Influence of the N-Substituents on the Nucleophilicity and Lewis Basicity of N-Heterocyclic Carbenes

Article abstract of DOI:10.1021/acs.orglett.6b01525

The ability to modulate the nucleophilicity and Lewis basicity of N-heterocyclic carbenes is pivotal to their application as organocatalysts. Herein we examine the impact of the N-substituent on the nucleophilicity and Lewis basicity. Four N-substituents popular in NHC organocatalysis, namely, the N-2,6-(CH₃O)₂C₆H₃, N-Mes, N-4-CH₃OC₆H₄, and N-tert-butyl groups, have been examined and found to strongly affect the nucleophilicity. Thus, the N-2,6-(CH₃O)₂C₆H₃ group provides the most nucleophilic imidazolylidene NHC reported and the N-tert-butyl group one of the least. This difference in nucleophilicity is reflected in the catalyst efficiency, as observed with a recently reported trienyl ester rearrangement.

Full text of DOI:10.1021/acs.orglett.6b01525

Letter
pubs.acs.org/OrgLett
Influence of the N‑Substituents on the Nucleophilicity and Lewis
Basicity of N‑Heterocyclic Carbenes
Alison Levens,† Feng An,‡ Martin Breugst,§ Herbert Mayr,‡ and David W. Lupton*,†
†School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
‡Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13 (Haus F), 81377 Munchen, Germany
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§Department fur Chemie, Universitat zu Koln, Greinstraße 4, 50939 Koln, Germany
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* Supporting Information
ABSTRACT: The ability to modulate the nucleophilicity and
Lewis basicity of N-heterocyclic carbenes is pivotal to their
application as organocatalysts. Herein we examine the impact
of the N-substituent on the nucleophilicity and Lewis basicity.
Four N-substituents popular in NHC organocatalysis, namely,
the N-2,6-(CH3O)2C6H3, N-Mes, N-4-CH3OC6H4, and N-tert-
butyl groups, have been examined and found to strongly affect
the nucleophilicity. Thus, the N-2,6-(CH3O)2C6H3 group
provides the most nucleophilic imidazolylidene NHC reported
and the N-tert-butyl group one of the least. This difference in
nucleophilicity is reflected in the catalyst efficiency, as
observed with a recently reported trienyl ester rearrangement.
-Heterocyclic carbene (NHC) catalysis provides access to
1
Na diverse range of intermediates for reaction discovery.
Among others, the acyl anion equivalent,2 homoenolates,3 acyl
azoliums4 and acyl azolium enols/enolates5 are now routinely
exploited in increasingly sophisticated reaction designs. While
other Lewis base catalysts can access some of these classes of
intermediates, few access all.6 Although the versatility of NHC
organocatalysis is striking, practical application requires highly
judicious catalyst selection. This can involve variation of the
heterocycle, with imidazole, triazole, and thiazole NHC catalysts
being common, although increasingly prevalent is N-substituent
modification to deliver optimal catalytic activity for a given
reaction design.7 In the context of acyl anion-mediated reactions,
the role of the N-substituent has been investigated.7b,c,8 In
contrast, an examination of NHC nucleophilicity as a function of
the N-substituent, to our knowledge, is yet to be reported.
Hence, catalyst design remains largely empirical.
Figure 1. Overview of the study.
nucleophilicity, as well as the Lewis basicity, of NHCs bearing the
N-2,6-(CH3O)2C6H3 (1a), N-Mes (1b), N-4-CH3OC6H4 (1c),
and N-tert-butyl groups (1d) determined. These N-substituents
have been exploited in recent discoveries in NHC catalys-
is,9h,15−18 particularly using ester substrates. The studies herein
demonstrate that the N-substituent plays a significant role in
defining the catalyst nucleophilicity, with 3 orders of magnitude
rate difference between 1a and 1d. Thus, the impact of the N-
substituent is at least as significant as the nature of the azolium
moiety in determining NHC nucleophilicity.
A series of p-quinone methide electrophiles (i.e., 2, 3, and 4)
were previously used to determine the nucleophilicity parame-
ters (N) of SIMes, IMes, and TPT (Figure 1). This was achieved
by exploiting the observation that the rate of addition of
nucleophiles to Michael acceptors or carbocations can be
predicted by eq 1:19
Since 2009 we have reported a series of transformations
involving enol esters and enolic anhydrides.9 In these studies, and
those from others using ester substrates, it is clear that the
required NHC catalysts are distinct from those suited to acyl
anion-mediated reactions.1g,10,11 While Tolman electronic
parameters (TEPs), pKa values, and 13C NMR studies give
information that is useful for catalyst selection,12 measures of
nucleophilicity are more scarce. Recently, as part of our studies
on reactivity scales for nucleophiles and electrophiles, we
reported the nucleophilicities of three common NHCs (SIMes,
IMes, and TPT; Figure 1).13,14 While this study addressed the
role of the heterocycle in nucleophilicity, the impact of the N-
substituent was not addressed. Herein, the dependence of the
nucleophilicity on the N-substituent is examined, with the
Received: May 29, 2016
© XXXX American Chemical Society
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formation of the expected adducts, attention was directed toward
the rates of these reactions.
