Mechanochemical solid state synthesis of copper(I)/NHC complexes with K3PO4 [original]

440

Mechanochemical solid state synthesis of copper(I)/NHC

complexes with K3PO4

Ina Remy-Speckmann‡1, Birte M. Zimmermann‡1, Mahadeb Gorai2, Martin Lerch1

and Johannes F. Teichert*2

Letter Open Access

Address:

1Institut für Chemie, Technische Universität Berlin, Straße des

17. Juni 115, 10623 Berlin, Germany and 2Fakultät für

Naturwissenschaften, Technische Universität Chemnitz, Straße der

Nationen 62, 09111 Chemnitz, Germany

Email:

Johannes F. Teichert* - [email protected]

* Corresponding author ‡ Equal contributors

Keywords:

ball mill; bifunctional catalysis; catalytic hydrogenations; copper;

mechanochemical synthesis; N-heterocyclic carbenes

Beilstein J. Org. Chem. 2023, 19, 440–447.

https://doi.org/10.3762/bjoc.19.34

Received: 04 December 2022

Accepted: 06 April 2023

Published: 14 April 2023

Associate Editor: J. G. Hernández

License and terms: see end of document.

Abstract

A protocol for the mechanochemical synthesis of copper(I)/N-heterocyclic carbene complexes using cheap and readily available

K3PO4 as base has been developed. This method employing a ball mill is amenable to typical simple copper(I)/NHC complexes but

also to a sophisticated copper(I)/N-heterocyclic carbene complex bearing a guanidine moiety. In this way, the present approach

circumvents commonly employed silver(I) complexes which are associated with significant and undesired waste formation and the

excessive use of solvents. The resulting bifunctional catalyst has been shown to be active in a variety of reduction/hydrogenation

transformations employing dihydrogen as terminal reducing agent.

440

Introduction

Prominent goals of green chemistry heralded for synthetic

chemistry are minimization or ideally the complete prevention

of chemical waste. In this vein, the use of innocuous chemicals,

replacement of hazardous reagents, atom efficient reactions and

overall safer chemical processes are desirable [1,2]. Therefore,

one current challenge for syntheses is the development of green

and environmentally friendly routes to access value-added prod-

ucts.

One important way to more economical syntheses is the concept

of catalysis to avoid stoichiometric amounts of reactants and to

design reactions more atom efficient [1-3]. However, the focus

has seldomly been on the preparative methods to access the re-

quired catalysts themselves. As case in point, we decided to

re-investigate the synthesis of copper(I)/N-heterocyclic carbene

(NHC) complexes, which are broadly applicable catalysts for a

wide variety of transformations [4-6]. While generally there are

many different synthetic routes to transition metal/NHC

complexes [7-15] not all of them are applicable to the prepara-

tion of copper(I)/NHC compounds (Scheme 1) [5,6,13,16-19].

Generally, the so-called direct routes via the appropriate

imidazol(in)ium salt, a copper precursor and a suitably strong

Beilstein J. Org. Chem. 2023, 19, 440–447.

441

Scheme 2: Preparation of sophisticated Cu(I)/NHC complexes: Synthesis of bifunctional catalyst 5 via transmetallation. Mes = mesityl [48,49].

Scheme 1: General synthetic routes to copper(I)/NHC complexes

(X = Cl, Br).

base (e.g., NaH, NaOt-Bu, KHMDS or n-BuLi) [20-26] are

challenging for copper complexes 2 as they tend to give low

yields (Scheme 1a) [5,6,13,16-19]. One elegant protocol em-

ploying K2CO3 as weak base in combination with copper(I)

salts for simple copper(I)/NHC complexes has been disclosed

(Scheme 1b) [27]. While this variant is the method of choice

due to its simplicity and practicability, other alternatives have to

be sought in cases where these direct synthesis approaches fail:

On the one hand, the so-called “built-in base” route relies on the

use of Cu2O which can be directly reacted with a suitable NHC

precursor 1 (Scheme 1c) [28]. In any case, the most common

approach hinges upon the use of the preliminary preparation of

an intermediate silver(I)/NHC complex followed by facile

transmetallation to copper(I) (Scheme 1d). In some cases, this

transmetallation step is carried out in situ [14,15,29-32].

Notably, these generally successful synthetic routes produce a

considerable amount of transition metal waste (next to the

inherent use of solvents) and are therefore in misalignment with

the principles of green chemistry.

