Experimental and Computational Mechanistic Studies of the β-Diketiminatoiron(II)-Catalysed Hydroamination of Primary Aminoalkenes

Article abstract of DOI:10.1002/chem.201804681

A comprehensive mechanistic study by means of complementary experimental and computational approaches of the exo-cyclohydroamination of primary aminoalkenes mediated by the recently reported β-diketiminatoiron(II) complex B is presented. Kinetic analysis

Full text of DOI:10.1002/chem.201804681

A Journal of
Accepted Article
Title: Experimental and computational mechanistic studies of the β-
diketiminatoiron(II)-catalysed hydroamination of alkenes tethered
to primary amines
Authors: Clément Lepori, Elise Bernoud, Régis Guillot, Sven Tobisch,
and Jérôme Hannedouche
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To be cited as: Chem. Eur. J. 10.1002/chem.201804681
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Experimental and computational mechanistic studies of the -
diketiminatoiron(II)-catalysed hydroamination of alkenes tethered
to primary amines
Clément Lepori,[a] Elise Bernoud,[a] Régis Guillot,[a,b] Sven Tobisch*[c] and Jérôme Hannedouche*[a,b]
Dedication ((optional))
Abstract:
A
comprehensive mechanistic study by means of
catalysts derived from late d-block metals or free of metals offer
the greatest opportunities for the development of versatile
catalytic systems with a broad scope and polar functional group
tolerance. Despite major advances in this direction, the
development of late d-block metal hydroamination catalysts for
unprotected primary aliphatic amines, arguably the most
versatile amines to start an “ideal synthesis”,[6] remains
challenging.[7,8] To date, only few research groups have tackled
this difficult issue with catalytic systems based on either Rh,[2j,l]
Ir,[2e,i-k] Pt,[2t] Au,[2a,b] Zn[3a,b] or Cu[3e] for mainly the
cyclohydroamination of primary amines tethered to unactivated
alkenes under mild to harsh conditions. However, these systems
are restricted in scope and/or derived from noble metals of
limited availability, high price and significant toxicity. Therefore,
some improvements are still required to elevate late transition
metal-mediated hydroamination of unprotected, primary aliphatic
amines up to the requirements of a truly efficient, economical
and eco-friendly methodology for the synthesis of nitrogen
containing compounds. In this context and with our interest in
base metal catalysis in mind,[3f,9] some of us have recently
complementary experimental and computational approaches of the
exo-cyclohydroamination of primary aminoalkenes mediated by the
recently reported diketiminatoiron(II) complex B is presented.
Kinetic analysis of the cyclisation of 2,2-diphenylpent-4-en-1-amine
(1a) catalysed by B revealed a first-order dependence of the rate on
both aminoalkene and catalyst concentrations and a primary KIE
(kH/kD) of 2.7 (90 °C). Eyring analysis afforded H‡ = 22.2 kcal.mol-1,
S‡
competitive avenues of direct intramolecular hydroamination and
oxidative amination have been scrutinised computationally.
=
–13.4 cal.mol-1.K-1. Plausible mechanistic pathways for
A
kinetically challenging proton-assisted concerted N–C/C–H bond
forming non-insertive pathway is seen not to be accessible in the
presence of a distinctly faster -insertive pathway. This operative
pathway involves (1) rapid and reversible syn-migratory 1,2-insertion
of the alkene into the Fe–Namido -bond at the monomer {N^N}FeII
amido compound; (2) turnover-limiting Fe–C -bond aminolysis at
the thus generated transient {N^N}FeII alkyl intermediate and (3)
regeneration of the catalytically competent {N^N}FeII amido, which
favours its dimer, likely representing the catalyst resting state,
through rapid cycloamine displacement by substrate. The collectively
derived mechanistic picture is consonant with all empirical data
obtained from stoichiometric, catalytic and kinetics experiments.
reported
that
novel
well-defined
low
coordinate
diketiminatoiron(II) alkyl complex
B
represents the first
example of the FeII-mediated hydroamination for electronically
unbiased primary amines by displaying unique catalytic abilities
of promoting the selective exo-cyclohydroamination of primary
alkenylamines (Scheme 1).[3f]
Introduction
Over the years, the direct addition of an amine across a carbon–
carbon double bond, the so-called alkene hydroamination
reaction has stimulated considerable interest among the
scientific community as evidenced by the plethora of catalytic
systems reported to promote this transformation intra- or
intermolecularly.[1] The systems reported thus far are mainly
based on alkali metals, alkaline- and rare-earth elements,
groups 4 and 5 elements, late transition metals or, although less
[2,3,4,5]
common, are without any metal involved.
Among them,
[a]
C. Lepori, Dr E. Bernoud, Dr R. Guillot, Dr J. Hannedouche
Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR 8182,
Université Paris-Sud, Université Paris-Saclay,
rue du doyen Georges Poitou, Orsay, F-91405 (France).
E-mail: jerome.hannedouche@u-psud.fr
CNRS, Orsay, F-91405 (France)
Scheme 1. Selective cyclohydroamination of 2,2-diphenylpent-4-en-1-amine
(1a) catalysed by the well-defined diketiminato iron(II) alkyl complex B.[3f]
[b]
[c]
Dr S. Tobisch
School of Chemistry,
Indeed, optimisation studies have shown that complex B is a
competent catalyst (10 mol%) capable of converting, for
example, 97% of the benchmark substrate 1a into 80% of
pyrrolidine 2a after 24h at 90 °C together with the formation of
the oxidative amination product 3a and the reduced substrate 4a
University of St Andrews, Purdie Building, North Haugh, St
Andrews, KY16 9ST (United Kingdom).
