Mechanochemical Activation of Iron Cyano Complexes: A Prebiotic Impact Scenario for the Synthesis of α-Amino Acid Derivatives

Article abstract of DOI:10.1002/anie.201713109

Mechanochemical activation of iron cyano complexes by ball milling results in the formation of HCN, which can be trapped and incorporated into α-aminonitriles. This prebiotic impact scenario can be extended by mechanochemically transforming the resulting α-aminonitriles into α-amino amides using a chemical route related to early Earth conditions.

Full text of DOI:10.1002/anie.201713109

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Accepted Article
Title: Mechanochemical Activation of Iron Cyano Complexes: A
Prebiotic Impact Scenario for the Synthesis of α-Amino Acid
Derivatives
Authors: Carsten Bolm, Rita Mocci, Christian Schumacher, Mathias
Turberg, Francesco Puccetti, and José G. Hernández
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713109
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10.1002/anie.201713109
Angewandte Chemie International Edition
COMMUNICATION
Mechanochemical Activation of Iron Cyano Complexes: A
Prebiotic Impact Scenario for the Synthesis of α-Amino Acid
Derivatives
Carsten Bolm, Rita Mocci, Christian Schumacher, Mathias Turberg, Francesco Puccetti, and José G.
Hernández*
R4 R5
N
Abstract: Mechanochemical activation of iron cyano complexes by
ball milling results in the formation of HCN, which can be trapped
and incorporated into α-aminonitriles. This prebiotic impact scenario
can be extended by mechanochemically transforming the resulting
α-aminonitriles into α-amino amides using a chemical route related
to early Earth conditions.
R4
R3
O
prebiotic
source of “CN−”
ball milling
+
+
HN
R1
CN
R1 R2
R2
CN− source : NH2COH, [Fe2+(CN)6], [Fe3+(CN)6], Fe3+[Fe2+(CN)6]
Scheme 1. Mechanochemical α-cyanohydrine formation with prebiotic sources
of cyanide by milling.
appealing candidates for cyanation reactions in prebiotic
terrestrial chemistry. Seeing an opportunity, we applied
formamide as potential cyanide source in a mechanochemical
Strecker-type reaction with benzaldehyde (1a) and benzylamine
(2a) in the presence of SiO2 using a high-speed mixer mill with a
WC jar and one WC ball (d = 15.6 g·cm–3) at 30 Hz for 90 min.
To our disappointment, 1H NMR spectroscopy of the reaction
mixture revealed (besides remaining formamide) only the
formation of imine 4aa, while α-aminonitrile 3aa remained
undetected Apparently, neither the energetic impact nor the
natural rise in temperature inside the ball mill[13] had led to a
productive reaction pathway.
Cyanoferrate complexes have also been proposed as
prebiotic cyanide sources.[4,14] In addition, their redox mediator
properties have rendered them particularly interesting.[14d] By
mechanochemical activation we hoped to overcome their
intrinsic stability, which commonly requires high temperature[15]
or preactivation procedures[16] for generating active CN– species.
Fulfilling our expectations, simple milling of 1a and 2a in the
presence of K4[Fe(CN)6]·3H2O or K3[Fe(CN)6] at 30 Hz for 90
min generated α-aminonitrile 3aa, albeit in limited quantities,
with imine 4aa being the main product (Table 1, entries 1 and 2).
In the search for feasible scenarios for the origin of life,
various reaction media such as water or formamide[1] have been
proposed for the early generation of biogenic molecules like
amino acids, sugars, nucleobases, phosphates, and fatty
acids.[1,2] For some prebiotic transformations involving
condensation reactions, non-aqueous environments have been
demonstrated to be more effective.[3] Along these lines,
Sutherland recently described potential geochemical scenarios
in which early chemistry could have taken place, for example “in
a submarine vent, or a drying lagoon, or an impact crater, or a
reduced atmosphere subject to lightning”.[4] Such dry condition
schemes involving physical impacts perfectly correlate to the
field of mechanochemistry,[5] in which milling and grinding of
non-dissolved reactants is used to induce or facilitate chemical
reactions. Compared to solution-based protocols, this technique
often shows shorter reaction times, higher yields, the possibility
to work with insoluble reactants, and to access difficult or
sometimes impossible targets.[6]
Linking our interest in mechanochemistry[7] to the seminal
work by Miller and Urey on the formation of α-amino acids under
simulated early Earth conditions,[8] we started wondering about
echoing such scenario in a ball mill. If a prebiotic cyanide source
could be activated by physical impact in analogy to triggering
chemical transformations by high-energy extraterrestrial bodies
on early Earth,[9] the formation of α-amino acids via α-
aminonitriles (Scheme 1) would be an ideal study case.[10]
Our first attempt was guided by a discovery of Civiš and
co-workers, who had found that formamide (H2NCHO)
generated key biogenic molecules such as nucleobases by
impact chemistry.[11] Dissociation of this simple compound led to
water and HCN,[12] making formamide and its derivatives
Table 1: Initial screening of the Strecker-type reaction starting
from iron complexes as cyanide source.[a]
Bn
Bn
H
O
HN
N
“CN−” source,
activator
H2N
+
+
H
CN
ball milling
30 Hz, 90 min
1a
2a
3aa
4aa
Bn = Benzyl
Ratio [%][b]
of 3aa:4aa
Entry
Additive
“CN–” Source
K4[Fe(CN)6]·3H2O[c]
K3[Fe(CN)6]
K4[Fe(CN)6]·3H2O
K3[Fe(CN)6]
Prussian blue
Prussian blue
3:97
[*]
Prof. Dr. C. Bolm, C. Schumacher, M. Turberg, F. Puccetti, Dr. J. G.
