molecules

Article
Mechanochemical Lignin-Mediated Strecker Reaction
Saumya Dabral 1 , Mathias Turberg 1 , Andrea Wanninger 2 , Carsten Bolm 1, * and
Jos G. Hernndez 1, *
1 Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany;
saumya.dabral@oc.rwth-aachen.de (S.D.); mathias.turberg@rwth-aachen.de (M.T.)
2 Angewandte Organische Chemie, Hochschule Niederrhein, University of Applied Sciences, Adlerstr. 32,
D-47798 Krefeld, Germany; andrea.wanninger@hs-niederrhein.de
* Correspondence: carsten.bolm@oc.rwth-aachen.de (C.B.); jose.hernandez@oc.rwth-aachen.de (J.G.H.);
Tel.: +49-241-809-4675 (C.B.); +49-241-809-4146 (J.G.H.)

Academic Editor: Derek J. McPhee

Received: 26 November 2016; Accepted: 10 January 2017; Published: 17 January 2017

Abstract: A mechanochemical Strecker reaction involving a wide range of aldehydes (aromatic,

heteroaromatic and aliphatic), amines, and KCN afforded a library of -aminonitriles upon
mechanical activation. This multicomponent process was efficiently activated by lignocellulosic
biomass as additives. Particularly, commercially available Kraft lignin was found to be the best
activator for the addition of cyanide to the in situ formed imines. A comparative study of the
31 P-NMR (Nuclear Magnetic Resonance) along with IR (Infrared) data analysis for the Kraft lignin

and methylated Kraft lignin samples ascertained the importance of the free hydroxyl groups in the
activation of the mechanochemical reaction. The solvent-free mechanochemical Strecker reaction was
then coupled with a lactamization process leading to the formation of the N-benzylphthalimide (5a)
and the isoindolinone derivative 6a.

Keywords: mechanochemistry; lignin; Strecker reaction; multicomponent reactions; ball milling

1. Introduction
Mechanochemistrythe use of mechanical energy to induce chemical transformationhas
flourished in recent years, providing chemists with the means to improve synthetic chemical design in
organic, inorganic, organometallic, and supramolecular chemistry, among others [15]. Commonly,
mechanochemical reactions are conducted by milling, grinding, shearing, or pulling reactants in the
absence of organic solvents or in the presence of a catalytic amount of them (liquid-assisted grinding,
LAG) [6]. In organic chemistry, the use of electric ball millswhich until very recently had been
used mostly to reduce the particle size of materials (rocks, inorganics, cellulose, lignin, etc.)has
enabled the study of numerous metal-catalyzed transformations [7], organocatalytic [8] and enzymatic
processes [9], lignin [10] and cellulose depolymerizations [1114], multicomponent reactions [15], and
many others [1619]. As a result of these investigations, mechanochemical activation and procedures
have revealed several benefits, such as short reaction milling times, higher yield, reduced waste
production, improved selectivity, and stoichiometry control, among others.
In the field of multicomponent reactions, our group very recently reported the use of inexpensive
and readily available silica gel to mediate the mechanochemical multicomponent Strecker reaction
(Figure 1a) [20]. The efficiency of this protocol enabled the high-yielding mechanosynthesis of diverse
-aminonitriles and some tetrahydroisoquinoline derivatives.
In the search for alternative materials capable of mediating the Strecker reaction under ball milling
conditions, we focused our attention on the utilization of the main constituents of lignocellulosic
feedstockssuch as cellulose or ligninas potential activators for the reaction between aldehydes
(or ketones), amines, and potassium cyanide in the ball mill. Cellulose is a readily available

Molecules 2017, 22, 146; doi:10.3390/molecules22010146 www.mdpi.com/journal/molecules

Molecules 2017, 22, 146 2 of 10
Molecules 2017, 22, 146 2 of 10

of glucose consisting
homopolymer of (14)
of glucose bonds,
consisting of which
(14)has beenwhich
bonds, recently
hasused
beenas an additive
recently used and
as anasadditive
a chiral
inducer
and as ain organic
chiral reactions
inducer [21]. Onreactions
in organic the other [21].
hand,On lignin
the isother
an inexpensive andisabundant
hand, lignin biopolymer
an inexpensive and
containing phenylpropanoid units that are linked together through a variety
abundant biopolymer containing phenylpropanoid units that are linked together through a varietyof C-C and C-O bonds,
resulting
of C-C andinC-O
the bonds,
presence of aliphatic
resulting in thehydroxyl
presence and phenolic
of aliphatic hydroxyl
hydroxyl groups
and (Figure
phenolic 1b) [22].
hydroxyl The
groups
structural
(Figure 1b)features
[22]. Thepresent in cellulose
structural featuresand lignin in
present arecellulose
envisioned andtolignin
conferare
these additivesto
envisioned Brnsted
confer
acidic functionality, which could be useful for the activation of organic reactions
these additives Brnsted acidic functionality, which could be useful for the activation of organic [23]. Therefore, in
order to evaluate
reactions the ability
[23]. Therefore, inoforder
natural heterogeneous
to evaluate activators
the ability to perform
of natural under mechanochemical
heterogeneous activators to
conditions, we decided to test the catalytic activity of peanut shell powder
perform under mechanochemical conditions, we decided to test the catalytic activity of peanut(PSP) as a raw source of
shell
lignocellulosic biomass, cellulose, and several lignin samples in the three-component
powder (PSP) as a raw source of lignocellulosic biomass, cellulose, and several lignin samples in the Strecker reaction
to afford -aminonitriles
three-component Strecker (Figure
reaction1cd).
to afford -aminonitriles (Figure 1cd).

