From Carbanions to Organometallic Compounds: Quantification of Metal Ion Effects on Nucleophilic Reactivities

Article abstract of DOI:10.1002/anie.201501385

The influence of the metal on the nucleophilic reactivities of indenyl metal compounds was quantitatively determined by kinetic investigations of their reactions with benzhydrylium ions (Ar₂CH⁺) and structurally related quinone methides. With the correlation equation logk₂=s_N(N+E), it can be derived that the ionic indenyl alkali compounds are 10¹⁸ to 10²⁴ times more reactive (depending on the reference electrophile) than the corresponding indenyltrimethylsilane. Different worlds: Kinetic investigations with reference electrophiles show that a reaction with an electrophile, which would proceed within milliseconds with indenyl lithium, would require much more than the age of the universe with the corresponding organosilicon compound. Met=metal.

Full text of DOI:10.1002/anie.201501385

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501385
German Edition: DOI: 10.1002/ange.201501385
Nucleophilicity
From Carbanions to Organometallic Compounds: Quantification of
Metal Ion Effects on Nucleophilic Reactivities**
Francisco Corral-Bautista, Lydia Klier, Paul Knochel, and Herbert Mayr*
Table 1: Reference electrophiles used in this study.
Abstract: The influence of the metal on the nucleophilic
reactivities of indenyl metal compounds was quantitatively
determined by kinetic investigations of their reactions with
benzhydrylium ions (Ar2CH+) and structurally related qui-
none methides. With the correlation equation logk2 = sN(N +
E), it can be derived that the ionic indenyl alkali compounds
are 1018 to 1024 times more reactive (depending on the reference
electrophile) than the corresponding indenyltrimethylsilane.
Reference electrophile
E[a]
lmax [nm]
1a
1b
1c
1d
1e
R1 =Me, R2 =Me
3.63
2.16
1.48
0.61
0.00
R1 =OPh, R2 =Me
R1 =OMe, R2 =Me
R1 =OMe, R2 =OPh
R1 =OMe, R2 =OMe
475
488
517
513
O
rganometallic compounds are standard reagents in
organic synthesis, which allow chemo- and stereoselective
transformations.[1] Depending on the nature of the metal, the
carbon–metal bond is more or less covalent and influences
various properties, such as reactivity, selectivity, and tolerance
towards functional groups. Organolithium compounds, for
example, are highly reactive and poorly selective,[1] whereas
organozinc[2] or organotin compounds[3] are much less reac-
tive, but show higher selectivity.[4] While this trend is well-
known, quantitative comparisons of the reactivities of free
carbanions and different organometallics have to our knowl-
edge so far not been described.
1 f
ꢁ0.81
520
1g
1h
1i
1j
1k
1l
1m
1n
1o
R1 =R2 =N(Ph)(CH2CF3)
R1 =R2 =N(Me)(CH2CF3)
R1 =R2 =NPh2
ꢁ3.14
ꢁ3.85
ꢁ4.72
ꢁ5.53
ꢁ5.89
ꢁ7.02
ꢁ7.69
ꢁ8.22
ꢁ8.76
601
593
672
620
622
613
620
618
627
R1 =R2 =morpholin-4-yl
R1 =R2 =N(Me)(Ph)
R1 =R2 =NMe2
R1 =R2 =pyrrolidin-1-yl
n=2
n=1
In the linear free-energy relationship (1),[5] E is an
1p
1q
n=2
n=1
ꢁ9.45
635
630
log k2ð20 ꢀCÞ ¼ sNðN þ EÞ
ð1Þ
ꢁ10.04
electrophile-specific parameter and N and sN are nucleophile-
specific parameters, which have been derived from the rates
of the reactions of p-, n-, and s-nucleophiles with benzhy-
drylium ions 1 and quinone methides 2 (reference electro-
philes; Table 1).[6] Equation (1) has already been used to
characterize the nucleophilic reactivities of a variety of
organosilicon[6a,c,7] and organotin[6a,c] compounds, as well as
of carbanions.[6b,8]
2a
2b
2c
R3 =4-Me
ꢁ15.83
ꢁ16.11
ꢁ17.29
371
393
486
R3 =4-OMe
R3 =4-NMe2
2d
ꢁ17.90
521
Herein we report on the kinetics of the reactions of
various organometallic derivatives of indene (3-Met;
Scheme 1) with reference electrophiles of widely differing
reactivity (Table 1). In this way we will quantitatively
[a] Electrophilicity parameters E from Ref. [6a–c,e].