log k20°C = sN(N + E)
(1)
In this equation, nucleophiles are characterized by a solvent-
dependent nucleophilicity parameter N and a sensitivity
parameter sN, while electrophiles are characterized by a
solvent-independent electrophilicity parameter E. To date, this
relationship has been used to examine 1039 nucleophiles and 272
electrophiles.20a
To determine the effect of the N-substituent on the
nucleophilicity, studies began with the preparation of the
required NHCs by deprotonation of the corresponding
imidazolium salts 1a−d·HI with KOt-Bu. Although triazolyli-
denes are more commonly exploited in NHC catalysis, the
impact on the nucleophilicity of changing between a
triazolylidene and an imidazolylidene has been previously
studied (vide supra), thus allowing trends to be extrapolated.
Since the nucleophilicities of the four new NHCs 1a−d are likely
to be within the range of those already reported, the reference
electrophiles 2a−c, 3a−d, and 4 used previously were employed
in this study (Table 1). These references are easily handled, have
absorption maxima monitorable in the presence of various
NHCs, and cover a suitable range of electrophilicities.
The reactions of NHCs 1a−d with the reference p-quinone
methides 2−4 were studied in THF at 20 °C by photometric
monitoring of the disappearance of the colored quinone
methides in the presence of a large excess of the NHC to
achieve pseudo-first-order conditions. Least-squares fitting of the
exponential function A = A0 exp(−kobst) + C to the observed
time-dependent absorbances A of the quinone methide provided
the first-order rate constants kobs. The slopes of the linear
correlations between kobs and the concentrations of 1 correspond
to the second-order rate constants k2 listed in Table 2. The rate
Table 2. Second-Order Rate Constants and Nucleophilicity
Parameters for the Reactions of NHCs 1a−d with Reference
Electrophiles 2−4 in THF at 20 °C
Table 1. Reference p-Quinone Methides 2−4
a
Electrophilicity parameters for 2−4 from refs 20b and 20c.
constants k2 were then used in association with the electro-
philicity parameters of 2−4 to construct correlation lines for the
four NHCs (Figure 2). As can be seen, in all cases good fits were
obtained, which allowed the nucleophilicity parameters to be
accurately determined.
The nucleophilicities of these newly characterized carbenes
can be compared with those of other NHCs and nucleophilic
To demonstrate that the outcome of the reaction of NHCs
1a−d with the reference electrophiles are the expected Michael
adducts (i.e., 5a−d), preparatory studies were undertaken
(Scheme 1). Paralleling earlier reports, the reactions of NHCs
1a−d with p-quinone methide 3b gave the adducts 5a−d in high
yields as the only isolable products. Structural confirmation was
obtained through regular spectroscopic methods as well as with
single-crystal X-ray diffraction for 5d. Having confirmed the
Scheme 1. Synthesis of 5a−d and X-ray Structure of 5d
Figure 2. Correlations of log k2 vs electrophilicity parameters for the
reactions of NHCs 1a−d with p-quinone methides 2−4.
B
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catalysts (Figure 3). From this comparison, it is clear that the
nucleophilicity is heavily influenced by the nature of the N-
group decreases the Lewis basicity while having little bearing on
the nucleophilicity. In contrast, switching from a methyl
substituent to a tert-butyl substituent has very little impact on
the Lewis basicity (719 kJ mol−1 vs 718 kJ mol−1 for R = CH3;
Figure 4).13 The dihedral angle between the imidazole and the
aromatic N-substituent indicates significant twisting out of plane
in both carbenes 1a and 1b (80.5° and 83.7°) and methyl
imidazoles 6a and 6b (69.5° and 88.9°). While some
planarization (1a → 6a) is observed, it is not sufficient to allow
through-space interactions of the ortho group and the azolium.
Studies from our group on NHC-catalyzed (4 + 2) annulations
show significant sensitivity to the N-substituent.9d−f To further
examine this sensitivity, the conversion of triene 7 to cycloadduct
8 was monitored over time using NHCs bearing the four N-
substituents examined herein (Figure 5). Preliminary studies on
Figure 3. Nucleophilicities of 1a−d and other catalysts.
substituent. Thus, the most nucleophilic of the NHCs bears an
N-2,6-(CH3O)2C6H3 substituent (i.e., 1a) and is more
nucleophilic than IMes. The least nucleophilic is the N-tert-
butyl NHC 1d, which is only moderately more nucleophilic than
the Enders carbene (TPT) and DBU. Interestingly, replacing a
single mesityl substituent with a methyl group has little impact on
the nucleophilicity of the catalyst (IMes, cf. 1b). Finally, a para
electron-donating substituent gives an NHC that is less
nucleophilic than either the N-Mes NHC 1b or the N-2,6-
(CH3O)2C6H3 NHC 1a.