Figure1.
Figure 1. (a)
(a) Mechanosynthesis
Mechanosynthesisof of-aminonitriles
-aminonitrilesmediated
mediatedby
bySiO
SiO22;; (b)
(b) Structure
Structure of
oflignin;
lignin;(c)
(c)General
General
mechanochemical Strecker
mechanochemical Strecker reaction;
reaction; (d)
(d)Natural
Natural heterogeneous
heterogeneous additives
additives tested
tested as
as activators
activators for
forthe
the
mechanochemicalStrecker
mechanochemical Streckerreaction.
reaction.

2. Results
2. Results and
and Discussion
Discussion

2.1. Lignocellulosic
2.1. Lignocellulosic Biomass
Biomassas
asActivator
Activatorofofthe
theMechanochemical
MechanochemicalStrecker
StreckerReaction
Reaction
Inorder
In orderto toevaluate
evaluatethetheeffect
effectof
ofthe
theaforementioned
aforementionedsolid solidadditives
additives on onthe
theStrecker
Streckerreaction,
reaction,we we
beganball
began ballmilling
millingaamixture
mixtureof ofbenzaldehyde
benzaldehyde(1a), (1a),benzylamine
benzylamine(2a), (2a),and
andpotassium
potassiumcyanide
cyanidein inaamixer
mixer
ball mill.
ball mill. The
The analysis
analysis ofof the
thereaction
reaction mixture
mixtureby by11H-NMR
H-NMR spectroscopy
spectroscopy after after two
two hours
hours of of milling
milling atat
30Hz
30 Hzindicated
indicatedfullfullconsumption
consumptionof of1a
1aandand2a. 2a.Additionally,
Additionally,the 1
the H-NMR
1H-NMR analysis
analysisalso
alsorevealed
revealedthe the
presenceof
presence ofthe
theexpected
expected-aminonitrile
-aminonitrile3a 3aininminor
minorquantity,
quantity,along
alongwith
withthe thealdimine
aldimine4a 4aasasthe
themajor
major
productpreceding
product precedingthe themilling
millingprocess
process(conversion
(conversion98%, 98%,3a/4a;
3a/4a;15/85;
15/85; Figure
Figure 2).2). The
The formation
formation of of the
the
-aminonitrile 3a in 15% upon milling
-aminonitrile milling isisremarkable,
remarkable,since
sincethethesame
sameuncatalyzed
uncatalyzedreaction
reaction attempted
attempted in
solution
in solution (acetonitrile)
(acetonitrile)afforded
affordedmainly
mainlyimineimine4a 4aand
andtraces
tracesof of the
the product
product 3a. Next, the reaction
reaction was
was
repeatedin
repeated inthe
thepresence
presenceof ofpeanut
peanut shell
shell powder
powder (PSP)
(PSP) as
as an
an additive
additive forfor the
the multicomponent reaction.
Toour
To ourdelight,
delight,under
underthese
theseconditions,
conditions, thethe amount
amount of of the
the-aminonitrile
-aminonitrile 3a 3a rose
rosesignificantly
significantly after
after
milling(3a/4a;
milling (3a/4a;59/41;
59/41; Figure 2). With the aim of examining
examining the the role
role of
of some
some of of the
the major
major components
components
present in
present inPSP
PSP(cellulose,
(cellulose,hemicellulose,
hemicellulose, lignin),
lignin), crystalline
crystalline cellulose
cellulose andand beechwood
beechwood ligninlignin (BWL1)
(BWL1)
weretested
were testedunder
undermechanochemical
mechanochemical conditions.
conditions. AfterAfter 22 hh of
ofmilling,
milling,in incomparison
comparisonto tocellulose,
cellulose, the
the
ligninsample
lignin sampleproved
provedto tobe
behighly
highlyactive
activein inpromoting
promotingthe theStrecker
Streckerreaction,
reaction,which
whichresulted
resultedin inaamixture
mixture
of-aminonitrile:imine
of -aminonitrile:imineof of90:10
90:10(Figure
(Figure2). 2).
Molecules 2017, 22, 146 3 of 10