[*] Dr. F. Corral-Bautista, Dr. L. Klier, Prof. Dr. P. Knochel,
Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Scheme 1. Organometallic derivatives of indene.
[**] We thank the Deutsche Forschungsgemeinschaft (SFB 749, Project
B1) for support of this work, Nathalie Hampel for providing the
reference electrophiles, and Dr. A. R. Ofial for help during the
preparation of the manuscript.
determine the influence of the variable covalent character
of the carbon–metal bond on its nucleophilic reactivity.
As the alkali and zinc derivatives of indene are highly
reactive and have low stability, they were not isolated in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501385.
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substance, but generated in DMSO solution by treating
indene (3-H) with circa 1.05 equivalents of alkali tert-but-
oxide (KOtBu, NaOtBu, LiOtBu) or TMP-ZnX·LiX (X = Cl,
Br, TMP = 2,2,6,6-tetramethylpiperidyl).[9]
The potassium salt 3-K was combined with the quinone
methide 2b in DMSO solution. Aqueous acidic work up and
subsequent purification by column chromatography yielded
65% of 4 as a mixture of two diastereoisomers (Scheme 2).
Scheme 4. Reaction of 3-SiMe3 with 1a-Br in acetonitrile at ambient
temperature.
reaction progress showed the formation of silylated product 7
within 4 to 6 h, which was isolated in 46% yield. The
subsequent protodesilylation is much slower, and 49% of the
2-substituted indene 8 was isolated when the reaction mixture
was worked up after 5 days. Evidence for electrophilic attack
at 1- or 3-position of the indenyl moiety of 3-SiMe3 was not
found. Obviously, the formation of a benzyl cation stabilized
by a remote silyl group is preferred over the formation of a b-
silyl stabilized alkyl cation.
Scheme 2. Representative combinations of indenyl alkali and indenyl
zinc derivatives 3-Met with quinone methides and benzhydrylium salts.
[a] Determined by 1H NMR spectroscopy after chromatographic purifi-
cation.
Treatment of a DMSO solution of 3-H with a solution of
TMP-ZnCl·LiCl (ca. 1.1 equiv) and subsequent combination
with the benzhydrylium tetrafluoroborate 1l-BF4 gave crude
5 after aqueous work-up, which was recrystallized from
dichloromethane/ethanol (Scheme 2).
(1H-Inden-1-yl)trimethylstannane (3-SnMe3) was synthe-
sized in 52% yield in analogy to the reported procedure for
the corresponding tributylstannyl compound[10] by deproto-
nation of indene with n-butyllithium and subsequent addition
of trimethyltin chloride. (1H-Inden-1-yl)trimethylsilane (3-
SiMe3) was prepared analogously by adding trimethylsilyl
chloride to a solution of lithium indenide (3-Li) in THF.[11]
Combination of indenyltin 3-SnMe3 with 1e-BF4 in
dichloromethane at ambient temperature yielded 97% of 6
after filtration over Al2O3 and chromatographic purification
(Scheme 3).
The kinetic studies of the reactions of the metal deriva-
tives of indene with benzhydrylium ions 1 and quinone
methides 2 were performed in dichloromethane or DMSO
solution at 208C and monitored by UV/Vis spectroscopy at or
close to the absorption maxima of the electrophiles. By using
the indenyl derivatives 3-Met in large excess (> 10 equiv),
pseudo first-order kinetics were observed. The first-order rate
constants kobs were obtained by least-squares fitting of the
exponential function At = A0 exp(ꢁkobs t) + C to the time-
dependent absorbances At of the electrophile (Figure 1).
Second-order rate constants k2 (Table 2) were obtained from
linear correlations of kobs with the concentrations of the
organometallics as shown for the reaction of 3-K with 2c in
Figure 1, and for other reactions in the Supporting Informa-
tion.