Syntheses via mechanochemical methods offer elegant and

atom-economic alternatives to liquid state synthesis approaches

[33-43]. In accordance with the in situ transmetallation route in

liquid state synthesis, a one-pot two-step procedure in a ball

mill was discovered (Scheme 1e) [44]. The possibility of

synthesizing copper(I)/NHC complexes in the ball mill is prom-

ising due to the avoidance of organic solvents. Direct ap-

proaches from the NHC-precursor to the copper(I)/NHC com-

plex not undergoing the transmetallation step have been

disclosed (Scheme 1f) [45-47]. These approaches are an elegant

alternative to the transmetallation route performing without

unwanted transition metal waste. Two possible direct

mechanochemical pathways have been presented for the synthe-

sis of copper(I)/NHC complexes: First, the complexes can be

synthesized by milling the ligand precursor 1 with metallic

copper powder in air [45]. Another mechanochemical pathway

was published using K2CO3 as a base and copper(I) chloride

[46,47]. This latter procedure is practical, avoids the use of sol-

vents, and relies on an abundant and cheap base.

We have recently disclosed an ester reduction with H2 as termi-

nal reducing agent utilizing bifunctional copper(I)/NHC com-

plex 5 bearing a guanidine moiety as additional catalytic unit

[48]. This catalyst acts by employing the copper(I)/NHC com-

plex for H2 activation on the one hand and by using the guani-

dine subunit for simultaneous organocatalytic activation of the

ester on the other hand. Following a previously established syn-

thetic pathway [49], we have found that transmetallation via

silver(I)/NHC complex 4 was the only viable synthetic entry

point to this sophisticated bifunctional catalyst (Scheme 2)

Beilstein J. Org. Chem. 2023, 19, 440–447.

442

Table 1: Attempted direct synthesis of bifunctional catalyst 5 from imidazolinium salt 3: liquid and solid state approaches.

Entry Reagents Conditions Results

Liquid state aproaches [20]

1 strong bases 1.00 equiv 3, 1.10 equiv CuCl,

3.00 equiv n-BuLi THF, 0 °C → rt, 16 h no formation of 5

2 1.00 equiv 3, 1.10 equiv CuCl,

1.05/2.00/3.00/5.00 equiv NaOt-Bu THF, rt, 16 h no formation of 5

3 weak bases 1.00 equiv 3, 1.10 equiv CuCl,

3.00 equiv NEt3

THF, 0 °C → rt, 16 h no formation of 5

4 1.00 equiv 3, 1.00 equiv CuCl,

2.00 equiv K2CO3

acetone, 60 °C, 16 h formation of catalytically

inactive 5∙CO2

5 1.00 equiv 3, 1.00 equiv CuCl,

2.00 equiv K3PO4

acetone, 60 °C, 16 h no formation of 5

6 “built-in base”

approach 1.00 equiv 3, 2.0 equiv Cu2O CH2Cl2, 4 Å MS, 60 °C, 16 h no formation of 5

Solid state approaches (steel vessel (12 mL), 6 steel balls (1 cm diameter) if not noted otherwise)

7 strong bases 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv NaOt-Bu 450 rpm, 4 h no formation of 5

8 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv NaOH 450 rpm, 4 h no formation of 5

9 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv KHMDS 450 rpm, 4 h no formation of 5

10 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv NaH gastight zirconia vessel

(45 mL), 6 zirconia balls

(1.5 cm diameter), 450 rpm,

4 h

formation of 5 observed,

inseparable mixture of

products

11 no added base

[46] 1.0 equiv 3, 1.0 equiv CuCl 450 rpm, 4 h formation of [3][CuClBr]–

observed by HRMS

12 “built-in base”

approach 1.0 equiv 3, 0.5 equiv Cu2O 450 rpm, 4 h no formation of 5

13 weak base 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv K2CO3

450 rpm, 4 h 44% of 5

14 1.0 equiv 3, 1.0 equiv CuCl,

1.5 equiv K3PO4

450 rpm, 4 h 91% of 5

[10,12,14,50]. First, the silver(I)/NHC complex 4 had to be syn-

thesized and isolated prior to transmetallation with copper(I)

chloride [48,49]. The required formation of silver(I) complex 4

diminishes the overall yield of copper complex 5. As an addi-

tional disadvantage, the silver(I) byproducts have to be care-

fully removed in order to maintain reproducible results in

subsequent catalytic hydrogenations [48]. We deemed this syn-

thetic route unattractive with regards to sustainable synthesis

due to the silver waste generated in the process and sought to

replace the transmetallation route with a more atom economic

approach to circumvent these problems.