O H 2N NHBn NBn
KCN
H + additives CN +
Ball milling
1a 2a 3a 4a

100"

90"

80"

70"
Percentage"[%]"

60"

50"

40"

30"

20"

10"

0"
b"
none" PSP" C" BWL1" BWL2" OL" CL" KL" KL"(250"mg)" CKL"
AddiEve"
a" a" a"
Conversion"[%]" 3a"[%]" 4a"[%]"

Figure 2. Conversion and selectivity of the mechanochemical Strecker reaction using biomass-derived
additives. Reaction conditions: unless otherwise stated, 1a (53.1 mg, 0.5 mmol), 2a (53.6 mg, 0.5 mmol),
KCN (35.8 mg, 0.55 mmol), and the additive (200 mg) were milled in a mixer mill for 2 h at 30 Hz
using a stainless steel milling jar of 10 mL and one milling ball of the same material 10 mm in diameter.
a Determined by 1 H-NMR spectroscopy; b 3 h of milling. PSP = peanut shell powder; C = cellulose;

BWL1 = beechwood lignin 1; BWL2 = beechwood lignin 2; OL = oak lignin; CL = cherry lignin;
KL = Kraft lignin; CKL = capped Kraft lignin.

Subsequently, different lignin samples (cherry, beechwood, and Kraft) were examined as additives
in the mechanochemical multicomponent reaction. In general, all the lignin samples clearly exhibited
a positive effect favoring the formation of the product 3a over the imine 4a (Figure 2). Among the
activators tested, commercial Kraft lignin showed the highest catalytic activity (3a/4a; 92/8; Figure 2)
after 2 h at 30 Hz. An increase in the lignin loading (from 200 mg to 250 mg) and time (from 2 h to
3 h) led to higher 3a:4a ratio of 95:5. However, higher additive loading or longer milling times had a
negligible impact on the output of the mechanochemical reaction. Finally, control experiments under
conventional stirring in organic solvents (CD3 CN and CDCl3 ) in the presence of Kraft lignin (KL)
revealed incomplete conversion of starting materials 1a and 2a. Furthermore, the selectivity of the
reaction in solution was found to mostly favor the formation of the imine 4a (in CD3 CN: 3a/4a; 47/53
and in CDCl3 : 3a/4a; 70/30).

2.2. Investigation of the Role of the Kraft Lignin in the Mechanochemical Reaction
To determine the role of the Brnsted acidic sites of lignin on the activation of the multicomponent
reaction, a sample of Kraft lignin was capped (methylated) following the procedure reported by
Argyropoulos and coworkers using dimethyl carbonate (DMC) in the presence of NaOH in DMSO [24].
Under these conditions, the hydroxyl groups present in lignin are known to undergo methylation,
which could have a direct impact on the overall functionality of the lignin, hence affecting its reactivity.
Indeed, the mechanochemical reaction of 1a, 2a, and KCN in the presence of capped Kraft lignin (CKL)
resulted in a slight decrease in the conversion of the reactants, and in lowering the amount of expected
-aminonitrile 3a (conv. 95%, 3a/4a; 78/22; Figure 2). Analysis by 31 P-NMR [25] (Figure 3 and Table 1)
Molecules 2017, 22, 146 4 of 10

and IR spectroscopy (Supplementary Material, Figure S1) of the lignin samples KL and CKL marked a
clear reduction in the hydroxyl group content in the CKL compared to the raw KL. As observed in
Figure 3, the content of aliphatic and phenolic OH groups decreased considerably after the capping
reaction with DMC, which correlates well to the lower catalytic activity observed experimentally using
CKL as additive.

ppm$ ppm$
(a)$31P$NMR$KL$ (b)$31P$NMR$CKL$

Figure 3. Functional group analysis of lignin by quantitative 31 P-NMR measurements after

phosphitylation; (a) Kraft Lignin (KL); (b) capped Kraft lignin (CKL) with dimethyl carbonate (DMC).
IS = internal standard.

Table 1. Hydroxyl content quantification by 31 P-NMR spectroscopy of KL and CKL.

OH OH (mmol/g)
Aliphatic 5-Substituted Guaiacyl p-Hydroxyphenyl Total Phenolic
Lignin OH OH OH OH OH
KL 1.79 0.90 1.77 0.17 2.84
CKL 0.7 0.3 0.5 0.04 0.84

Finally, the recyclability of Kraft lignin was evaluated. Both filtration and centrifugation of the
reaction mixture after milling allowed the expedient separation of the lignin additive. This recovered
lignin sample was then reused in the standard Strecker reaction. Again, the mechanochemical milling of
1a, 2a, KCN, and recycled KL showed full consumption of the benzaldehyde (1a) and the benzylamine
(2a), although now the 1 H-NMR analysis revealed a decrease in selectivity of the reaction (fresh KL:
3a/4a; 92/8, recycled KL: 3a/4a; 62/38).