E-mail: st40@st-andrews.ac.uk
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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in 10 and 6% GC yields respectively (Scheme 1). This catalyst
exhibits a reaction selectivity in favour of the hydroamination
product of only 83%. In our preliminary study,[3f] we
demonstrated that the selectivity could be enhanced up to 96%
by the addition of a catalytic amount of a moderately bulky
primary amine, such as cyclopentylamine. Unfortunately, the
gain in selectivity comes at the expense of the catalyst
performance, as a prolonged reaction time is required to achieve
complete conversion. In an attempt to guide the rational design
of iron catalysts exhibiting improved capabilities for selective
hydroamination catalysis, we aimed at obtaining more detailed
The first-order dependence on both aminoalkene and
catalyst concentrations would be reconcilable with alternative
mechanistic avenues for alkene hydroamination that emerged
over past years including a stepwise -insertive pathway[11]
featuring turnover-limiting aminolysis and a concerted proton-
assisted, non-insertive pathway.[12] The stepwise -insertive
pathway involves migratory 1,2-insertion of the alkene into the
metal–amido -bond to be followed by protonolytic cleavage of
the metal–C linkage by an adducted amine substrate molecule
at the resulting metal alkyl intermediate (Scheme 2). In contrast,
the concerted pathway evolves through a multi-centre transition
insights into mechanistic intricacies of the iron-catalysed process. state (TS) structure for concomitant C–N/C–H bond formation at
We opted for a collaborative approach that involves kinetic,
deuterium-labelling and stoichiometric experiments
a metal amido-/amino-alkene species (Scheme 2).
complemented by a comprehensive computational analysis.
Herein, we provide the complete account of our comprehensive
mechanistic investigations. As it turns out the process favours a
stepwise -insertive pathway that involves the rapid and
reversible syn-migratory insertion of the pendant alkene into the
iron–amido -bond at a low-coordinate iron(II) complex to be
followed by turnover-limiting aminolysis of the resulting iron–
alkyl -bond.
Results and Discussion
Kinetic studies
We start with a full kinetic analysis for the cyclohydroamination
of 1a by B that is aimed at determining the empirical rate law,
kinetic isotopic effects (KIEs) and thermodynamic parameters
and also at providing insights into catalyst activation.
Scheme 2. Schematic representation of alternative stepwise -insertive and
concerted proton-assisted, non-insertive mechanisms. M = metal
Empirical rate law. To determine the kinetic dependence of the
cyclohydroamination upon substrate concentration, the
consumption of 1a over time was monitored by GC analysis for
different initial concentrations in substrate ([1a]0 = 0.56–1.65 M)
and with a constant catalyst B concentration of 0.096 M. As
shown in Figure S4[10], plots of ln([1a]t/[1a]0) versus time are
linear for more than two half-lives over the initial concentration
range studied and reveal a first order dependence in amine
concentration. The kinetic order in catalyst concentration was
subsequently determined at constant initial substrate
Kinetic isotope effect. The measurement of the rate of
conversion of N-deuterated 1a at our optimised reaction
conditions gives some insight into the identity of the turnover-
limiting step. The cyclisation of d2-1a in toluene at 90 °C is found
much slower when compared to 1a, which transforms into a
kinetic isotope effect (KIE) kH/kD that amounts to 2.7 (90 °C)
(Scheme 3). This significant primary KIE suggests that the
turnover-limiting step involves N–H (or N–D) bond breaking.
concentration ([1a]0
= 0.96 M) by varying the catalyst
concentration over a fourfold range ([B] = 0.048–0.192 M). For
each catalyst concentration, the pseudo first-order rate constant
kobs is extracted from the linear plot of ln([1a]t/[1a]0) versus time
over the course of more than three half-lives. The observed
linear relationship between the measured first-order rate
constants kobs and [B] in the considered concentration range is
indicative of first-order dependence of the rate upon catalyst
concentration (Figure S5[10]). The kinetic data are consistent with
the empirical second-order rate law given in eq. 1, which may
suggest that a single adducted aminoalkene 1a may participate
in the turnover-limiting event.
Scheme 3. H/D kinetic isotope effect for the cyclohydroamination reaction of
1a and d2-1a catalysed by complex B.
Activation parameters. To further probe the nature of the
turnover-limiting step, the temperature dependence of the rate
for the cyclisation of 1a by B was studied. The second-order rate
constant k was determined at an 80–100 °C temperature range
from the kobs values extracted from the pseudo-first order plots of
ln[1a] over time. The Eyring plot of ln(kh/kBT) versus 1/T shown
in Figure 1 provides the following activation parameters: H‡ =
22.2 kcal.mol-1, S‡ = –13.4 cal.mol-1.K-1. The magnitude of the
d[1a]/dt = kH[1a]1[B]1 (kH (363 K) = 4.7 ×10-4 M-1 s-1)
(1)
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negative S‡ value is indicative of a highly ordered TS structure
associated with the turnover-limiting event.
Figure 2. ORTEP diagram of [D2]2 showing 30% probability ellipsoids.
Hydrogen atoms are omitted for clarity.
Figure 1. Eyring plot in the temperature range 80–100 °C for the cyclisation of
1a catalysed by B. (H‡ 22.2 kcal.mol-1, S‡  –13.4 cal.mol-1.K-1).