Results and Discussion

We therefore examined different approaches to avoid the trans-

metallation step (4→5) and to establish a protocol for the direct

synthesis of 5 in solution from imidazolium salt 3 (Table 1,

liquid state approaches) [48]. The use of strong bases such as

n-BuLi or NaOt-Bu (in various equivalents, Table 1, entries 1

and 2) or weak bases (Et3N, K2CO3 or K3PO4, Table 1, entries

3–5) either did give no conversion to 5 at all or delivered a cata-

lytically inactive complex, which we assign to a CO2 adduct of

5 (Table 1, entry 4) [51,52]. We hypothesize that in this CO2

adduct, the guanidine moiety is unavailable to perform its

Beilstein J. Org. Chem. 2023, 19, 440–447.

443

assisting part in catalysis through hydrogen-bonding interaction

[48]. As additional evidence to support the formation of the

CO2 adduct of 5, we can show that bubbling of CO2 through a

solution of 5 leads to catalytically inactive complexes (see Sup-

porting Information File 1 for details). This also supports the

notion that during catalytic ester hydrogenation, the guani-

dinium moiety acts as a hydrogen bond donor to the esters [48].

The formation of a CO2 adduct hinders the ability to form

hydrogen bonds. Furthermore, utilizing Cu2O for a “built-in

base” approach did not give complex 5 (Table 1, entry 6).

Since our attempts to establish direct synthetic routes to 5 from

3 in liquid state were not fruitful, we turned our attention to the

mechanochemical synthesis of bifunctional catalyst 5, based on

two recent reports on preparation of copper(I)/NHC complexes

[45,47].

All mechanochemical syntheses were carried out in a planetary

ball mill and the vessel was loaded in an argon-filled glovebox.

Copper(I) chloride, imidazolium salt 3 and the appropriate base

were mixed (in a molar ratio of 1.0:1.0:1.5, respectively) and

ground for 4 hours. Afterwards purification included dissolving

the crude product in CH2Cl2, filtration over a PTFE syringe

filter and concentrating the filtrate under reduced pressure. Em-

ploying strong bases such as KHMDS, NaOt-Bu or NaOH did

not lead to the desired product (Table 1, entries 7–9). All three

approaches have in common that the conjugated acid of the

added base is a liquid. In the literature, the improvement of

mechanochemical syntheses by addition of small amounts of a

liquid have been reported (LAG, liquid-assisted grinding) [43].

However, in our case, the formation of small amounts of

liquid during the milling process lead to agglutination

of the remaining solids and therefore insufficient homo-

genization of the reaction mixture. This gave a mixture of com-

pounds, in which the envisaged complex 5 could not be identi-

fied.

A different approach was made using sodium hydride as a base

(Table 1, entry 10). Instead of small amounts of liquid, here, de-

protonation leads to the formation of dihydrogen. Hence,

another gastight mill was utilized for this approach. Unfortu-

nately, a successful synthesis of 5 directly from 3 was not

possible under these conditions: NMR analysis of the resulting

mixture indicated the presence of 5, but also of unwanted side-

products that could not be identified. Purification of 5 from

this complex mixture turned out not to be feasible. Further

modifications of the milling conditions did not lead to the elimi-

nation of these side-products, therefore the experiments with

NaH as a base were discontinued. As a side comment, the addi-

tion of no base at all led to the formation of the imidazolinium

cuprate ([3][CuClBr]−, Table 1, entry 11) [46]. The direct

transition of the “built-in base” approach conditions to

mechanochemical synthesis (copper(I) oxide and imidazolium

salt 3 as starting materials), lead to no formation of 5 (Table 1,

entry 12).

