Aerobic CuCl2-Catalyzed Dehydrogenative Cross-Coupling of Tertiary

Subscriber access provided by Drexel University Libraries

A: Spectroscopy, Molecular Structure, and Quantum Chemistry 2

Aerobic CuCl-Catalyzed Dehydrogenative Cross-Coupling of Tertiary Amines. A Combined Computational and Experimental Study Pierpaolo Morgante, Stefano Dughera, and Giovanni Ghigo J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.9b00324 • Publication Date (Web): 12 Mar 2019 Downloaded from http://pubs.acs.org on March 21, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Aerobic CuCl2-Catalyzed Dehydrogenative Cross-Coupling of Tertiary Amines. A Combined Computational and Experimental Study

Pierpaolo Morgante,# Stefano Dughera,* Giovanni Ghigo* Dipartimento di Chimica, Università di Torino Via Giuria 7, 10125 Torino, Italy. * Address correspondence to either author: [email protected] (G. Ghigo, Phone +39-0116707872), [email protected] (S. Dughera, Phone +39-011-6707645) # Present address: Chemistry Program, Florida Institute of Technology, 150 W. University Boulevard, 32901, Melbourne, FL (USA)

Abstract The generation of an iminium from amines is a way to functionalize the α carbon by coupling reactions. The reaction mechanism of the conversion of tertiary amines to iminium with CuCl2(H2O)2 as catalyst in aerobic conditions has been computationally and experimentally studied in this work. This process is initiated by the oxidation of the amine to a radical cation dichlorocuprate through the reduction of CuII to CuI. Then, the iminium dichlorocuprate is generated from the radical-ion through a hydrogen-transfer. The H atom can be accepted by molecular oxygen or by a second molecule of catalyst (in anaerobic conditions). Therefore, O2 also assumes the important role of acceptor along with that of regenerator of the catalyst. The experimental study confirmed the computational study and lead to the synthesis of four new molecules from the cross-coupling of N,N-diethyl- and N,N-diisoproylaniline with nitromethane and dimethylmalonate.

1 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 49

Introduction. The selective activation of carbon-hydrogen (C‒H) bond for coupling reaction, is an important goal in organic chemistry, and it has been widely utilized in the syntheses of nitrogen-containing drugs, natural products, and biologically active compounds. 1 - 8

C‒H bonds are relatively inert, and since they are ubiquitous in

organic molecules, selectivity issues may arise.

The presence of an activating

group near the C-H bond to be activated offers some possibilities to circumvent them. Among the several alternatives, we are focused on the activation of the C‒H bonds in the α-position to the nitrogen atom in tertiary amines. 9 - 1 4

In fact, their

cross-coupling with nucleophiles is an important carbon‒carbon bond-forming reaction. The reaction (Scheme 1) is supposed to proceed with the generation of an iminium (or some activated metal‒complex of the imine) intermediate from the amine. 1 5 - 1 9 In the following steps, this cation reacts with a suitable nucleophile HNu as in the traditional Mannich reaction.

Scheme 1. Common mechanistic suggestion for metal-catalyzed oxidative cross-coupling of tertiary amines. In the Mannich reaction, the iminium is generated starting from an imine, while in the oxidative mechanism the cation is generated by oxidation of the amine with an oxidant and in presence of a catalytic metallic cation.

Several transition metals

(Pd, Ni, Co, and many more) have been used. 5 , 2 0 , Nevertheless, some variants without metallic catalyst have been developed. 2 1 .

Since the seminal papers

published by Miura and Murahashi 2 2 , 2 3 but most importantly after the work by Li and Li, 1 7 the non-toxic, less expensive copper seems to be the most used catalyst. 6 , 1 4 , 2 4

Along with it, tert-butyl hydroperoxide and dichlorodicyano-

benzoquinone (DDQ) are the most used oxidants. hazardous.

However, they are toxic or

This fact seriously limits their applications.