Nature of the cyclisation step
Catalyst activation. To inform ourselves about the initial stages
of the catalytic transformation the stoichiometric reaction of B
with one molar equivalent of 1a and 2,2-dimethylpent-4-en-1-
amine (1b) have been conducted and monitored by 1H NMR
(Scheme 4). Firstly, addition of B dissolved in toluene to 1a and
1b at room temperature lead to the immediate formation of dark-
red solutions, from which red-orange crystals could be extracted.
To gain more insight into the nature of the cyclisation step,
efforts have been devoted to study the reactivity of the isolated
intermediate
[
D1
]
and the stereochemistry of the N–H(D)
2
addition across the C=C double bond.
Stoichiometric reactivity. A slurry solution of isolated iron
amido dimer [D1] was heated to 90 °C for 24 h. After air
2
Solid-state analysis reveals the formation of centrosymmetric
[3f]
dimers [D1]2
and [D2]2 (Figure 2)[13] with two iron centres
exposure to the crude reaction mixture, GC analysis highlights
the presence of 1a, 2a, 3a and 4a in a 9:16:58:18 ratio (Table 1,
entry 2). The observed formation of cycloamine 2a
concomitantly with cyclic imine 3a is highly suggestive of a
migratory insertion of the unsaturated alkene carbon–carbon
featuring a distorted tetrahedral geometry that are bridged by
two amido groups.
linkage into the iron–amido bond at [D1] or its monomer, which
2
generates an iron alkyl intermediate. Although a high thermal
stability towards -hydride elimination has been demonstrated
for some similar coordinatively unsaturated iron alkyl
complexes,[14] this intermediate is, nevertheless, expected
displaying a strong tendency toward undergoing -hydride
elimination, a presumption that is reflected in the preferential
formation of oxidative amination over hydroamination products.
Such reactivity pattern represents a rare example of direct
evidence for alkene insertion into the metal–N -bond of
structurally well-defined metal amido complexes.[15] To our
delight, the selectivity of the stoichiometric reaction can be
diverted in favour of the hydroamination product by the addition
Scheme 4. Stoichiometric reactivities of B and aminoalkenes 1a and 1b.
Isolated yields are in brackets and Ar1 = 2,4,6-(Me)3C6H2.
Secondly, monitoring the reaction of B (1 equiv) with 1a (2
equiv) by 1H NMR shows the complete disappearance of the
methyl signals of the CH2SiMe3 fragment in less than 40 (at
25 °C) and 10 (at 50 °C) minutes, respectively (Figures S1–
S3[10]). It clearly indicates that catalyst activation is probably not
kinetically decisive at our optimised catalytic conditions (90 °C,
24 h).
of cyclopentylamine. Indeed, heating
cyclopentylamine (1.2 equiv per Fe) gives rise to 2a as major
product (Table 1, entry 3). It is worth noticing that dimer D1
and its alkyl precursor B display similar abilities to cyclise 1a
(Table 1, entries 4 vs. 1). It indicates that amido dimer D1 2 and
[D1] in the presence of
2
[
]
2
[
]
its monomer are both catalytically competent to promote
cyclohydroamination. Moreover, the fact that C–N bond
formation occurs commencing directly at [D1] without requiring
2
the assistance of an additional proton source strongly militates
against a proton-assisted concerted C–N/C–H bond-forming
pathway.[11a,12a]
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the gem-dimethyl-substituted S furnishes pyrrolidine CP1, whilst
cyclic imine CP2 and reduced substrate CP3 result from
traversing the oxidative amination avenue. A reliable DFT
methodology (dispersion-corrected hybrid meta-GGA PW6B95-
D3 functional in conjunction with flexible basis sets of def2-TZVP
quality and a sound treatment of bulk solvent effects)[10] has
been employed.
The various plausible pathways for direct HA and OA have
been examined for species adopting reasonable spin states; in
all, but two steps (viz. -hydride elimination (HE) and its
microscopic reverse) the quintet state is found to prevail
energetically. While the presentation herein will be focusing on
the most accessible pathways, a complete account of all
scrutinised species can be found in the Supporting Information.
In what follows, different isomers of a given species are labelled
by subscript numbers.
Table 1. Influence of the catalyst structure on the reactivity and selectivity of
the cyclohydroamination of 1a.[a]
GC Yields [%]
Catalyst
(mol %)
Entry
1a
3
2a
80
16
77
82
3a
10
58
6
4a
6
1
B (10)
2[b]
3[b,d]
4[e]
[
[
D1
]
]
2 (100[c]
2 (100[c]
)
)
9
18
1
D1
17
2
[
D1]
2 (5[c]
)
12
4
[a] Reaction conditions: [1a] = 0.96 M, toluene, 90 °C, 24 h unless otherwise
stated. [b] Without 1a. [c] Related to iron. [d] With cyclopentylamine (120 mol%
relative to Fe) as additive. [e] 21 h.