As the reaction of 3-SiMe3 with the pregenerated
benzhydrylium salts, which were used for the kinetic inves-
tigations (see below), led to complex product mixtures, 3-
SiMe3 was combined with the covalent benzhydryl bromide
1a-Br in acetonitrile (Scheme 4). GC/MS monitoring of the
Figure 1. Plot of the absorbance A (at 486 nm) vs. time for the reaction
of 3-K (9.78ꢂ10ꢁ4 m) with 2c (2.03ꢂ10ꢁ5 m) in DMSO at 208C. Inset:
Plot of pseudo-first-order rate constants kobs versus nucleophile
*
*
Scheme 3. Reaction of 3-SnMe3 with the benzhydrylium tetrafluorobo-
rate 1e-BF4 in dichloromethane at ambient temperature.
concentrations. in absence of 18-crown-6, in presence of 1.2 equiv
of 18-crown-6 with respect to 3-K.
2
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Table 2: Second-order rate constants k2 for the reactions of the
metalated indenes 3-Met with reference electrophiles at 208C in DMSO
or CH2Cl2.[a]
Nucleophile
N (sN)
Electrophile
k2
[Lmolꢁ1 sꢁ1
]
2a
2b
2c
2d
5.70ꢂ105
2.82ꢂ105
4.69ꢂ104
2.04ꢂ104
24.16 (0.68)
(DMSO)
2a
2b
2c
2d
4.19ꢂ105
2.37ꢂ105
3.35ꢂ104
1.44ꢂ104
23.74 (0.71)
(DMSO)
2a
2b
2c
2d
3.47ꢂ105
1.77ꢂ105
2.85ꢂ104
1.14ꢂ104
23.66 (0.70)
(DMSO)
1l-BF4
1.4ꢂ105
6.9ꢂ104
1.9ꢂ104
1.1ꢂ104
5.5ꢂ103
18.1
(0.46)
(DMSO)
1m-BF4
1o-BF4
1p-BF4
1q-BF4
1l-BF4
2.0ꢂ104
1.2ꢂ104
5.2ꢂ103
2.8ꢂ103
15.6
(0.51)
(DMSO)
1m-BF4
1n-BF4
1o-BF4
1g-BF4
1h-BF4
1i-BF4
1j-BF4
1k-BF4
7.36ꢂ102
1.92ꢂ102
3.74ꢂ101
7.70
6.68
(0.81)
(CH2Cl2)
Figure 2. Correlation of logk2 for the reactions of the metalated
indenes with reference electrophiles versus their electrophilicity param-
eters E: a) alkali metals: 3-K and 3-Li, b) zinc: 3-ZnCl·LiCl and 3-
ZnBr·LiBr, c) tin and silicon: 3-SnMe3 and 3-SiMe3.
4.79
1b-BCl4
1c-BCl4
1d-BCl4
1e-GaCl4
1 f-GaCl4
1.15ꢂ102
3.77ꢂ101
3.40
ꢁ0.10
listed in Table 2 are affected by parallel reactions of 1m with
either DMSO or Clꢁ. Analogous experiments showed that
tetramethylpiperidine (TMPH), which was released by the
reactions of indene with TMP-ZnX·LiX, did not affect the
kinetics.
(1.05)
(CH2Cl2)
7.69ꢂ10ꢁ1
1.04ꢂ10ꢁ1
[a] The rate constants for the reactions of 3-ZnX·LiX are given with lower
precision because only one to two half-lives were evaluated to determine
Plots of logk2 for the reactions of the indenyl derivatives
3-Met with the reference electrophiles against their electro-
philicity parameters E are linear, as shown in Figure 2 (the
correlation for the sodium salt is shown in the Supporting
Information). From the slopes of these correlations, the
nucleophile-specific parameters sN were derived, and the
negative intercepts on the abscissa (logk2 = 0) correspond to
the nucleophilicity parameters N (Table 2).
kobs
.
As the first-order rate constants kobs, which are measured
in the presence and in the absence of 18-crown-6, are on the
same plots of kobs versus concentration [3-K] (Figure 1 and
Supporting Information), we conclude that the reactivities of
the potassium salt 3-K determined in DMSO correspond to
those of the free indenyl anion.