Molecular oxygen, is

instead safe, eco-friendly, and less expensive. Thus it has been proposed 1 8 , 2 5 - 2 7 as a valid alternative. 2 8 , 2 9 In this work, we are focused on the mechanism of the cross-coupling of tertiary amines catalyzed by CuCl 2 in the presence of molecular oxygen. Among the most relevant contributions to this matter, special mention goes to Klussmann and co2 ACS Paragon Plus Environment

Page 3 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

workers,


who

focused

their

phenyltetrahydroisoquinoline

as

attention tertiary

on

the

cross-coupling

amine. 3 0 - 3 2

The

general

using

N-

reaction

mechanism for this amine with a nucleophile H‒Nu is illustrated in Scheme 2.

Scheme 2. Mechanism of the Cu-catalyzed aerobic oxidative coupling of Nphenyltetrahydroisoquinoline 1. While the reaction of the iminium 2 with the nucleophile to generate the final product 3 (STEP 2) does not present particular mechanistic challenges, the generation of the iminium (STEP 1) still needs to be clarified (ref. 2, par. 11.2.4). In 2011 3 0 Klussmann and co-workers determined the X-ray structure of iminium 2, thus demonstrating its the existence of the generated by the dehydrogenative oxidation of N-phenyltetrahydroisoquinoline 1 of its salt with CuCl 2 - as counterion (see Fig. 1, ref. 30).

They also observed an equilibrium among 2, the

methylhemiaminal 4, and the hemiaminal 5 influenced by the reactivity of the nucleophile. They isolated 4 and 5 and concluded that they should act as reservoir of the iminium 2 according to Scheme 3.

Scheme 3. The iminium 2 and its derivatives (the methylhemiaminal 4 and the hemiaminal 5) generated by the dehydrogenative oxidation of N-phenyltetrahydroisoquinoline. The discovery of Cu I in the counter-ion of the salt 2 and the formation (as precipitate) of Cu I I Cl(OH) in the reaction medium ‒ generated by the oxidation of Cu I by O 2 ‒ suggested the role of CuCl 2 as oxidant. The reaction between 1 and CuCl 2 was also performed without O 2 .

The observation that the salt 2 was

generated even without any other oxidant than CuCl 2 suggested a mechanism in two steps (Scheme 4). In the first step a Single Electron Transfer (SET) from the amine to copper would generate the radical cation 6 with CuCl 2 - as counterion. 3 ACS Paragon Plus Environment


Page 4 of 49

The C‒H cleavage would take place in the second step through a second SET followed or preceded by a proton transfer or through a Hydrogen Atom Transfer (HAT).

Scheme 4. Proposed mechanism for the generation of iminium 2 from N-phenyltetrahydroisoquinoline 1. As further support for this mechanism Klussmann and co-workers reported a primary intramolecular Kinetic Isotope Effect (KIE) k H /k D = 4.5. 3 1 Initially, this result was interpreted as an indication that the first SET should be a fast process. Later, Klussmann and co-workers 3 2 admitted that their result only proves that the C‒H cleavage is the product-determining step but it cannot confirm whether this is also the rate-determining step or not. Other KIE experiments confirmed that the C‒H cleavage cannot be the rate-determining step. However, these results are still in agreement with the mechanism shown in Scheme 4.

In their 2014 paper

Klussmann and co-workers 3 2 also reported a detailed kinetic study of the reaction (Scheme 2) collecting interesting and, in part, surprising data. The reaction order for CuCl 2 was find slightly larger than the unit (1.25) while it is substantially lower than the unit (0.45) for the amine.

Also the reaction order of the

nucleophile (a silyl enol ether) was find almost null (0.2) confirming that the formation of the iminium is the rate-determining step of the whole reaction.

In

this hypothesis, the role of molecular oxygen would be confined to the regeneration of the catalyst through the oxidation of Cu I to Cu I I . The SET step was suggested by other authors both in the reaction of 1 3 3 as well as of other systems like N,N-dimethylaniline. 2 2 , 2 3 , 3 4

The presence of the radical

cation 6 was confirmed by the observation of an EPR signal. Its g value (2.014) is interpreted as an indication of a radical predominantly centered at the nitrogen atom. If it was centered at the carbon atom, it should show a lower value of g (2.002). 3 5 To the best of our knowledge, only three papers report the computational study of this reaction involving N-phenyltetrahydroisoquinoline: the first one is by Cheng and co-workers, 3 6 the second is by Klussmann, Thiel and co-workers, 3 7 the third one by Chan, Todd and co-workers. 3 8

The first one studies the substrate in 4

ACS Paragon Plus Environment

Page 5 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


different reaction conditions: with CuBr as an oxidant with and without molecular oxygen, with the SET followed by a HAT, and viceversa. Among all the pathway explored, the one involving a SET and then the hydrogen atom abstraction seems Following the conclusions of Klussmann’s 2012 paper, 3 1

to be the most likely.