Mechanistic avenue for direct hydroamination. Given that
{N^N}Fe alkylsilyl C1•T (≡ B) rapidly converts into the
[{N^N}Fe(NHR)]2 C2dim (≡ [D2]2) almost quantitatively in the
presence of amine substrate in less than 40 min at 50 °C, whilst
HA catalysis requires 24h at an elevated temperature of 90 °C to
be completed (see above), one can safely conclude that the
initial generation of the catalytically active [{N^N}Fe(NHR)]n
compound is distinctly more facile than effective HA catalysis
and thus not likely limiting either the catalyst turnover or the
{N^N}Fe amido population. Hence, our examination starts with
analysing the identity of the [{N^N}FeII(NHR)]n compound. On
the one hand, dimer C2dim is well characterised (see above),
whilst amine substrate S can otherwise associate at iron in
several ways to stabilise its monomer C2. A moderately
encumbering -diketaminato {N^N}Fe ligation favours amine
association at iron, which is seen capable of accommodating up
to two amine molecules (Figure S8[10]). Among the multitude of
monomer {N^N}Fe amido species, all of which are expected to
participate in rapid association/dissociation equilibria,[17] mono
Stereochemistry of the insertion step. To ascertain the
preferable pathway for C–N bond formation its stereochemistry
was established by employing complex B through isotopic
labelling studies (Scheme 5). Measurements of JH,H coupling
constants of tosylated products evolving from cyclisation of N-
3
deutero-amines
(E)-d2-1c
and
(Z)-d2-1c
featuring
a
stereochemically defined carbon–carbon double bond have
been performed.
adduct C2•S is found most stable, with C2 and C2•(S)2 are
placed somewhat higher in free energy by 1.3 and 5.4 kcal mol-1,
respectively. Hence, the various species can be expected to be
populated in various, but appreciable amounts.
5
5
5
Scheme 5. Isotopic labelling studies aimed at determining the stereochemistry
of the insertion step.
1
A dimer C2dim (≡ [D2]2) could be located that reflects the
metrics of the X-ray structure of [D2]2 well. It adopts a singlet as
the favourable spin state and is placed 2.8 kcal mol-1 below
5C2•S in free energy. Thus, the catalytically relevant {N^N}FeII
amido favours its dimer over all the substrate-free and substrate-
adducted monomer species. It renders 1C2dim a plausible
candidate for the catalyst resting state, which we therefore
chose (plus appropriate substrates) as reference for free
energies reported throughout this study, unless noted otherwise.
However, monomer 5C2•(S)n species and not 1C2dim, both of
which are in mobile equilibria,[17] are the direct precursor for
cyclisation (see below) and thus likely representing the
catalytically active species.
The comparison with proteo amine (E)-1c reveals that in
both cases only one diastereomer is formed with the exclusive
incorporation (>95%) of deuterium at the nitrogen’s -position
and syn-addition of the N–D bond across the C=C bond.[10,16]
The syn-stereochemistry clearly hints towards C–N bond
formation to preferably proceeding through syn-1,2 migratory
insertion.
Computational study
To further inform our mechanistic understanding, we embarked
on a detailed computational perusal of plausible mechanistic
pathways for rival avenues of direct intramolecular
hydroamination (HA) and oxidative amination (OA) of 2,2-
dimethylpent-4-en-1-amine 1b (≡ S) by -diketaminato {N^N}FeII
alkylsilyl precatalyst B (≡ C1•T). Productive hydroamination of
-Insertive mechanism. Migratory olefin 1,2-insertion into the
Fe–Namido -bond: Several conceivable trajectories for insertive
cyclisation featuring an axial or equatorial approach of the olefin
double bond to commence from C2’ or its substrate adducts
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C2•(S)n have been examined. Notably, all the species
participating in the various trajectories favourably adopt a quintet
spin state, with the respective triplet species are found well
separated above in free energy and are thus not accessible
thermally. Moreover, all the trajectories traverse a four-centre TS
structure along the minimum-energy pathway, describing a
metal-assisted syn-migratory olefin 1,2-insertion into the Fe–
Namido -bond that occurs at distances of approximately 2.0 Å for
the emerging N...C bond (Figure S9[10]). The further progress
along the reaction path delivers {N^N}Fe alkyl intermediate
C3•(S)n which has the azacycle bound to iron through its
methylene tether together with a stabilising metal–N donor
centre contact.
somewhat uphill association of amine substrate to give adducts
5C3•(S)n aminolysis evolves through a metathesis-type TS
structure that describes the cleavage of an already suitably
polarised N–H bond with simultaneous C–H bond formation.
Figure 4 reveals the cleavage of an equatorial iron alkyl -bond
by a proton delivered from an axially iron bound, thus N–H
activated, substrate molecule to be the prevailing trajectory. The
located 5TS[C31•S–C4] of lowest energy represents an
intermediate point on the reaction coordinate, where
intramolecular H transfer is only partially accomplished, as
evidenced by the relatively short (1.26 Å) N...H and long (1.54 Å)
C...H distances (Figure S13[10]) and is directly connected to
5
{N^N}Fe amido pyrrolidine C4. Incoming substrate S readily[17]
The energy profile in Figure 3 (Figures S10–S12)[10] reveals
that an axial approach of the C=C linkage does prevail for N–C
bond generating cyclisation at the {N^N}FeII(NHR) compound
irrespective of whether none, one or two spectator substrate
molecules participate. The substrate-free 5C2’ is found most
competent at effecting insertive cyclisation, whilst enhanced
spatial demands around the iron centre due to association of
spectator substrate molecules render migratory olefin insertion
at 5C2’•S and even more so at 5C2’•(S)2 substantially less
favourable on both kinetic and thermodynamic grounds. The
releases pyrrolidine CP1 from 5C4 in a virtually thermoneutral
transformation (G = –0.4 kcal mol-1 for 5C3 + S → 5C2•S +
CP1) with the regeneration of the catalytically active
{N^N}FeII(NHR) compound for another catalyst turnover.