Hernández
1
2
3
---
---
SiO2
SiO2
---
24:76
49:51
95:5
16:84
86:14
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
R. Mocci
4[d]
5
On leave from: Dipartimento di Scienze Chimiche e Geologiche,
Università degli Studi di Cagliari, Cittadella Universitaria, SS 554
bivio per Sestu, 09028 Monserrato (CA), Italy
F. Puccetti
On leave from: Department of Chemistry “Ugo Schiff”, University of
Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
E-mail: jose.hernandez@oc.rwth-aachen.de
Supporting information for this article is given via a link at the end of
the document.
6
SiO2
[a] 1a (53.1 mg, 0.5 mmol), 2a (53.6 mg, 0.5 mmol), cyanide source (0.5
mmol), and SiO2 (240 mg, 4.0 mmol) were milled in a 10 mL WC milling jar
with one 10 mm milling ball of the same material. [b] Determined by 1H NMR
spectroscopy. [c] The use of anhydrous K4[Fe(CN)6] gave similar results. [d]
The use of substoichiometric amounts of K3[Fe(CN)6] favored the formation of
4aa.
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10.1002/anie.201713109
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From the two iron complexes, potassium ferricyanide (III) proved
superior. To our delight, milling with silica gel as a potential
prebiotic additive significantly improved the multicomponent
reaction providing almost exclusively α-aminonitrile 3aa with little
imine 4aa (95:5) (Table 1, entries 2 and 4). Finally, Prussian
blue[17] was tested under the standard milling conditions (SiO2,
30 Hz, 90 min), and to our surprise, it also served as cyanide
source yielding preferentially α-aminonitrile 3aa (Table 1, entry
6).[18]
The unexpected ability of activating iron cyanide
complexes by milling requested studying the role of the
mechanical energy and of the additives on the activation
process. The first hypothesis was that the highly energetic
mechanical stress and the intrinsic temperature increase by
milling,[13b] led to complex decompositions providing KCN,[4,19]
a
Figure 2. Mechanochemical activation of K3[Fe(CN)6] with SiO2 by ball milling
and formation of HCN.
known cyanide source capable of imine additions in ball mills.[7d]
However, although analysis by powder X-ray diffraction (PXRD)
of K3[Fe(CN)6] samples milled for 60 min with and without SiO2
revealed structural changes in the Fe-complex (Figure 1c-d),
none of the new reflections in the PXRD patterns corresponded
to KCN (Figure 1b). Thus, the CN– source had to be different.
small molecules from K3[Fe(CN)6] occurred concomitant with the
disproportionation of the iron (III) complex into various iron-
bound cyanides. The mechanochemical evolution of HCN
reported here was probably aided by the atmospheric moisture
inside the milling container, the residual water in the silica gel, or
H2O generated from the condensation of 1a and 2a.