Thiel and co-workers 3 7 proved that in presence of tert-butylhydroperoxide as oxidant, the reaction could proceed through a HAT, instead of through the production of a radical-cation. No copper catalysis was taken into account. In the work of Chan, Todd, and co-workers 3 8 copper was not taken into account, and the oxidant used was DDQ. In contrast to the previous study, the authors proved the occurrence of the SET followed by the HAT, both by experimental and computational data.

In this work, Chan and co-workers showed that different

substituted aryl amines undergo the same reaction, exhibiting about the same mechanism. To the best of our knowledge, nobody explored the reactivity of differently substituted amines. In conclusion, the previous studies demonstrated (not surprisingly) that different catalysts or different reaction conditions lead to different reaction mechanisms as well.

Therefore, the conclusions drawn for a particular system cannot be easily

extended to other ones. The general mechanism for the formation of the iminium from N-phenyltetrahydroisoquinoline using O 2 as oxidant and CuCl 2 as catalyst shown in Scheme 4 still has some points that need to be clarified. Interestingly, two of the previously published studies 3 6 , 3 7 did not explored the formation of the radical cation 6, and more importantly, neither of them determined which species actually takes the hydrogen atom. In addition, the role of molecular oxygen could be more important that just regenerating the catalyst through the oxidation of Cu I to Cu I I . To shed light on all the previous points, we performed a computational study of the reaction mechanism for the generation from the iminium from tertiary amines using CuCl 2 as catalyst (actually, the real catalyst, i.e. the planar square complex with water, CuCl 2 (H 2 O) 2 ) and molecular oxygen as oxidant.

The study will

include N-phenyltetrahydroisoquinoline and other tertiary amines (see below).

Results and Discussion. We began our computational mechanistic study with a preliminary screening of different tertiary amines.

We wanted to explore the Potential Energy Surface

(PES) of the reaction as accurately as possible while keeping the structure as small 5 ACS Paragon Plus Environment


Page 6 of 49

as possible in order to save time and effort. The only guideline we had was on the reaction energies: we wanted the reaction energy of our models to be as close as possible to that of N-phenyltetrahydroisoquinoline. We also defined two key steps as reported in Scheme 4: the first one, equation 1 (Scheme 5), is the generation of the radical cation of the amine, which involves a SET from the amine to copper, and the second (equation 2) is the generation of the iminium ion. The overall reaction is equation 3.

Scheme 5. Key steps (see also Scheme 4). Among

the

seven

tertiary

amines

tested

(the

data

can

be

found

in

the

Supplementary Information, section 2), triethylamine was the one that best matched our initial requirement. The generation of the radical-cation. The first process for the generation of the iminium from triethylamine is the SET, as reported in eq. 4. (CH 3 CH 2 ) 3 N + CuCl 2 (H 2 O) 2 → (CH 3 CH 2 ) 3 N . + CuCl 2 - + 2 H 2 O

eq. 4

As said above, the catalyst is the planar square aquo-complex CuCl 2 (H 2 O) 2 .

Our

calculated molecular and electronic structures for this species are in agreement with experimental data 3 9 (see also the Supplementary Information, section 3). Because the counterion of the iminium is CuCl 2 - we assume that this species is also the counterion of the radical-cation formed in this step. The study of the PES led us to describe this process as a sequence of Cu‒O bond breaking followed by 6 ACS Paragon Plus Environment

Page 7 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the removal of two water molecules, as described in Scheme 6 (energy values and structures can be found in the Supplementary Information, section 4.1). Therefore, the SET is described as desolvation of copper, coherently with the theory of the solvent reorganization. 4 0 , 4 1 The reactants [ (CH 3 CH 2 ) 3 N and CuCl 2 (H 2 O) 2 , I ] first form the complex II. The first Cu‒O bond breaking takes place through Transition Structure TS I I - I I I forming complex III. In this complex, water is completely dissociated from the copper but it still interacts, via hydrogen bonding, with the two chloride ions. In complex IV, the dissociated water molecule is taken away.