The protonolytic cleavage of the Fe–C alkyl -bond entails
an overall barrier of 25.8 kcal mol-1 (relative to {½×1C2dim +
appropriate substrates}, Figure 4) along the most accessible
5C31 + S → 5C4 pathway. One should bear in mind that this
overall barrier does not solely reflect the intrinsic ability of S to
effect protonolytic Fe–C bond cleavage, since it also includes
the thermodynamic penalty associated with substrate binding to
C3. Furthermore, the aminolysis is downhill driven by a strong
5
5
non-competitive energy profile derived for C2’•S → C3•S and
5
5C2’•(S)2 → C3•(S)2 is a direct consequence of the necessity to
5
5
activate the olefin unit through close contact with the iron centre
to accomplish N–C bond formation, which is made ever more
difficult for increasing numbers of associated spectator substrate
molecules with whom the C=C linkage has to compete for
access to the metal centre.
thermodynamic force (G = –9.9 kcal mol-1 for C3 + S → C4),
which is primarily a consequence of the difference in strength of
N–H and C–H bonds. All in all, the DFT-derived smooth energy
profile (Figure 4) is indicative of a kinetically challenging, but
nevertheless viable (in the context of the applied reaction
condition) and downhill, thus irreversible, intramolecular
aminolysis of the Fe–C alkyl linkage along the energetically
5
prevalent 5C31 + S → C4 pathway.
Figure 3. Most accessible pathway for migratory olefin 1,2-insertion into the
Fe–Namido -bond at the catalytically relevant [{N^N}Fe(NHR)] complex. Free
energies are given in kcal mol-1 relative to {½×1C2dim + reactants}.
Migratory olefin syn-insertion into the Fe–Namido -bond
Figure 4. Most accessible pathways for Fe–C -bond aminolysis at the
{N^N}Fe alkyl intermediate. Free energies are given in kcal mol-1 relative to
{½×1C2dim + reactants}.
preferably traverses
a trajectory featuring an axial olefin
approach through a quasi-planar four-centre TS structure, which
does not benefit from the participation of associated spectator
5
5
substrate molecules. The most accessible C2’ ⇄ C3 pathway
has a rather modest total barrier (G‡ = 13.5 kcal mol-1 relative
to {½×1C2dim + appropriate substrates}) to traverse and is
slightly exergonic. It characterises insertive ring closure to be
kinetically facile and reversible.
Concerted proton-triggered cyclisation mechanism. The
alternative cyclisation scenario outlined above, whereby the
pyrrolidine product would be formed in a concerted single step
transformation through N–C ring closure triggered by
concurrently occurring proton transfer onto the adjacent C=C
linkage, will be studied next. Similar to the findings for insertive
cyclisation and protonolysis steps the quintet is the only
thermally accessible spin state. The located most accessible
pathway for concerted amidoalkene→cycloamine conversion is
shown in Figure 5. It traverses a six-centre TS structure
describing N–C bond formation through an axial olefin approach
at the Fe–Namido -bond, provoked by a proton delivered from an
Fe–C azacycle tether -bond aminolysis: Protonolytic cleavage
of the Fe–C linkage to progress from {N^N}Fe alkyl 5C3
generated via the most accessible 5C2’
→
5C3 insertive
cyclisation pathway requires the association of at least one
molecule of S. Various plausible trajectories for intramolecular H
transfer have been probed (Figures S14–S16),[10] the preferably
traversed one is shown in Figure 4. After the initial facial,[17] but
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equatorially bound NH-acidified substrate molecule onto the
is liberated through Fe–C bond aminolysis by another molecule
S with the regeneration of {N^N}Fe(NHR) C2. Alternatively,
protonolysis of substrate S by C5 would convert the {N^N}Fe
hydride directly back into C2 with the facile liberation of H2 (1
equiv).
5
adjacent olefin-C5 centre. When following the dominant C2•S →
5C4 pathway the 5TS[C2•S–C4] arrives at a N...C4 distance of
1.93 and features vanishing N...H (1.24 Å) and emerging C...H
(1.47 Å) bonds, all of which points to a concerted, but
asynchronous proton transfer (Figure S17[10]). The large
separation of the C4 centre from the iron centre (>3.5 Å) is
particularly striking and clarifies that ring closure takes places
outside of the immediate vicinity of the metal centre. In sharp
contrast to the inevitability of a close interaction of the C=C bond
with the metal to facilitate N–C bond formation along the
insertive cyclisation pathway, such close proximity to iron is no
longer required here, since amino proton delivery activates the
unsaturated carbon–carbon linkage. It furthermore renders the
proton-triggered concerted cyclisation less susceptible to steric
demands imposed by the ligand sphere when compared with the
insertive cyclisation. After passing through the TS structure the
reaction coordinate leads directly to C4, from which pyrrolidine
CP1 can readily be exchanged for S (see above).
Hydride elimination: For HE to be effective a vacant
coordination site cis to the alkyl and an empty metal d orbital is
required. However, high-spin FeII centres have no such empty d
orbital available to accept the incipient hydride’s two electrons,
but a triplet has. This makes a spin-crossover[18] to a lower-spin
state, which would deliver the requisite empty d orbital, almost
inevitably to occur along the HE path.[19] The {N^N}Fe alkyl
precursor favours the quintet 5C3, which has a tetrahedral
geometry (Figure S21[10]), over the square-planar triplet 3C3.
Likewise, the initially formed product of HE is a tetrahedral
quintet {N^N}Fe cycloenamine hydride 5C5•CP2’ with the
corresponding triplet is less preferable and is pseudo-square
planar at the iron centre. Transition-state structures for HE
5
featuring vanishing C...H (1.75/1.53 Å for TS/3TS, respectively)
and emerging Fe...H (1.70/1.58 Å for 5TS/3TS, respectively)
bonds could be located for both spin states (Figure S21[10]
)
displaying a reverse order in relative energy. The facile HE
requires a pseudo quasi-planar geometry around the iron centre
3
whilst traversing TS[C3–C5•CP2’], although both reactant and
product favour the quintet over the triplet spin state.