2.3. Scope of the Mechanochemical Strecker Reaction

With the optimized conditions, we evaluated the scope of the lignin-mediated Strecker reaction
in the ball mill. Starting with benzylamine (2a) as amine partner, benzaldehydes substituted either
with electron-donating functional groups (1bc) or aromatic aldehydes bearing electron-withdrawing
substituents were tested, giving the corresponding -aminonitriles 3bf as the major products after
three hours of milling (entries 26 in Table 2). Similarly, heterocyclic and aliphatic aldehydes such as
3-pyridinecarboxaldehyde (1g) (Supplementary Materials, Figure S2) and cyclohexanecarboxaldehyde
(1h) also proved to be suitable for the multicomponent reaction in the ball mill, affording the products
(4gh) preferentially. Finally, a set of experiments using aniline (2b) as amino component with
1a (entry 9 in Table 2), and cyclohexanone (1i) as carbonyl compound together with benzylamine
(2a) (entry 10 in Table 2) were also successful, highlighting the wide range of applicability for the
mechanochemical method.
Molecules 2017, 22, 146 5 of 10
Molecules 2017, 22, 146 5 of 10

Molecules 2017, 22, 146 5 of 10

Molecules Molecules
2017,
Molecules 22,
2017,
Molecules2017,
146
22, 22,22,
146
2017, 146146 5 aof 5 of 510of5 10
a 10 of 10
Molecules Table
2017,
Table22, 2.
146
2. Mechanochemical
Mechanochemical Streckerreaction
Strecker reactionofofaldehydes,
aldehydes,ketones,
ketones,and
andvarious
variousamines
amines
5 of ..
10
Table 2. Mechanochemical Strecker reaction of aldehydes, ketones, and various aminesa a. a a a
Table
Table Table
2.2.
Table 2. Mechanochemical
Mechanochemical
Table
Mechanochemical Strecker
2. Mechanochemical Strecker
reaction
Strecker
2. Mechanochemical
Strecker reaction
of
reaction
Strecker
reaction of of of
aldehydes,
aldehydes, ketones,
of aldehydes,
reaction
aldehydes, ketones,
and
ketones,
aldehydes,
ketones, and and and
various
ketones, various
amines
various
variousand a. amines
amines
various
amines . . .
. amines

Entry Carbonyl Compound Amine -aminonitrile 3aj Imine 4aj

b
Yield [3:4] (%) b
Entry Carbonyl
Entry CarbonylCompound
Compound Amine -aminonitrile 3aj
-Aminonitrile 3aj ImineImine4aj 4ajYield [3:4] (%)b[3:4]
Yield b
b (%)
Entry
Entry Entry
Entry Entry
CarbonylCarbonyl
Carbonyl Compound
Compound
Carbonyl Compound
Carbonyl
Compound Amine
Compound
Amine Amine
Amine
Amine -aminonitrile
-aminonitrile
-aminonitrile
-aminonitrile
-aminonitrile 3aj 3aj
3aj3ajImine
Imine Imine
4aj
3ajImine
4aj 4aj4aj
Imine Yield Yield
[3:4]
4ajYield
Yield [3:4] (%)b[3:4]
[3:4]
Yield
(%) (%) (%)
[3:4] b b
(%)