Correspondingly, the PXRD analysis of the milled K3[Fe(CN)6]
samples (Figure 1c-d), revealed the formation of new phases,
among which, some of the new reflections resembled the
experimental diffraction pattern of the mixed-iron complex
Prussian blue Fe4(II)[Fe(III)(CN)6]3 (Figure 1e).
a)"K3[Fe(CN)6];""
manually"ground"
b)"KCN;""
manually"ground"
From a prebiotic perspective, the release of HCN from
c)"K3[Fe(CN)6];""
milled"(60"min,"30"Hz)"
metal-bound
cyanide
complexes
under
environmental
mechanical stress could have been key for the formation of
prebiotic building blocks such as α-aminonitriles[4,20] or
nucleobases.[21]
d)"K3[Fe(CN)6]"+"SiO2;"
milled"(60"min,"30"Hz)"
The possibility to safely generate HCN by mechano-
chemical activation of readily available iron complexes was
recognized as an opportunity for organic synthesis.[22] The proof-
e)"Prussian"blue;"
manually"ground"
of-principle was demonstrated by
a Strecker-type reaction
5"
10"
15"
20"
25"
30"
35"
40"
45"
50"
involving the preparation of α-aminonitriles 3 starting from
potassium ferricyanide (III) (Scheme 2). Various aromatic and
aliphatic aldehydes reacted with benzylamine (2a) and
R3
2Θ/°"
Figure 1. PXRD analysis of mechanochemically activated K3[Fe(CN)6] by
milling.
HN
O
SiO2
R3
+
+
K3[Fe(CN)6]
H2N
ball milling
90 min, 30 Hz
R1
R1 R2
1a-i
While conducting these experiments, a slight increase in
the pressure inside the milling container was noticed, especially
when potassium ferricyanide (III) was ground with SiO2. This
observation raised the question whether a mechanochemical
reaction of the iron cyanides with intrinsically acidic silica gel led
to the generation of gaseous cyanogen (CN)2 and/or hydrogen
cyanide (HCN).[19b] To test this idea, a mixture of SiO2 and
K3[Fe(CN)6] or Prussian blue was ball milled inside a modified
milling jar set (Figure 2; for details see the Supporting
Information). After 15 min of milling, a bubbling was observed,
and the formed gas was trapped by an aqueous media. Using a
commercially available paper test revealed the presence of HCN.
Alternatively, bubbling the gas through a vial containing a
solution of 1a and 2b led to α-aminonitrile 3aa.
CN
R2
2a-b
3
NHBn
CN
NHBn
CN
NHBn
CN
3aa R = H
yield = 70%[a] (54%)
3ba R = Me
N
yield = 71%[a] (44%)
3ca R = OMe
NHBn
CN
3ia
3ga
3ha
yield = 56%[a]
(35%)
yield = 60%[a,c]
(50%)
yield = 70%[a]
(54%)
yield = 69%[a] (60%)
3da R = F
R
yield = 66%[a] (42%)
3ea R = Cl
NC NHBn
NHPh
CN
yield = 71%[a] (49%)
3fa R = Br
yield = 73%[a,b] (48%)
3ja
3ab
yield = 56%[a] (42%) yield = 62%[a] (61%)
A mixture of 1 (0.5 mmol), 2 (0.5 mmol), K3[Fe(CN)6] (0.5 mmol), SiO2 (4.0 mmol), 90 min,
30 Hz. [a] Determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard;
yields after column chromatography are given in parenthesis.[23] [b] After 140 min of milling.
[c] After 60 min of milling.
In previous work it was shown that thermal degradation of
K3[Fe(CN)6] (>350 °C) in inert or hydrogen containing
environments such as NH3 or H2O resulted in the formation of
gaseous (CN)2 or HCN, respectively.[19b] The release of these
Scheme 2. Mechanosynthesis of α-aminonitriles 3 using K3[Fe(CN)6].
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10.1002/anie.201713109
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COMMUNICATION
K3[Fe(CN)6] affording the expected products 3aa-3ia in good
yields. Using benzaldehyde (1a) and aniline (2b) led to α-
aminonitrile 3ab in 61% yield, confirming the assumption that the
process involved a cyanide-imine addition and not an oxidative
α-cyanation of an alternatively formed amine intermediate.[24]
With the aim to stay as close as possible to early Earth
conditions, mechanochemistry was also set into the focus for the
transformation of α-aminonitriles 3 into amino acid derivatives.
The initial attempts targeted the development of ball milling
protocols for basic hydrations with urea-hydrogen peroxide
complex (UHP). However, neither the use of substoichiometric
amounts of inorganic NaOH monohydrate nor applying 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as organic base led to
satisfying results. In each case, the yields of amino amide 5aa
were low (10-43%) and dehydrocyanation of 3aa led to
significant amounts of imine 4aa (for details, see Supporting
Information). Finally, a breakthrough was achieved by altering
the approach and using the carbonyl-mediated hydration of
nitriles with paraformaldehyde (PFA) and base originally
Mechanochemical hydration of 3aa (PFA-NaOH·H2O method): A mixture
of 3aa (50 mg, 0.225 mmol), PFA (6.7 mg, 0.225 mmol; [using the molar
mass of formaldehyde as the monomer of the PFA]), NaOH·H2O (6.55
mg, 0.113 mmol) and H2O (4.0 mg, 0.225 mmol) were milled in a 5 mL
stainless steel milling jar with two milling ball made of the same material
(5 mm in diameter). After 30 min of reaction at 25 Hz 5aa was purified by
flash column chromatography on silica gel (eluent = n-pentane/EtOAc;
1/1).