Consequently, this process features two-state reactivity and
evolves through two spin-crossover transitions.[10]
The most accessible pathway for HE that starts from
tetragonal 5C3 evolves through 3TS[C3–C5•CP2’], which
benefits from an available empty d orbital at a pseudo square-
planar iron centre and decays thereafter into tetragonal
5C5•CP2’, has a total barrier of 26.7 kcal mol-1 (relative to
{½×1C2dim + appropriate substrates}) to overcome (Figures
S20, S22[10]). It hints to a kinetically demanding HE, which,
considering the applied catalytic conditions of prolonged reaction
time and elevated temperature, likely is still traversable. The
initially generated cyclic enamine can be expected to readily
Figure 5. Most accessible pathways for N–C ring closure with concurrent
delivery of the amino proton to the olefin moiety at the catalytically relevant
[{N^N}Fe(NHR)] compound. Free energies are given in kcal mol-1 relative to
{½×1C2dim + reactants}.
The concerted amidoalkene→cycloamine conversion along
the dominant pathway for proton-assisted concurrent N–C/C–H
bond formation that starts from 5C2•S and evolves through a six-
centre TS structure has a total barrier of 30.4 kcal mol-1 (relative
to {½×1C2dim + appropriate substrates}) to climb and furnishes
5C4 in a process that is downhill by 10.9 kcal mol-1 (Figure 5).
Hence, proton-assisted concerted cyclisation is irreversible as is
Fe–C alkyl bond aminolysis and both steps afford compound C4.
Furthermore, the process does not benefit from the association
of excess substrate molecules on either thermodynamic or
kinetic grounds (Figure 5), therefore paralleling the findings for
insertive cyclisation and aminolysis steps.
5
convert into pyrroline CP2,[20] thereby driving the overall C3 →
5C5•CP2’ ⇄ 5C5•CP2 process (G = –3.7 kcal mol-1) further
down thermodynamically. Moreover, the cycloimine is readily
liberated[17] by incoming S to furnish substrate adducted {N^N}Fe
5
5
hydride species C5•(S)n (G = –0.1 kcal mol-1 for C3•CP2 + S
5
→ C2•S + CP2).
Migratory olefin insertion into the Fe–H linkage: With the
{N^N}Fe hydride C5 built, migratory insertion of the
aminoalkene’s C=C bond into the Fe–H linkage would lead to
{N^N}Fe aminoalkyl C6. The pattern of substrate association
onto C5 closely follows those for {N^N}Fe(NHR) C2, with all the
several located C5•(S)n and C5•(S’)n adducts preferably
adopting the quintet spin state.
Mechanistic avenue for oxidative amination. We shall now
turn our attention to the competitive avenue for oxidative
amination (OA). In accordance with a wealth of knowledge the
{N^N}Fe alkyl C3 appears as a plausible junction from which the
two separate avenues for direct intramolecular HA and OA divert.
The -hydride elimination (HE) at C3 affords {N^N}Fe hydride
C5 together with cyclic enamine CP2', which readily tautomerize
into pyrroline CP2 thereafter. The regioselective migratory
insertion of the aminoalkene C=C bond into the Fe–H linkage at
substrate adducted forms of the {N^N}Fe hydride would lead to
{N^N}Fe aminoalkyl C6, from which the reduced substrate CP3
Migratory olefin insertion to proceed via regioisomeric 1,2-
and 2,1 pathways furnishes {N^N}Fe aminoalkyl intermediates
C6b and C6a, respectively. The process shares common
features with its microscopic reverse, viz. HE. Firstly, it features
two-state reactivity and evolves through two spin-crossover
5
transitions connecting the quintet reactant C5•(S)n and product
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5C6•(S)n with the triplet 3TS structure along the pathway of
minimum energy. Secondly, additionally adducted spectator
molecules S do not serve stabilising any of the involved species.
5
We start with examining the first 5C5 + n×S→ C6a•(S)n-1
migratory 1,2-insertion.
A detailed examination of various
conceivable trajectories can be found in the Supporting
Information (Figures S24–S27); here we wish to focus
exclusively on the dominant 5C5 + S→ C6a pathway. Starting
5
from square planar 5C51•S’ spin crossover takes places to arrive
Figure 7. Most accessible pathway for Fe–C -bond aminolysis at the
{N^N}Fe aminoalkyl intermediate. Free energies are given in kcal mol-1 relative
to {½×1C2dim + reactants}.
at 3TS[C51•S’–C6a] with
a distorted trigonal bipyramidal
geometry around the iron centre. The triplet TS decays
thereafter into quintet {N^N}Fe aminoalkyl 5C6a through a
second spin-crossover transition (Figure S27[10]). The assessed
total activation energy of 27.1 kcal mol-1 (relative to {½×1C2dim
+ appropriate substrates, Figure 6}) is of similar magnitude as
the barrier for HE (see above), but migratory 1,2-insertion is
distinctly more downhill (G = –17.9 kcal mol-1), hence is
irreversible.