a Reaction conditions: carbonyl compound (0.5 mmol), amine (0.5 mmol), KCN (35.8 mg, 0.55 mmol),
a Reaction
a Reaction conditions:
aconditions: carbonyl compound (0.5 mmol), amine (0.5 mmol), KCN (35.8 mg, 0.55 mmol),
a Reaction
aa Reaction
Reaction Reaction
conditions:
conditions: carbonyl
conditions:
conditions:
carbonyl compound
carbonylcarbonyl
compound (0.5
compound mmol),
(0.5
compound
(0.5 mmol), amine
mmol),
(0.5
amine (0.5(0.5
amine
mmol), mmol),
(0.5
amine
mmol), KCN
mmol),
(0.5
KCN (35.8
KCN
mmol),
(35.8 mg,
(35.8
KCN
mg, 0.55
mg,
0.55 mmol),
0.55
(35.8 mg,
mmol), mmol),
0.55
and mmol),
Kraft
and Kraft lignin (250carbonyl
mg) were compound
milled in a(0.5mixermmol),
mill atamine
30 Hz(0.5 for mmol),
3 h using KCN a 10 (35.8 mg, 0.55steel
mL stainless mmol),
milling
and
lignin
and Kraft
(250
and
Kraft and
mg)
KraftKraft
lignin
and
lignin were lignin
(250
lignin
Kraft
(250 mg)
milled
(250 (250
lignin
mg) in
mg)
were amg)
werewere
(250 were
milled
mixer
mg)
milled milled
in
mill
milled
were
in a amilled
mixer a in
mixer
at
in30 Hzamill
inmixer
mixer
mill forat330
aatmill
mixer
30 mill
hHz Hz30at
atusing
mill
for 30
for
Hz
at
3 Hz
3for
ah h
10
30 3for
using
mL
Hz
using 3 10
ah310
using
h1 amL
stainless
hfor
using
a mL 10 astainless
10
steel
using mL mL stainless
steel
milling
stainless
a 10
stainless mL jar steel
milling
with
steel
stainless
steel milling 1milling
ball
milling
steel of
milling
jar with 1 ball of 10 mm in diameter of b the same material; 1
b Determined by H-NMR spectroscopy with
10 jar
mm in with
with
jar diameter
jar
1 with
ball
1
jar of1
ball
withof
10 the
ball
mm
of
1 of
10 same
mm
ball 10
in
of mmmaterial;
in
10 in
diameter diameter
of
diameter
mm in Determined
the
of
diameter of
same
the the
same
of by
same
material;
the same H-NMR
material;
b
material; spectroscopy
b
Determined
b Determined
Determined
material; by 1H-NMR
b Determinedby 1with
by
H-NMR1
by 1,3,5-trimethoxy-benzene
H-NMR spectroscopy
spectroscopy with
spectroscopy
1H-NMR with
spectroscopy with
with
jar with 1 ball of 10 mm in diameter
1,3,5-trimethoxy-benzene of the same
as the internal material; Determined by H-NMR spectroscopy with
standard.
b 1
as 1,3,5-trimethoxy-benzene
the internal standard.
1,3,5-trimethoxy-benzene
1,3,5-trimethoxy-benzene as
1,3,5-trimethoxy-benzenethe
as as the
internal
the as internal
thestandard.
internal standard.
standard.
internal standard.
1,3,5-trimethoxy-benzene as the internal standard.
aReaction
Next, conditions:
in order carbonyl
to further compound
exhibit (0.5 mmol),
the suitability ofamine (0.5 mmol), KCN (35.8
the mechanochemical mg, 0.55
Strecker mmol), we
reaction,
and Kraft lignin (250 mg) were milled in a mixer mill at 30 Hz for 3 h using a 10 mL stainless steel milling
extended the protocol to the reaction between 2-(methoxycarbonyl)benzaldehyde (1j), 2a, and KCN.
jar with 1 ball of 10 mm in diameter of the same material; b Determined by 1H-NMR spectroscopy with
The expected -aminonitrile 3k could in principle undergo a lactamization process in the milling
1,3,5-trimethoxy-benzene as the internal standard.
vessel, leading to the formation of the isoindolinone derivative 6a (Scheme 1) [26].
Molecules 2017, 22, 146 6 of 10
Molecules 2017, 22, 146 6 of 10

Next, in order to further exhibit the suitability of the mechanochemical Strecker reaction, we
Next, in order to further exhibit the suitability of the mechanochemical Strecker reaction, we
extended the protocol to the reaction between 2-(methoxycarbonyl)benzaldehyde (1j), 2a, and KCN.
extended the protocol to the reaction between 2-(methoxycarbonyl)benzaldehyde (1j), 2a, and KCN.
The expected
Molecules 2017, 22,-aminonitrile
146 3k could in principle undergo a lactamization process in the milling
6 of 10
The expected -aminonitrile 3k could in principle undergo a lactamization process in the milling
vessel, leading to the formation of the isoindolinone derivative 6a (Scheme 1) [26].
vessel, leading to the formation of the isoindolinone derivative 6a (Scheme 1) [26].

Scheme 1.
Scheme 1. Mechanosynthesis of N-benzylphthalimide
Mechanosynthesis of
of N-benzylphthalimide (5a)
(5a) and
and isoindolinone
isoindolinone (6a).
(6a).
Scheme 1. Mechanosynthesis N-benzylphthalimide (5a) and isoindolinone (6a).

