M. Bolte, M. W. Göbel, J. Org. Chem. 2007, 72, 5618–
5624; c) K. Murai, S. Fukushima, S. Hayashi, Y. Takahara, H.
Fujioka, Org. Lett. 2010, 12, 964–966.
A. Weatherwax, C. J. Abraham, T. Lectka, Org. Lett. 2005, 7,
3461–3463.
Equilibrium Constants: Equilibrium constants were determined by
UV/Vis spectroscopy. Small amounts of stock solutions of the nu-
–
cleophiles 1, 3, and 4 were added to solutions of Ar2CH+BF4 and
[6]
[7]
[8]
12 in CH2Cl2 and the absorbances of electrophiles were monitored
at their corresponding λmax before (A0) and immediately after (A)
the addition of nucleophiles. This procedure was carried out with
different concentrations of the nucleophiles 1, 3, and 4. The tem-
perature was kept constant at 20.0Ϯ0.1 °C by using a circulating
bath thermostat. For details, see the Supporting Information.
J. Xu, Y. Guan, S. Yang, Y. Ng, G. Peh, C.-H. Tan, Chem.
Asian J. 2006, 1, 724–729.
For selected reviews on Baylis–Hilman reactions, see: a) D. Ba-
savaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103,
811–891; b) G. Masson, C. Housseman, J. Zhu, Angew. Chem.
2007, 119, 4698; Angew. Chem. Int. Ed. 2007, 46, 4614–4628.
a) H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990; Angew.
Chem. Int. Ed. Engl. 1994, 33, 938–957; b) H. Mayr, T. Bug,
M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R.
Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J. Am. Chem.
Soc. 2001, 123, 9500–9512; c) R. Lucius, R. Loos,
H. Mayr, Angew. Chem. 2002, 114, 97; Angew. Chem. Int. Ed.
2002, 41, 91–95; d) H. Mayr, B. Kempf, A. R. Ofial, Acc.
Chem. Res. 2003, 36, 66–77; e) H. Mayr, A. R. Ofial, Pure Appl.
Chem. 2005, 77, 1807–1821; f) H. Mayr, Angew. Chem. 2011,
123, 3692; Angew. Chem. Int. Ed. 2011, 50, 3612–3618; g) J.
Ammer, C. Nolte, H. Mayr, J. Am. Chem. Soc. 2012, 134,
13902–13911; h) for a comprehensive listing of nucleoph-
ilicity parameters N and electrophilicity parameters E, see
http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html.
For pyridines, see: a) F. Brotzel, B. Kempf, T. Singer, H. Zipse,
H. Mayr, Chem. Eur. J. 2007, 13, 336–345; b) N. De Rycke, G.
Berionni, F. Couty, H. Mayr, R. Goumont, O. R. P. David,
Org. Lett. 2011, 13, 530–533; for azoles, see: c) M. Baidya, F.
Brotzel, H. Mayr, Org. Biomol. Chem. 2010, 8, 1929–1935; for
phosphanes, see: d) B. Kempf, H. Mayr, Chem. Eur. J. 2005,
11, 917–927; for DBU and DBN, see: e) M. Baidya, H. Mayr,
Chem. Commun. 2008, 1792–1794; for isothioureas, see: f) B.
Maji, C. Joannesse, T. A. Nigst, A. D. Smith, H. Mayr, J. Org.
Chem. 2011, 76, 5104–5112; for guanidines, see: g) B. Maji,
D. A. Stephenson, H. Mayr, ChemCatChem 2012, 4, 993–999;
for DABCO and DMAP, see: h) M. Baidya, S. Kobayashi, F.
Brotzel, U. Schmidhammer, E. Riedle, H. Mayr, Angew. Chem.
2007, 119, 6288; Angew. Chem. Int. Ed. 2007, 46, 6176–6179;
for a review, see: i) H. Mayr, S. Lakhdar, B. Maji, A. R. Ofial,
Beilstein J. Org. Chem. 2012, 8, 1458–1478.
Reactions of the Nucleophiles 1–4 with Benzhydrylium Ions: A de-
tailed description of the preparation and characterization of the
reaction products 7–11 is given in the Supporting Information.
[9]
Supporting Information (see footnote on the first page of this arti-
cle): Preparation and characterization of the products, details of
the individual runs of the kinetic experiments, determination of the
equilibrium constants, and NMR spectra.
Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft (DFG)
(SFB 749) for financial support and Dr. Sami Lakhdar for helpful
discussions.