The protonolytic release of aminoalkane CP3 at C6a by
aminoalkene S is distinctly downhill, mainly driven by the
enhanced strength of the Fe–Namido vs. Fe–Calkyl bonds and has
an affordable total barrier (G‡ = 17.4 kcal mol-1 relative to
{½×1C2dim + appropriate substrates}, Figure 7). Among the two
5
consecutive 5C5 + S→ C6a migratory insertion and 5C6a +
5
S→ C2•CP3 Fe–C -bond aminolysis steps, the first migratory
insertion dictates the overall kinetic demands (Figure 6) for the
irreversible generation of reduced substrate CP3 commencing
from {N^N}Fe hydride C5.
Protonolysis of the substrate by the {N^N}Fe hydride: We now
examine the alternative scenario for {N^N}Fe hydride C5 to
effect protonolysis of aminoalkene S, thereby converting C5
back directly into the catalytically active {N^N}Fe(NHR) C2. The
process starting from either mono- and bis-substrate adducts
C5•(S)n evolves through a metathesis-type TS structure that
favours the formation of the new H–H bond taking place
between an axial Fe–H linkage and a cis N–H acidic amino unit
over alternatively available trajectories (Figures 8, S35[10]). The
assessed total activation barrier (G‡ = 31.1 kcal mol-1 relative to
Figure 6. Most accessible pathways for migratory 1,2-insertion of the olefin
double bond into the Fe–H linkage at the {N^N}Fe hydride intermediate. Free
energies are given in kcal mol-1 relative to {½×1C2dim + reactants}.
5
The alternative migratory 2,1-insertion via 5C5 + S→ C6b
likewise evolves through a formal four-centre quasi-planar triplet
3TS structure describing metal-mediated migratory insertion of
the aminoalkene C=C linkage into the polar Fe–H bond, which
occurs at a distances of 1.61/1.53 Å for the emerging C5...H bond
and vanishing Fe...H bonds (Figure S28[10]). Among the two
regioisomeric pathways migratory 1,2-insertion is predicted more
rapid owing to an assessed kinetic gap of 1.5 kcal mol-1 (G‡)
Figures 6, S29[10]) in its favour and is thus likely traversed
predominantly.
{½×1C2dim
prohibitively large and thus hints to a rather slow, if kinetically
+ appropriate substrates}, Figure 8) appears
5
5
achievable at all, C5 + S → C2’ + H2 substrate protonolysis by
{N^N}Fe hydride C5. In the presence of a stepwise generation of
aminoalkane CP3 from C5, which is distinctly more accessible
kinetically (cf. Figures 6, 7), one can safely conclude that C5 is
unlikely effecting protonolysis of the substrate.
Fe–C -bond aminolysis: The protonolytic cleavage of the Fe–C
alkyl linkage at C6a by an iron-bound substrate furnishes the
reduced aminoalkane CP3 and regenerates the catalytically
active {N^N}Fe amidoalkene for another catalyst turnover. The
early stage of the process sees the facile axial association[17] of
a
substrate molecule, with protonolytic cleavage of the
equatorial Fe–C linkage by a proton delivered from the axially
5
iron-bound S proceeding thereafter through TS[C6a•S–3•CP3].
Figure 8. Most accessible pathways for protonolysis of substrate S by
{N^N}Fe hydride C5 through liberation of H2. Free energies are given in kcal
mol-1 relative to {½×1C2dim + reactants}.
The metathesis-like TS structure describes the simultaneous
cleavage/generation of N–H/C–H bonds features an already
weakened Fe...C linkage (Figure S31[10]) and is directly linked to
5
the {N^N}Fe amido C2•CP3. The newly built aminoalkane CP3
5
Proposed catalytic cycle
initially remains associated with the iron amido in C2•CP3 but
could easily be replaced[17] by aminoalkene S (G = –0.4 kcal
The accumulated collective experimental and computational
results lead us to define the preferably accessed pathways
traversed along competing avenues of direct intramolecular
hydroamination and oxidative amination. In all, but two steps (viz.
HE and its microscopic reverse) species involved preferably
5
mol-1 for 5C2•CP3 + S ⇄ C2•S + CP3).
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10.1002/chem.201804681
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adopting the quintet spin state. Scheme 6 summarises the thus
derived mechanistic picture exemplified for aminoalkene 1d (≡
S) substrate and B (≡ C1•T). The initial facile conversion of
starting material C1•T into the catalytically relevant
[{N^N}FeII(NHR)]n compound is unlikely limiting either the
catalyst turnover or the {N^N}FeII amido population. The iron
amido compound favours its dimer 1C2dim (≡ [D2]2), which likely
corresponds to the catalyst resting state, but monomer species
5C2•(S)n appear as direct precursor for amidoalkene cyclisation
and hence representing the catalytically active species.
olefin 1,2-insertion into the Fe–Namido -bond. It is followed by
5
5
downhill, turnover-limiting C3 + S → C4 protonolytic cleavage
of the Fe–C -bond at the thus formed transient {N^N}FeII alkyl
intermediate and the rapid displacement of the cycloamine by
incoming substrate thereafter to regenerate the {N^N}FeII amido
active catalyst complex. The proton-assisted concerted N–C/C–
H bond-forming non-insertive pathway is seen to be kinetically
prohibitive in the presence of a distinctly faster -insertive
pathway. The magnitude of the DFT assessed kinetic disparity
(G‡ = 4.6 kcal mol-1; Figures 4, 5) together with the observed
simultaneous generation of pyrrolidine 2a and cyclic imine 3a
upon heating {N^N}FeII amido dimer [D1]2, without additional
amine present, let us confidently conclude that the -insertive
pathway is exclusively traversed along the avenue for direct
intramolecular hydroamination. The DFT assessed total barrier
Considering the avenue for direct HA first, a plausible
pathway for concerted amidoalkene→cycloamine conversion
through proton-assisted concurrent N–C/C–H bond formation
taking place outside of the immediate proximity of the iron centre
via a six-centre TS structure is irreversible, but kinetically
challenging. The observed substantial KIE is easily reconcilable
with this concerted proton-assisted non-insertive pathway, but
the stepwise -insertive pathway is equally consistent. This
1
of 25.4 kcal mol-1 (relative to the C2dim catalyst resting state)
for turnover-limiting {N^N}Fe–C alkyl -bond aminolysis matches
the empirically determined Eyring parameter (G‡ = 27.1 kcal
mol-1 (363 K) for cyclisation of 1a, Figure 1) gratifyingly well.