In the presence of Kraft lignin, the milling process instead afforded the N-benzylphthalimide (5a) (5a)
In the presence of Kraft lignin, the milling process instead afforded the N-benzylphthalimide (5a)
(33%). The formation of 5a can be
(33%). be explained
explained as aa result
result of
of aa cyanide-catalyzed
cyanide-catalyzed oxidative amidation of
The formation of 5a can as cyanide-catalyzed oxidative amidation of
the isoindolinone
the isoindolinone6a 6a under the
underthe
6aunder aerobic
theaerobic
aerobicreaction
reaction conditions
conditions(ambient
(ambient atmosphere)
atmosphere) present in the
present ball
inball mill
the mill
ball
isoindolinone reaction conditions (ambient atmosphere) present in the
(Scheme 2)
mill (Scheme [2729]. Next,
2) [2729]. the same reaction was repeated, but this time Zn(OTf) 2 (10 mol%) was added
(Scheme 2) [2729]. Next,Next, the same
the same reaction
reaction was repeated,
was repeated, but
but this thisZn(OTf)
time time Zn(OTf) 2 (10 mol%)
2 (10 mol%) was
was added
in addition
added to Kraft lignin
in addition in the milling vessel. UnderUnder
these conditions, the mechanical milling led to
in addition to Krafttolignin
Kraft in
lignin in the milling
the milling vessel.vessel. these conditions,
Under these conditions, the mechanical
the mechanical millingmilling
led to
the to
led formation of the of
the formation products 5a and 6aand
the products in 34% and
6a inand 31%
34%31% yield
andyield (Scheme
31% (Scheme 1). A control
yield (Scheme reaction
1). A control using
reaction
the formation of the products 5a and5a 6a in 34% 1). A control reaction using
only Zn(OTf)
usingZn(OTf)
2 (10 mol %) as a catalyst showed traces of the products 5a and 6a.
only Zn(OTf)
only 2 (10
2 (10 mol %)mol
as a%) as a catalyst
catalyst showed showed
traces traces
of the of the products
products 5a and5a6a.and 6a.

H CN HO 2 CN HO 2 CN
H CN HO 2 CN HO 2 CN
O2
N Bn O2 N Bn N Bn
N Bn N Bn electron N Bn
electron
transfer
O O transfer O
O O O
6a radical stabilized A
6a byradical stabilized
capto-dative effect A
by capto-dative effect

HO CN O
HO CN O
H 2O
A H 2O N Bn N Bn
A N Bn N Bn
H 2O 2 O HCN O
H 2O 2 O HCN O
5a
5a

Scheme 2. Possible reaction mechanism for the formation of 5a in the ball mill.
Scheme
Scheme 2.
2. Possible
Possible reaction
reaction mechanism
mechanism for
for the
the formation
formation of
of 5a in the
5a in the ball
ball mill.
mill.

3. Materials and Methods

3.
3. Materials
Materials and
and Methods
Methods
3.1. Materials
3.1. Materials
Aldehydes, ketone, amines, and KCN were purchased commercially and used without further
Aldehydes, ketone, amines,
amines, and KCN were purchased commercially and used without further
purification. Cellulose (50 m) was obtained from (J&K Scientific GmbH, Freiburgerstrasse 11, D-75179
purification. Cellulose
Cellulose (50
(50 m)
m) was obtained from (J&K Scientific GmbH, Freiburgerstrasse 11, D-75179
Pforzheim, Germany).
Pforzheim, Germany).
Peanut shell powder was obtained after milling pieces of peanut shells (5 g) in a FRITSCH
Peanut shell powder was obtained after milling pieces pieces of peanut shells (5 g) in a FRITSCH
Planetary micro mill model Pulverisette 7 classic line, using milling vessels made of ZrO2 (45 mL)
Planetary micro mill model Pulverisette 7 classic line, using milling vessels made of ZrO22 (45 (45 mL)
mL)
with five milling balls of the same material (10 mm in diameter) for 30 min at 600 rpm.
with five milling balls of the same same material
material (10
(10 mm
mm inin diameter)
diameter) forfor 30
30 min
min at
at 600
600 rpm.
rpm.
Dioxasolv cherry and oak lignins were extracted following a previously established literature
Dioxasolv cherry and oak lignins were extracted following a previously established literature
procedure [30]. To cherry or oak sawdust (200 g) in a 2 L flask was added 1,4-dioxane (1.5 L) followed
procedure [30]. To cherry or oak sawdust (200 g) in a 2 L flask was added 1,4-dioxane (1.5 L) followed
by the addition of 2 N HCl (0.16 L) solution. The following mixture was heated to a gentle reflux under
by the
the addition
additionofof2 2NN HCl
HCl(0.16 L) L)
(0.16 solution. TheThe
solution. following
followingmixture was heated
mixture to a gentle
was heated reflux under
to a gentle reflux
an N2 atmosphere for 1 hour. The mixture was then cooled down to room temperature, and the lignin-
an N2 atmosphere
under for 1 hour.
an N2 atmosphere forThe
1 h.mixture was then
The mixture cooled
was thendown to room
cooled downtemperature, and the lignin-
to room temperature, and
containing liquor was collected by filtration. The collected liquor was concentrated under vacuum,
containing liquor was collected by filtration. The collected liquor was concentrated
the lignin-containing liquor was collected by filtration. The collected liquor was concentrated under under vacuum,
resulting in a gummy residue, which was then taken up in acetone/water (9:1, 250 mL) and precipitated
resulting in
vacuum, a gummy
resulting inresidue,
a gummy which was then
residue, whichtaken
wasupthen
in acetone/water
taken up in (9:1, 250 mL) and(9:1,
acetone/water precipitated
250 mL)
by the addition to rapidly stirring water (2.5 L). The crude lignin was collected by filtration and dried
by
andthe addition toby
precipitated rapidly stirring to
the addition water (2.5 stirring
rapidly L). The crude
waterlignin was
(2.5 L). Thecollected by filtration
crude lignin and dried
was collected by
under vacuum. The dried crude lignin was taken up in acetone/methanol (9:1) and precipitated by
under vacuum. The dried crude lignin was taken up in acetone/methanol (9:1) and
filtration and dried under vacuum. The dried crude lignin was taken up in acetone/methanol (9:1) and precipitated by
dropwise addition to rapidly stirring Et2O (2 L). The precipitated lignin was collected by filtration
dropwise addition
precipitated to rapidly
by dropwise stirring
addition Et2O (2stirring
to rapidly L). TheEtprecipitated
2 O (2 L). Thelignin was collected
precipitated by filtration
lignin was collected
by filtration and dried under vacuum to give purified samples of cherry/oak lignin (approximately
20 g). These lignins were used in subsequent experiments without further processing.
Molecules 2017, 22, 146 7 of 10