Acknowledgements
This research was possible thanks to the financial support from
the RWTH Aachen University through the RWTH Start-up grant
StUpPD_221-16 funded by the Excellence Initiative of the
German federal and state governments and to the Distinguished
Professorship Program funded by the Excellence Initiative of the
German Federal and State Governments. M. Müller (RWTH-
Aachen University) is acknowledged for the access to PXRD
and the technical assistance. R.M. acknowledges the University
of Cagliari for financial support. R.M. and F.P. thank the
Erasmus+ Programme of the European Union.
reported by Taillades and Commeyras,[25,26] and recently re-
[27]
studied independently by Beauchemin
and Blackmond.[28]
Thus, grinding a mixture of 3aa, PFA, and NaOH·H2O for only
30 min generated amino amide 5aa in 51% (Scheme 3). Also in
this case, the collateral formation of imine 4aa limited the yield of
5aa.
Keywords: Mechanochemistry • prebiotic chemistry • Strecker
reaction • ferricyanide •
PFA (1.0 equiv)
Ph
Ph
NaOH·H2O (50 mol%)
H2O (1.0 equiv)
O
[1]
J. E. Šponer, J. Šponer, O. Nováková, V. Brabec, O. Šedo, Z. Zdráhal,
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3572–3586.
.
4aa
+
BnHN
5aa
.
BnHN
3aa
CN
ball milling
30 min, 25 Hz
5aa yield = 51%
NH2
[2]
[3]
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Scheme 3. Mechanochemical hydration of 3aa.
In summary, the mechanochemical activation by milling of
highly stable iron cyano complexes enabled the synthesis of α-
aminonitriles in a prebiotic impact scenario. Subsequently, the α-
aminonitriles were hydrolyzed in a ball mill under prebiotic
conditions to give amino amides. The transformation of these
products to the corresponding amino acids could have occurred
by ageing reactions facilitated by hydrolytic prebiotic wet-dry
cycles.[29] In a more general perspective, the mechanochemical
activation of prebiotically accepted HCN-surrogates such as
ferrocyanides complexes also opens new routes for the
formation of cyanamide, a key condensing reagent for peptide
elongation,[8d] nucleotide synthesis[30] and cyclic phosphate
formation[31] under early Earth conditions.
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Experimental Section
Mechanochemical Strecker reaction: A mixture of carbonylic compound 1
(0.5 mmol), amine 2 (0.5 mmol), K3[Fe(CN)6] (164.6 mg, 0.5 mmol) and
SiO2 (240 mg, 4.0 mmol) were milled in a 10 mL tungsten carbide milling
jar with one milling ball made of the same material (10 mm in diameter).
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was analyzed by 1H NMR spectroscopy using 1,3,5 trimethoxybenzene
as an internal standard. Purifications of α-aminonitriles 3 were carried out
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pentane/EtOAc).[22]
=
n-
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10.1002/anie.201713109
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COMMUNICATION
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[18] Reacting 1a, 2a and K3[Fe(CN)6]/SiO2 in CD3CN for 6 h at 80 °C
yielded only imine 4aa. Repeating the experiment in DMSO-d6 at
110 °C provided a mixture of 3aa:4aa (30:70), highlighting the role of
the mechanical activation in the formation of the HCN upon ball milling.
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10.1002/anie.201713109
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
Mechanochemistry enabled
simulating and studying a prebiotic
impact scenario for the formation
α-amino acid derivatives under
ball milling conditions.
C. Bolm, R. Mocci, C. Schumacher,
M. Turberg, F. Puccetti, J. G.
Hernández*
Mechanochemical+
prebio/c++
impact+scenario+
NHR2
CONH2
R1
Page No. – Page No.
NHR2
O
K3[Fe(CN)6]!
Mechanochemical Activation of
Iron Cyano Complexes: A
Prebiotic Impact Scenario for the
Synthesis of α-Amino Acid
Derivatives
ball1milling!
R1
CN
R1
H
+!
NH2
HCN!
ball1milling!
ball1milling!
R2
This article is protected by copyright. All rights reserved.