The second water molecule

dissociates from copper through TS I V - V forming the complex V. As for structure III, the water molecule still interacts via hydrogen bonding with a chloride. Then the second water molecule is taken away, having the complex VI (an ion-couple between the radical-cation and CuCl 2 - ). Before the first water molecule leaves III, a second Cu‒O bond breaking (TS I I I - I I I ' ) can take place yielding complex III'. The alternative pathway seems disfavored but the loss of a water molecule generates IV as well.

The spin on the copper and nitrogen atoms, shown in Figure 1, clearly

confirms that this is a SET process.

We can see that in the complex II, the spin

density (S) on copper is 0.61, coherently with the electronic structure d 9 s 0 of Cu I I [while S = 0.99 on CuCl 2 (H 2 O) 2 ]. The S value on copper decreases as the reaction proceeds. On the same time, the spin density on nitrogen increases (initially S = 0.01 in II). In the final structure VI, copper is almost a closed-shell species (S = 0.01) coherently with the electronic structure d 1 0 s 0 of Cu I (S = 0.11 on the CuCl 2 moiety). The nature of radical-cation of the amine moiety in VI is confirmed by a spin density of 0.70 on the nitrogen atom and of 0.20 on the triethyl fragments (so the total S on the radical-cation is 0.90). The acquisition of a negative charge of the CuCl 2 (H 2 O) X moiety is also coherent with the SET: from a value of -0.01 in II it reaches -0.88 in VI where it is now the counter-ion CuCl 2 - of the radical-cation.



Page 8 of 49

Scheme 6. The mechanism for the SET from triethylamine to CuCl 2 (H 2 O) 2 (I) generating the radical-cation dichlorocuprate (CH 3 CH 2 ) 3 N . + CuCl 2 - (VI). The figures show the most relevant bond distances in Ångstroms.


Page 9 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. The atomic spin distributions on the CuCl 2 (H 2 O) X moiety (purple line), on copper (red line), on nitrogen (blue line), and on the three ethyl fragments (green line) during the SET from triethylamine (see Scheme 5 for labels and structures). The corresponding electronic (∆E 0K = ∆E +∆ZPE ) and free (∆G 363K at 90°C) energy profiles are shown in Figure 2. The first step is the formation of the complex of the reactants II which is located 1.1 kcal mol - 1 below the reactants in terms of energy but 7.8 kcal mol - 1 above in term of free energy.

As the picture clearly

shows, the rate determining step for this phase is the overcoming of TS I I - I I I , corresponding to the first Cu‒O bond breaking, and leading to III. The free energy barrier, with respect to II, is 6.5 kcal mol - 1 (∆E 0K‡ = 7.2 kcal mol - 1 ). This step is endoergic both in terms of energy and free energy (∆E 0K = 5.3 and ∆G 363K = 4.2 kcal mol - 1 with respect to II). The first water loss (forming IV + H 2 O) is endoergic in terms of energy (∆E 0K = 2.6 kcal mol - 1 ) but exoergic in terms of free energy (∆G 363K = -5.3 kcal mol - 1 ) because of the entropy gain.

The second Cu‒O bond

breaking is easier and it takes place through TS I V - V I (∆E 0K = 0.5 and ∆G 363K = 0.6 kcal mol - 1 ) generating V (+ H 2 O) which is almost isoergonic with IV + 2 H 2 O (∆E 0K = -0.6 and ∆G 363K = -1.0 kcal mol - 1 ). The second water release leads to the radical-cation dichlorocuprate which is 7.4 kcal mol - 1 above the reactants in terms 9 ACS Paragon Plus Environment


Page 10 of 49

of energy but 3.2 kcal mol - 1 below the reactants in terms of free energy thanks to the favorable entropy factor. In fact, the whole reaction (eq. 7) releases two water molecules.