Organosolv beechwood Lignin (BWL1) was obtained after a pulping process using mixtures of
ethanol and water.
Organosolv beechwood Lignin (BWL2) was extracted from beechwood chips using the following
ethanol-based organosolv process. The lignin was extracted with aqueous ethanol (50% w/w) without
the addition of an acid catalyst. Lignin was then precipitated with water and afterwards washed with
water to remove the residual carbohydrates. The precipitate was sedimented by centrifugation, and
the liquor above decanted. Finally, the lignin was dried and pulverized.
Kraft lignin-370959 was purchased from Sigma-Aldrich (Sigma-Aldrich Co., St. Louis, MO, USA).

3.2. Methods

3.2.1. Monitoring of the reactions and purification of the products

Reactions were monitored by thin-layer chromatography using TLC plates with silica gel 60 on
aluminum with fluorescence indicator F254 from MERCK. Qualitative analysis of the TLC plates was
carried out using UV light ( = 254 nm and = 366 nm) or by immersion in an aqueous solution of
potassium permanganate (KMnO4 ).
Column chromatography was performed using silica gel 60 (4063 m) and distilled grade
solvents (n-pentane/ethyl acetate) as eluent.

3.2.2. Characterization of the Products 3, 4, 5 and 6 (NMR, IR Spectroscopy, MS Spectrometry)

All NMR spectra were recorded on 300, 400, and 600 MHz spectrometers (Varian Mercury 300,
Varian V-NMRS 300 and 600). Proton chemical shifts are reported in parts per million on the scale
and are calibrated using the residual non-deuterated solvent signal as an internal reference: CDCl3
( 7.26 ppm). Carbon chemical shifts are reported in parts per million on the scale and are referenced
to the centermost carbon signal of the deuterated solvent: CDCl3 ( 77.16 ppm). Spectral data is
provided as follows: chemical shift in ppm (from downfield to upfield), multiplicity (s = singlet,
d = doublet, dd = doublet of doublets, t = triplet, br = broad, m = multiplet), coupling constant J in Hz,
and integration. IR-spectra were recorded on a Perkin Elmer 100 FT/IR spectrometer (PerkinElmer Life
and Analytical Sciences, Shelton, 710 Bridgeport Avenue, CT, USA). Mass spectra were acquired on a
Finnigan SSQ7000 (EI (Electron Ionization), 70 eV) spectrometer (Finningan Corporation, Waltham,
MA, USA).

3.2.3. Mechanochemical Synthesis

Caution! Potassium cyanide is toxic and may also release highly toxic hydrogen cyanide.
All operations involving KCN should be conducted in a well-ventilated fume hood.
Typical procedure for the Strecker reaction in the mixer mill: A mixture of the carbonyl compound
(1; 0.50 mmol), amine (2; 0.50 mmol), KCN (35.8 mg, 0.55 mmol), and additive was milled in a 10 mL
stainless steel milling vessel with one stainless steel milling ball of 10 mm in diameter at 30 Hz for
3 h. After the milling was complete, the content of one milling vessel was transferred into a beaker
using a small amount of organic solvent (DCM or ethyl acetate). Then, a known amount of the internal
standard (1,3,5-trimethoxy-benzene) was added, and the mixture was filtered to remove the insoluble
material. Next, the filtrate was evaporated under reduced pressure. The residue was dissolved in
CDCl3 and analyzed by 1 H-NMR spectroscopy to determine the yield. The content of the second
milling vessel was filtered with ethyl acetate, washed with aqueous saturated NaHCO3 solution and
brine. The combined organic layers were dried over anhydrous Na2 SO4 , concentrated in vacuum, and
further dried under reduced pressure to give the product.