5
pathway entails a first kinetically facile, reversible insertive C2’
⇄
5C3 N–C bond-forming cyclisation through syn-migratory
Scheme 6. Proposed catalytic cycles for {N^N}FeII(NHR)-catalysed direct intramolecular hydroamination and rival oxidative amination.
The competitive avenue for oxidative amination branches at
{N^N}FeII alkyl 5C3 via kinetically viable, competitive HE. Its
most accessible pathway evolves through two spin-crossover
transitions connecting quintet reactant and product with a triplet
TS, which requires a pseudo-planar geometry at the iron centre.
The reversible HE favours the reactant and entails a total
barrier of 26.7 kcal mol-1 (relative to the 1C2dim). The thus
generated short-lived hydride is seen kinetically sufficiently
regioselective for migratory aminoalkene olefin 1,2-insertion to
predominantly afford 5C6a. It shows two-state reactivity as its
microscopic reverse does. The kinetically easy, strongly downhill
Fe–C -bond protonolysis by incoming substrate releases
thereafter the reduced aminoalkane, thereby closing the cycle
for oxidative amination with the regeneration of the {N^N}FeII
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10.1002/chem.201804681
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amido active catalyst complex. The remarkably similar
magnitude of DFT assessed total barriers for HE and migratory
olefin 1,2-insertion does not allow any firm conclusions about the
nature of the turnover-limiting event along the avenue for
complexes and are thus well suited assisting the design of base
metal catalyst systems offering novel reactivity and selectivity for
alkene hydrofunctionalisation. Efforts in this direction are
currently underway.
5
oxidative amination. Gratifyingly, turnover-limiting 5C3 + S → C4
aminolysis for direct hydroamination is predicted to be
somewhat faster than either of these two steps. Thus, pyrrolidine
can be expected as major product together with pyrroline and
aminoalkane, but only should the amine concentration not drop
below a level sufficient at effecting Fe–C -bond aminolysis
along the avenue for direct hydroamination. The mechanistic
intricacies delineated in Scheme 6 are consonant with all our
empirical data obtained from both stoichiometric and catalytic
studies, including the empirical second-order rate law, the
substantial primary KIE and the negative activation entropy.[21]
Acknowledgements ((optional))
Financial supports from MENSR, Univ Paris Sud and the CNRS,
are gratefully acknowledged.
Keywords: homogeneous catalysis • hydroamination • iron •
kinetics • density functional calculations
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a
stepwise -insertive mechanism over a proton-assisted
concerted N–C/C–H bond-forming non-insertive pathway. This
entails: (1) kinetically facile, reversible 5C2’ ⇄ 5C3 cyclisation
through syn-migratory olefin 1,2-insertion into the Fe–Namido -
5
5
bond; (2) irreversible, turnover-limiting C3 + S → C4 Fe–C -
bond aminolysis at the thus formed transient {N^N}FeII alkyl
intermediate; and (3) regeneration of the catalytically active
{N^N}FeII amido, which favours its dimer 1C2dim (≡ [D2]2), likely
representing the catalyst resting state, through rapid cycloamine
displacement by aminoalkene substrate. The stepwise -
insertive pathway easily rationalises the observed substantial
primary KIE and also the empirically determined negative S‡
and is supported by the direct alkene insertion into the Fe–N
amido -bond observed in the absence of a proton source. Its
DFT predicted barrier for turnover-limiting aminolysis compares
favourably with empirically determined Eyring parameter. The
rival avenue for oxidative amination branches at {N^N}FeII alkyl
5C3 via kinetically viable, competitive HE that evolves through
two spin-crossover transitions connecting quintet reactant and
product with a triplet TS. The reversible HE releases the cyclic
imine and affords short-lived {N^N}FeII hydride, which is seen
kinetically sufficiently regioselective for migratory olefin 1,2-
insertion (also exhibiting two state reactivity) to eventually
generate the reduced substrate via ensuing fast, strongly
downhill Fe–C -bond protonolysis. Our combined mechanistic
studies have disclosed factors governing reactivity and
selectivity of alkene hydroamination of unprotected primary
amines promoted by well-defined diketiminatoiron(II)
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[10] See the Supporting Information for details.
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10.1002/chem.201804681
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A comprehensive mechanistic study
by means of complementary
experimental and computational
studies regarding the exo-
Clément Lepori, Elise Bernoud, Régis
Guillot, Sven Tobisch* and Jérôme
Hannedouche*
Page No. – Page No.
cyclohydroamination of primary
aminoalkenes mediated by a recently
reported diketiminatoiron(II)
complex is presented.
Experimental and computational
mechanistic studies of the -
diketiminatoiron(II)-catalysed
hydroamination of alkenes tethered
to primary amines
This article is protected by copyright. All rights reserved.