Figure 2. Energy ∆E 0K (dashed line) and free energy ∆G 363K (thick line) in kcal mol -1 for the SET from triethylamine (Et 3 N) (see Scheme 5 for labels and structures). On the basis of the results on triethylamine, we optimized the key structures for the

generation

of

the

radical-cation

chlorocuprate

with

N-phenyltetra-

hydroisoquinoline (Scheme 7, additionally, energy values and structures can be found in the Supplementary Information, section 4.1a).

The complex of the

reactants II a is located 1.6 kcal mol - 1 below the reactants in terms of energy but 7.9 kcal mol - 1 above in terms of free energy (Figure 3).

From this species we

found the transition structure for the first desolvation (the rate determining step), TS a I I - I I I .

The barriers with respect to II a , are ∆E 0K‡ = 4.9 and ∆G 363K‡ = 4.9 kcal

mol - 1 respectively. The subsequent structures, III a , IV a , TS a I V - V , V a (+ H 2 O) and the final species VI a (+ 2 H 2 O) are located (with respect to the reactants) at 2.8, 4.8, 7.3, 7.0, and 7.9 kcal mol - 1 in terms of energy and 12.3, 5.4,7.3, 5.2, and -0.1 kcal mol - 1 in terms of free energy, respectively. The rate determining step for Nphenyltetrahydroisoquinoline is the first Cu‒O bond breaking passing through TS a I I - I I I as for triethylamine. 10 ACS Paragon Plus Environment

Page 11 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


We can compare the calculated atomic spin densities S in the radical-cation dichlorocuprate VI a (Figure 4.1a in the Supplementary Information) with the experimental EPR results. 2 8 As in the case of VI, most of the spin density is on the radical-cation moiety (S = 0.75).

Slightly more than half of it (52%) it is

localized on the nitrogen atom (S = 0.39). This result seems in agreement with the conclusions of Wang and coworkers. 2 8 The remaining spin density is essentially delocalized on the ortho and para positions of the phenyl group which collects the 41 % of the spin density (S = 0.31) of the radical-cation. The remaining 6% (S = 0.02 each) is mostly localized on the two methylenes bound to the nitrogen. The occurrence of the SET was also proved by the experimental observation of the radical anion of DDQ by Chan, Todd, and co-workers. 3 8 However, they did not identify any transition structure for its formation.

Figure 3. Energy ∆E 0K (dashed line) and free energy ∆G 363K (thick line) in kcal mol -1 for the SET from N-phenyltetrahydroisoquinoline (NPhTHiQ) to CuCl 2 (H 2 O) 2 (I) generating the radical-cation dichlorocuprate VI a (see Scheme 6 for labels and structures).



Page 12 of 49

Scheme 7. The mechanism for the SET from N-phenyltetrahydroisoquinoline to CuCl 2 (H 2 O) 2 (I) generating the radical-cation dichlorocuprate VI a . The figures show the most relevant bond distances in Ångstroms.


Page 13 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The generation of the iminium. Once the radical-cation dichlorocuprates (VI or VI a ) are generated by the SET, the second phase for the generation of the iminium is the C‒H bond breaking. This process consists in a Hydrogen Atom Transfer (HAT) from VI (or VI a ) to a suitable acceptor A (eq. 5). [R 2 N‒CH 2 R'] . + CuCl 2 - + A → [R 2 N=CHR'] + CuCl 2 - + HA . Six alternative acceptors were taken into account.

eq. 5

As for the SET, the HAT

reactions will be studied first with triethylamine, and then with N-phenyltetrahydroisoquinoline (starting from VI and VI a respectively). 1. Intramolecular HAT.