The use of K2CO3 for the mechanochemical synthesis of

copper(I)/NHC complexes [46,47] was feasible for the prepara-

tion of 5 (Table 1, entry 13). Importantly, we found that

extending on this concept also K3PO4 could be employed

equally well while giving significantly higher yields than the

previous protocol [46,47] (Table 1, entry 14). All of the ap-

proaches discussed here are attractive due to the use of

copper(I) chloride as the copper source. Interestingly, the use of

K2CO3, which led to the formation of a catalytically inactive

postulated CO2 adduct of 5 in the liquid state synthesis, did lead

to catalytically active 5 in the mechanochemical approach. In a

similar vein, the different outcome with K3PO4 as a base (which

led to no catalytically active complexes in the liquid state syn-

thesis) was surprising, as in the ball mill, clean and catalytical-

ly active copper(I) complex 5 was obtained. To avoid the

possible formation of the catalytically inactive CO2 adduct

when employing K2CO3 for the synthesis of 5 we decided to

use K3PO4 for subsequent investigations (see also below,

Table 2). Even though the imidazolium bromide salt 3 was em-

ployed in combination with CuCl as copper(I) precursor,

elemental analysis of 5 clearly supported the formation of 5 as a

chloride salt (see Supporting Information File 1).

For the optimized protocol, the starting materials were mixed in

a steel vessel and ground at 450 rpm for a total time of four

hours. After ball milling, an off-white powder was obtained

which gave complex 5 in very good yield of 91% after extrac-

tion with CH2Cl2 and filtration. NMR analysis of 5 matched

previously reported data [48,49] and showed no side products.

It has to be mentioned that complex 5 synthesized via the

mechanochemical route is isolated as a CH2Cl2 adduct

(5/CH2Cl2 = 1:1) as confirmed by NMR spectroscopy and

elemental analysis. If complex 5 is formed via the liquid state

synthesis [48,49], also a CH2Cl2 adduct is isolated, albeit with a

5/CH2Cl2 ratio of 2:1.

In order to demonstrate the general applicability of the K3PO4-

based protocol for the mechanochemical synthesis of copper(I)/

NHC complexes, we decided to prepare the most common

copper(I)/NHC complexes 7a–d [5,6] employing our method

(Table 2). When the corresponding imidazoli(ni)um salts 6a–d

were submitted to the standard protocol, complexes 7a–d were

obtained with acceptable yields, with similar yields compared to

previous methods. In some cases, the homoleptic cationic

copper(I) complexes [(NHC)2Cu]+CuCl2− were observed as

side products [48,53].

Beilstein J. Org. Chem. 2023, 19, 440–447.

444

Table 2: Synthesis of standard Cu(I)/NHC-complexes using K3PO4 as a weak base (standard procedure: steel vessel (12 mL), 6 steel balls (1 cm di-

ameter), 450 rpm, 4 h). (dimer = [(NHC)2Cu+]Cl−).

Complex Yield Cu(0)/O2 [45] CuCl/K2CO3 [46]

[Cu(IMes)Cl] (7a) 71% (8% homoleptic cationic Cu(I) complex) 85% 65%

[Cu(SIMes)Cl] (7b) 73% 76% 53%

[Cu(IPr)Cl] (7c) 63% 82% 78%

[Cu(SIPr)Cl] (7d) 64% (12% homoleptic cationic Cu(I) complex) 65% 66%

We decided to directly compare complex 5 from mechanochem-

ical synthesis (5bm) with its counterpart from the liquid state

transmetallation route (5ls) in catalysis. We found that 5bm was

catalytically active, however displaying slightly diminished

activity in general most likely due to different adduct ratio

inhibiting the catalytic activity (Scheme 3). This was estab-

lished using the standard reactions for catalytic hydrogenations

with copper(I)/NHC complexes [4]. In this vein, we tested

complex 5 from solid and liquid phase synthesis in the catalytic

hydrogenation of esters, carbonyl compounds and in the

semihydrogenation of alkynes. In the catalytic hydrogenation

of ethyl benzoate (8) lower overall conversion to benzyl alcohol

(9) and lower yield was found with 5bm (65% conv.

and 53% yield with 5bm, in comparison to 100% conv.

and 80% yield with 5ls; Scheme 3a). We hypothesize that the

higher amount of CH2Cl2 as part of the prepared complex,

which is not a suitable solvent for catalytic ester reduction

with H2 [48], led to lower catalyst activity. Possible coor-

dination of residual phosphate to the guanidine moiety was

excluded as analysis by 31P NMR experiments. The copper(I)-

catalyzed 1,2-reduction of functionalized ester 10 was also suc-

cessfully achieved using the ball mill synthesized bifunctional

catalyst 5bm, again with slightly diminished yields and conver-

sions.

Application of the ball mill-synthesized complex 5bm in the

alkyne semihydrogenation of tolane (12) gave (Z)-stilbene (13)

with full stereoselectivity in good yield (86%, Scheme 3b).