In previous studies, the Lewis basicities of NHCs have been
studied computationally because of an inability to determine
equilibrium constants from their interactions with p-quinone
methides. This is a result of their exceptionally high Lewis
basicity. To allow Lewis basicity to be determined in this study,
methyl cation affinities (MCAs), as defined in Figure 4, have
been calculated for NHCs 1a−d employing MP2/6-31+G-
(2d,p)//B86/6-31G(d), a method previously shown to result in
reliable MCAs.13,21
Figure 5. Conversion of ester 7 to diene 8 with catalysts 9a−d.
imidazolium-derived NHCs were hampered by kinetic difficul-
ties due to very high reaction rates. In contrast, monitoring with
the triazolium series of NHCs demonstrated that the reaction is
successful with the most nucleophilic triazolium-derived catalysts
9a and 9b and fails with N-substituents associated with the least
nucleophilic NHCs. These results are consistent with our
observations that NHC addition to esters is significantly more
challenging than that to aldehydes. The success or failure of this
reaction is correlated with the catalyst nucleophilicity and not its
Lewis basicity, with catalyst 9b likely to display similar Lewis
basicity to 9c but giving a significantly different reaction
outcome.
The capacity of NHCs to enable reactions that are unattainable
with other nucleophilic catalysts is associated with their unique
Lewis basicity and nucleophilicity profiles. As applications of
NHCs in organocatalysis develop, the capacity to modulate these
properties takes on increasing importance. In recent years, the N-
substituents examined in this report have allowed new
discoveries in NHC catalysis. Herein we report that the N-2,6-
(CH3O)2C6H3 substituent gives one of the most nucleophilic
and Lewis basic NHC catalysts, while the impact of remote
electron-donating groups on the NHC properties is modest.
Finally, hindered alkyl groups give one of the least nucleophilic
and Lewis basic NHCs.
Most strikingly, we found that the N-2,6-(CH3O)2C6H3
substituent in 1a led to the most Lewis basic catalyst, with an
MCA some 28 kJ mol−1 higher than that of the variant bearing a
single mesityl group (1b). Interestingly, the MCA of 1b was 23 kJ
mol−1 lower than that of IMes (MCA = 767 kJ mol−1),13
indicating that replacement of a mesityl group with a methyl
The studies reported herein demonstrate that the N-
substituent plays a significant role in defining catalyst
nucleophilicity. Together with the known role of heterocycle
selection in nucleophilicity,13 these studies demonstrate that
Figure 4. Gas-phase methyl cation affinities (MCAs) calculated at the
MP2/6-31+G(2d,p)//B98/6-31G(d) level of theory.
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01525.
K.; Frohlich, R.; Muck-Lichtenfeld, C.; Mayr, H.; Studer, A. Angew.
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Procedures and additional data (PDF)
Chem., Int. Ed. 2012, 51, 5234. (j) Ryan, S. J.; Stasch, A.; Paddon-Row,
M. N.; Lupton, D. W. J. Org. Chem. 2012, 77, 1113.
(9) For selected studies with esters from our group, see: (a) Reference
4c. (b) Kowalczyk, M.; Lupton, D. W. Angew. Chem., Int. Ed. 2014, 53,
5314. (c) Candish, L.; Levens, A.; Lupton, D. W. J. Am. Chem. Soc. 2014,
136, 14397. (d) Candish, L.; Levens, A.; Lupton, D. W. Chem. Sci. 2015,
6, 2366. (e) Levens, A.; Zhang, C.; Candish, L.; Forsyth, C. M.; Lupton,
D. W. Org. Lett. 2015, 17, 5332. For selected studies using activated
acids, see: (f) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc.
2011, 133, 4694. (g) Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2013,
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Org. Lett. 2013, 15, 5028. (c) Chen, S.; Hao, L.; Zhang, Y.; Tiwari, B.;
Chi, Y. R. Org. Lett. 2013, 15, 5822.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: david.lupton@monash.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the Australian
Research Council (DP150101522 and FT110100319), the
Deutsche Forschungsgemeinschaft (SFB 749, Project B1), the
Fonds der Chemischen Industrie (Liebig Scholarship to M.B.),
and the Alexander von Humboldt Foundation (Ludwig
Leichardt Memorial Fellowship to D.W.L.). We are grateful to
Ms. Nathalie Hampel (LMU) for synthesizing the reference
electrophiles and Dr. Peter Mayer (LMU) for the X-ray analysis.
This work used the DFG-funded Cologne High Efficiency
Operating Platform for Sciences (CHEOPS).
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