In this case, there is no intervention of an external

oxidant (see Scheme 8 and Supplementary Information, section 5.1). In fact, the acceptor is one of the chlorines in the radical-cation dichlorocuprate complex. More specifically, a chlorine, after detaching from copper, takes the hydrogen atom, thus generating the iminium dichlorocuprate and HCl (eq. 6). (CH 3 CH 2 ) 3 N . + CuCl 2 - → [(CH 3 CH 2 ) 2 N=CH 2 CH 3 ] + CuCl - + HCl

eq. 6

The radical-cation dichlorocuprate VI first isomerizes to VII i which is located 14.0 kcal mol - 1 below VI in terms of energy (6.6 kcal mol - 1 below the starting reactants, triethylamine + CuCl 2 (H 2 O) 2 ) and 8.8 kcal mol - 1 below VI in terms of free energy (11.9 kcal mol - 1 below the reactants). The exploration of the PES suggests that the isomerization of VI to VII i takes place through a full dissociation of the N‒Cl bond followed by a re-association to form the N‒Cu bond.

Despite multiple attempts

using different search algorithms, we were not capable of locating the transition structures corresponding to this dissociation-reassociation step. Therefore, we conclude that the PES is very flat, and we will show later that this step is not relevant, because VII i does not have any role. Then the isomer VII i undergoes the intramolecular HAT through TS H A T - i .

This step is strongly disfavored: the

activation energy (calculated with respect to VII i ) is 34.2 kcal mol - 1 (TS H A T - i is 27.7 kcal mol - 1 above the starting reactants) and its activation free energy is 33.7 kcal mol - 1 (21.8 kcal mol - 1 above the starting reactants).

The complex of the

products VIII i is located 17.9 kcal mol - 1 above VI in terms of electronic energy (25.3 kcal mol - 1 above the starting reactants) and 20.2 kcal mol - 1 above VI in terms of free energy (17.0 kcal mol - 1 above the starting reactants). The molecular and electronic structure of the product in VIII i describes a complex between Cu I Cl and 13 ACS Paragon Plus Environment


Page 14 of 49

an organic radical with the unpaired electron delocalized on the carbon and nitrogen atoms.

Such a pathway was already taken into account by Cheng and

coworkers, 2 9 who found it to be disfavored.

Scheme 8. The intramolecular RHT in the radical-cation dichlorocuprate VI. The figures show the most relevant bond distances in Ångstroms. 2. Second Catalyst molecule. Since the intramolecular HAT is highly disfavored, we hypothesize that the acceptor might be one of the chlorines in another CuCl 2 (H 2 O) 2 molecule, as illustrated schematically in eq. 7: (CH 3 CH 2 ) 3 N . + CuCl 2 - + CuCl 2 (H 2 O) 2 → [(CH 3 CH 2 ) 2 N=CHCH 3 ] + CuCl 2 - + HCl + CuCl(H 2 O) + H 2 O

eq. 7

Scheme 9a shows the reaction mechanism for the HAT from VI, i.e. the radicalcation dichlorocuprate formed from triethylamine. First, VI and a second molecule of catalyst CuCl 2 (H 2 O) 2 (I) form the complex VII C l , which is located 1.4 kcal mol - 1 below VI + I in terms of energy (6.0 kcal mol - 1 above all initial reactants, i.e. NEt 3 and two catalyst molecules) and 14.3 kcal mol - 1 above VI + I in terms of free energy (11.1 kcal mol - 1 ).

The species undergoes to the HAT through TS H A T - C l

with an energy barrier (with respect to VI + I) of 7.7 kcal mol - 1 (15.1 kcal mol - 1 above all initial reactants) and a free energy barrier of 21.4 kcal mol - 1 (18.2 kcal mol - 1 ).

The product of the RHT is a complex (VIII C l ) between the iminium

dichlorocuprate, the water complex of Cu I Cl (X), hydrochloric acid and a water molecule.

These species are located 16.7 kcal mol - 1 below VI + I in terms of

energy (9.3 kcal moldis below all initial reactants) and 3.2 kcal mol - 1 below VI + I in terms of free energy (7.5 kcal mol - 1 ).


Page 15 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


We also report an alternative transition structure (TS' H A T - C l ) for the HAT between I and the isomer of VI, VII i (see also Supplementary Information, section 5.2). Its energy, with respect to all initial reactants, is 19.8 kcal mol - 1 (to be compared with 15.1 kcal mol - 1 for TS H A T - C l ) and its free energy is 26.3 kcal mol - 1 (18.2 kcal mol - 1 for TS H A T - C l ).