To be able to exclude that reactions of the chloride ions
with the benzhydrylium ions affect the kinetic measurements,
the benzhydrylium salt 1m-BF4 (ca. 1.4 ꢀ 10ꢁ5 m) was com-
bined with excess LiCl (3.8 ꢀ 10ꢁ3 m) or Bu4NCl (2.1 ꢀ 10ꢁ3 m)
in DMSO. After mixing, the absorbance of the benzhydrylium
ion decreased to 40–50% within 30 min, which is probably
caused by a slow reaction of 1m-BF4 with DMSO. As the
reactions of 1m-BF4 with the organozinc reagent 3-ZnCl·LiCl
proceed within less than 1 to 5 s under the conditions of the
kinetic experiments, it can be excluded that the rate constants
As discussed above, the common correlation line for the
reactions of 3-K in the presence and absence of 18-crown-6
implies that the rate constants measured for 3-K in DMSO
correspond to the reactivities of the free indenyl anions.
Table 2 (and for 3-Li also Figure 2a) shows that the sodium
and lithium indenyls are roughly 1.2 to 1.4 (Na) and 1.6 (Li)
times less reactive than the free indenyl anion. These small
reactivity differences can be expected to disappear com-
pletely when electrophiles with E > ꢁ10 will be used (dif-
fusion control).
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Figure 2b illustrates that the relative reactivities of the
indenylzinc halides 3-ZnX·LiX are almost independent of the
electrophilicity of their reactions partners. The indenylzinc
chloride is 6 to 7 times more reactive than the indenylzinc
bromide. Kinetics of the reactions of 3-ZnI·LiI with 1l–o
could not be unequivocally evaluated and are therefore not
reported herein. They indicated, however, that 3-ZnI·LiI is
approximately five times less nucleophilic than 3-ZnBr·LiBr.
Since the reactions of indenylzinc halides with 1m–q follow
complex kinetics in the absence of LiX, the influence of LiX
on the nucleophilic reactivities of the indenylzinc halides
cannot be described quantitatively.
Figures S1–S5).[12a–d] Though Allenꢁs electronegativities[12e]
indicate the trend of the observed nucleophilicities of 3-Met
correctly, if it is taken into account that all indenyl alkali
compounds are almost ionic, Figure 3 provides to our knowl-
edge the first quantitative comparison of nucleophilic reac-
tivities of organometallics that differ that much in electro-
negativity.
Keywords: kinetics · linear free-energy relationships ·
nucleophilicity · organotin · organozinc
The reactions of indenylmagnesium halides with quinone
methides 2 in DMSO and THF did not follow second-order
kinetics, even when Li salts were added. As a consequence, we
failed to characterize indenyl Grignard compounds analo-
gously.
Figure 3 illustrates that the nucleophilicity parameters of
the metalated indenes cover a reactivity range of 24 units of N.
Owing to the different sensitivities sN, the resulting relative
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Figure 3. Nucleophilicity parameters of indenyl metal compounds 3-
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electrophiles. For reactions with a one-bond electrophile of
E = ꢁ20 one can calculate relative reaction times from 1 ms to
1013 years. The effect of metal coordination on the reactivities
of the indenyl moiety, as illustrated in Figure 3, can be
considered typical for carbanions of related structures.
However, the effect can be expected to be greater for less
stabilized carbanions and to decrease for better stabilized
carbanions.
The nucleophilic reactivities of main-group organometal-
lics are often associated with the differences of the electro-
negativities of carbon and the corresponding metals. The
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Mulliken, Pauling, or Sanderson (Supporting Information,
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Received: February 12, 2015
Published online: && &&, &&&&
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Nucleophilicity
Different worlds: Kinetic investigations
with reference electrophiles show that
a reaction with an electrophile, which
would proceed within milliseconds with
indenyl lithium, would require much
more than the age of the universe with the
corresponding organosilicon compound.
Met=metal.
F. Corral-Bautista, L. Klier, P. Knochel,
H. Mayr*
&&&& — &&&&
From Carbanions to Organometallic
Compounds: Quantification of Metal Ion
Effects on Nucleophilic Reactivities
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!