3.2.4. Capping of Kraft Lignin with Dimethyl Carbonate

Kraft lignin (1 g) was dissolved in dimethyl sulfoxide (20 mL). Then, NaOH (240 mg) and DMC
(6 mL) were added to the above mixture. The reaction mixture was heated at 150 C for 5 h. After this
Molecules 2017, 22, 146 8 of 10

time, the reaction mixture was cooled to room temperature, and then 2 N HCl (100 mL) was added to
the mixture to precipitate the lignin. The precipitated lignin was transferred to a filter, and washed
with water (3 100 mL). The solid residue was then dried overnight under vacuum at 50 C.

3.2.5. 31 P-NMR Spectroscopy

The quantitative 31 P-NMR analysis for the phenolic and the aliphatic hydroxyl groups in
the ligninsboth before and after the DMC capping reactionwere conducted using a standard
phosphorus pulse program following previous literature reports [25]. A weighed amount of
vacuum-dried lignin sample (30 mg) was dissolved in 700 L of an anhydrous solvent mixture
(pyridine:CDCl3 1.6:1, v/v). A cyclohexanol solution (100 L, 10.85 mgmL1 ) was added as an
internal standard along with 100 L of chromium (III) acetylacetonate solution (5.2 mgmL1 ) as
the relaxation reagent. Finally, 100 L of the phosphitylating agent (2-chloro-4,4,5,5-tetramethyl-1,3,2-
dioxaphospholane) was added, and the mixture was transferred into a 5 mm-NMR tube for-NMR
acquisition using 512 scans and a relaxation delay of 10 min on a 300 MHz spectrometer.

4. Conclusions
In summary, we first demonstrated the use of peanut shell powder followed by the cellulose and
lignin components of lignocellulosic biomass as solid promoters for the mechanochemical Strecker
reaction. Out of the set of lignin samples tested, commercial Kraft lignin was found to be the best
activator to enhance the cyanation step of imines in the ball mill. The relationship between the
molecular architecture of lignin and its catalytic activity is believed to be highly complex. In this
regard, 31 P-NMR and IR analysis of raw Kraft lignin and methylated (capped) lignin highlighted
the role of the hydroxyl group content in lignin with its ability to facilitate the formation of the
-aminonitriles. Kraft lignin also proved to be very effective at promoting the multicomponent Strecker
reaction between several aldehydes (aromatic, heteroaromatic, and aliphatic), amines, and KCN.
Furthermore, improvement in the separation method of the lignin after the reactionwhich enables
higher recyclability of this additiveis currently ongoing in our group. Finally, the high efficiency
of the mechanochemical approach was further demonstrated during the solvent-free synthesis
of the N-benzylphthalimide (5a) and the isoindolinone (6a) through a one-pot three-component
Strecker-lactamization catalyzed by the system Zn(OTf)2 -Kraft lignin in the ball mill.

Supplementary Materials: The following are available online at: http://www.mdpi.com/1420-3049/22/1/146/

s1, Figure S1S2 and characterization of the products 3aj, 5a and 6a.
Acknowledgments: This research was supported by the Distinguished Professorship Program at RWTH Aachen
University funded by the Excellence Initiative of the German federal and state governments (C.B., J.G.H.) and
by the European Union (Marie Curie ITN SuBiCat PITN-GA-2013-607044, S.D.). We are grateful to Nicholas J.
Westwood for supplying CL and OL samples, and to Moritz Leschinsky for supplying the BWL1 sample.
Author Contributions: Saumya Dabral, Mathias Turberg, Andrea Wanninger, Carsten Bolm and
Jos G. Hernndez conceived and designed the experiments; Saumya Dabral and Jos G. Hernndez performed
the experiments; Saumya Dabral and Jos G. Hernndez analyzed the data; Saumya Dabral, Mathias Turberg,
Carsten Bolm and Jos G. Hernndez wrote the paper. All the authors contributed and approved the manuscript.
Conflicts of Interest: The authors declare no conflicts of interests.

Abbreviations
BWL Beachwood lignin
C Cellulose
CKL Capped Kraft lignin
CL Cherry lignin
DMC Dimethyl carbonate
IS Internal standard
KL Kraft lignin
LAG Liquid assisted grinding
OL Oak lignin
PSP Peanut shell powder
Molecules 2017, 22, 146 9 of 10

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Sample Availability: Not available.

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