Noteworthy, the complex 5 was never evaluated in this re-

ported reaction. Therefore, 5bm behaves similarly to other

copper(I)/NHC complexes in this transformation [54-60]. The

catalytic 1,2-reduction of carbonyl compounds is mainstay for

copper(I)/NHC complexes [61-67], which is why we also tested

5bm in these transformations: The 1,2-reduction of benzalde-

hyde (14) and acetophenone (15) proceeded with good yields

Scheme 3: Application of bifunctional catalyst 5 in copper(I)-catalyzed

hydrogenations: comparison of 5 prepared by solid state/ball milling

(5bm) and liquid state (5ls) synthesis. Standard conditions: Substrate

(0.40 mmol), 10 mol % 5, 1.1 equiv NaOt-Bu, 1.3 equiv 15-crown-5,

100 bar H2, 1,4-dioxane (3 mL), 70 °C, 24 h.

Beilstein J. Org. Chem. 2023, 19, 440–447.

445

(Scheme 3c). No aldol addition for the acetophenone substrate

has been observed although working under strongly basic

conditions [68,69].

Conclusion

In conclusion, we have disclosed a practical approach to a

sophisticated bifunctional copper(I)/NHC complex based on a

mechanochemical protocol. This operationally simple synthetic

route circumvents the previously necessary use of surplus tran-

sition metal reagents and therefore diminishes unwanted waste

formation. The new protocol presented here is based on K3PO4

and has successfully displayed the activity of the resulting cata-

lyst in a variety of hydrogenative transformations. We show that

the new protocol is also amenable to the synthesis of other stan-

dard copper(I)/NHC complexes. Our results do not only add to

the wide area of applications of mechanochemical synthesis but

also showcase that transition metal complexes bearing addition-

al functional groups can be prepared with a ball milling synthe-

sis. We think that our protocol could be useful for the atom

economic preparation of other complex catalysts, which are

difficult or wasteful to be prepared by typical liquid state syn-

thesis methods.

Experimental

Mechanochemical synthesis procedure for 5: The product was

synthesized using a Fritsch Pulverisette 7 classic line, a high-

energy planetary ball mill. The starting materials 1-(2-(2,3-

diisopropyl-1-methylguanidino)ethyl)-3-mesityl-1H-imidazol-

3-ium bromide (3, 75 mg, 0.16 mmol, 1.0 equiv), CuCl (17 mg,

0.16 mmol, 1.0 equiv) and K3PO4 (53 mg, 0.25 mmol,

1.5 equiv) were filled into a 12 mL steel vessel equipped with

six steel balls (1 cm diameter). The beaker was sealed in an

argon-filled glovebox. Milling was carried out with 450 rpm for

a total of four hours. After each hour the milling was paused for

30 minutes to avoid overheating of the machine. The raw prod-

uct was obtained as an off-white powder after milling. The

ground product was mixed with CH2Cl2 (3 mL) and the result-

ing suspension was filtered over a PTFE syringe filter

(0.45 μm). The filtrate was concentrated under reduced pres-

sure. The product 5 was obtained as the CH2Cl2 adduct as a

colourless solid (86 mg, 0.15 mmol, 91%).

Supporting Information

Supporting Information File 1

General procedures, experimental details, analytical data

and copies of NMR spectra.

[https://www.beilstein-journals.org/bjoc/content/

supplementary/1860-5397-19-34-S1.pdf]

Acknowledgements

Prof. Dr. Martin Oestreich (TU Berlin) is kindly thanked for

generous support. Some parts of this work have been published

in the dissertation theses by Dr. Birte M. Zimmermann and Dr.

Ina Remy-Speckmann (both TU Berlin).

Funding

This research was funded by the Deutsche Forschungs-

gemeinschaft (DFG, German Research Foundation) under

Germany’s Excellence Strategy EXC 2008-390540038-

UniSysCat, and through an Emmy Noether Fellowship for

J.F.T. (TE1101/2-1). M.G. is supported by a fellowship by the

Einstein Center for Catalysis (EC2).

ORCID® iDs

Johannes F. Teichert - https://orcid.org/0000-0003-1043-8092

Preprint

A non-peer-reviewed version of this article has been previously published

as a preprint:

https://chemrxiv.org/engage/chemrxiv/article-details/6166e9398b620d14b4

4e0c13

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