[10]
[1] M. R. Grimmett, in: Comprehensive Heterocyclic Chemistry
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon
Press, Oxford, UK, 1996, vol. 3, pp. 77–120.
[2] a) S. Tsujii, K. L. Rinehart, S. P. Gunasekera, Y. Kashman,
S. S. Cross, M. S. Lui, S. A. Pomponi, M. C. Diaz, J. Org.
Chem. 1988, 53, 5446–5453; b) R. R. Ruffolo Jr., J. E. Waddell,
J. Pharmacol. Exp. Ther. 1982, 222, 29–36; c) P. Bousquet, J.
Feldman, J. Schwartz, J. Pharmacol. Exp. Ther. 1984, 230, 232–
236; d) C. Dardonville, I. Rozas, Med. Res. Rev. 2004, 24, 639–
661.
[3] a) A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1–45; b) M. Gomez, G. Muller, M. Roca-
mora, Coord. Chem. Rev. 1999, 193–195, 769–835; c) C. E. An-
derson, L. E. Overman, J. Am. Chem. Soc. 2003, 125, 12412–
12413; d) H. A. McManus, P. J. Guiry, Chem. Rev. 2004, 104,
4151–4202; e) J. Zhou, Y. Tang, Chem. Soc. Rev. 2005, 34, 664–
676; f) T. Arai, T. Mizukami, N. Yokoyama, D. Nakazato, A.
Yanagisawa, Synlett 2005, 2670–2672; g) S. Bhor, G. Anilku-
[11]
CCDC-891470 (for 7b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
Nucleophilic Reactivities and Lewis Basicities of Imidazolines
[12] a) J. Ammer, M. Baidya, S. Kobayashi, H. Mayr, J. Phys. Org. [15]
Chem. 2010, 23, 1029–1035; b) X.-H. Duan, B. Maji, H. Mayr,
a) C. F. Bernasconi, Adv. Phys. Org. Chem. 1991, 27, 119–238;
b) C. F. Bernasconi, Acc. Chem. Res. 1992, 25, 9–16.
N. Streidl, B. Denegri, O. Kronja, H. Mayr, Acc. Chem. Res.
2010, 43, 1537–1549.
Org. Biomol. Chem. 2011, 9, 8046–8050; c) J. Ammer, C. F.
Sailer, E. Riedle, H. Mayr, J. Am. Chem. Soc. 2012, 134, 11481–
11494.
[16]
[17] a) D. Li, Y. Zhang, G. Zhou, W. Guo, Synlett 2008, 225–228;
b) J.-F. Gong, X.-H. Fan, C. Xu, J.-L. Li, Y.-J. Wu, M.-P. Song,
J. Organomet. Chem. 2007, 692, 2006–2013; c) R. N. Butler,
K. J. Fitzgerald, J. Chem. Soc. Perkin Trans. 1 1989, 155–157.
Received: February 8, 2013
[13] a) O. Kaumanns, H. Mayr, J. Org. Chem. 2008, 73, 2738–2745;
b) F. Seeliger, S. T. A. Berger, G. Y. Remennikov, K. Polborn,
H. Mayr, J. Org. Chem. 2007, 72, 9170–9180; c) S. T. A. Berger,
F. H. Seeliger, F. Hofbauer, H. Mayr, Org. Biomol. Chem. 2007,
5, 3020–3026.
Published Online: ᭿
[14] a) R. A. Marcus, J. Phys. Chem. 1968, 72, 891–899; b) W. J.
Albery, Annu. Rev. Phys. Chem. 1980, 31, 227–263.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30213
/KAP1
Date: 08-04-13 11:39:33
Pages: 10
H. Mayr et al.
FULL PAPER
Nucleophilicity Parameters
B. Maji, M. Baidya, J. Ammer,
S. Kobayashi, P. Mayer, A. R. Ofial,
H. Mayr* ........................................ 1–10
Nucleophilic Reactivities and Lewis
Basicities of 2-Imidazolines and Related N-
Heterocyclic Compounds
Rate and equilibrium constants for the re-
actions of 2-imidazolines and related N-
heterocyclic compounds with diarylcarben-
ium ions have been measured in CH2Cl2 at
20 °C. These data were employed to deter-
mine their nucleophilicities and Lewis ba-
sicities, which were compared with other
nucleophilic organocatalysts.
Keywords: Kinetics / Structure–reactivity
relationships / Lewis basicities / Thermo-
dynamics
/
Nucleophilic addition
/
Organocatalysis
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0