We believe that the higher energy of TS' H A T - C l is due to the fact

that the radical-cation character of the amine is smaller in VII i than in VI, and therefore VII i is less reactive. This is also confirmed by the smaller spin density on the nitrogen atom (0.22) and on the whole amine (0.26) with respect to VI (0.70 and 0.89, respectively). The final products of the HAT (the iminium dichlorocuprate IX) plus the byproducts X, HCl and three water molecules (one from this step plus the two from the SET) are located 3.2 kcal mol - 1 above all reactants in terms of energy but 22.5 kcal mol - 1 below all initial reactants in terms of free energy. The HAT to I has been studied for N-phenyltetrahydroisoquinoline (Scheme 9b) limitedly to the transition structure TS a H A T - C l and the final products. The energy barrier (with respect to VI a + I) is 6.2 kcal mol - 1 (14.0 kcal mol - 1 above all initial reactants, i.e. N-PhTHiQ and two catalyst molecules) and the free energy barrier is 18.7 kcal mol - 1 (18.7 kcal mol - 1 ). The final products (the iminium dichlorocuprate IX a plus the by-products X, HCl and three water molecules) are located 1.8 kcal mol - 1 above all initial reactants in terms of energy but 22.0 kcal mol - 1 below in terms of free energy.

The structure of IX a (Figure 4 and Figure 5.2a in the

Supplementary Information) is in very good agreement with the one characterized by X-ray diffraction (ref. 23: Figure 1 and Supplementary Information, file ja201610c_si_003.cif).

The energy barriers for the reaction mechanism as

illustrated in Schemes 7 and 9b are relatively low and compatible with the anaerobic reaction performed by Klussmann. 2 4



Page 16 of 49

Figure 4. The structure of the iminium dichlorocuprate IX a generated from N-phenyltetrahydroisoquinoline. Carbon is black, nitrogen is blue, hydrogen is white, chlorine is green, and copper is red.


Page 17 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 9. The mechanisms for the generation of the iminium dichlorocuprates by HAT to a second catalyst molecule [CuCl 2 (H 2 O) 2 ] (I) from for triethylamine (a) or N-phenyltetrahydroisoquinoline (b). The figures show the most relevant bond distances in Ångstroms. 17 ACS Paragon Plus Environment


Page 18 of 49

3. Molecular Oxygen. Molecular oxygen is an inert species versus stable neutral closed-shell molecules but in can react readily with radical-cations like VI (or VI a ). As by-products, the HAT to O 2 generates the hydroperoxyl radical (eq. 8). (CH 3 CH 2 ) 3 N . + CuCl 2 - + O 2 → [(CH 3 CH 2 ) 2 N=CHCH 3 ] + CuCl 2 - + HOO .

eq. 8

Scheme 10a shows the reaction mechanism. VI forms a complex with O 2 , VII O 2 , which is located 1.1 kcal mol - 1 below VI + O 2 in terms of energy (4.7 kcal mol - 1 above all initial reactants, i.e. NEt 3 , I, and O 2 ) and 7.9 kcal mol - 1 above VI + O 2 in terms of free energy (4.7 kcal mol - 1 ).

This species undergoes the HAT through

TS H A T - O 2 with an energy barrier (with respect to VI + O 2 ) of 0.7 kcal mol - 1 (8.1 kcal mol - 1 above all initial reactants) and a free energy barrier of 14.6 kcal mol - 1 (11.4 kcal mol - 1 ).

The product (VIII O 2 ) of the HAT is a complex between the

iminium dichlorocuprate and the radical hydroperoxide.

This species is located

20.3 kcal mol - 1 below VI + O 2 in terms of energy (12.9 kcal mol - 1 below all initial reactants) and 8.6 kcal mol - 1 below VI + O 2 in terms of free energy (12.3 kcal mol - 1 below). In this case, we have found an alternative transition structure (TS' H A T - O 2 ) for the HAT from the isomer of VI, VII i . Its energy, with respect to all initial reactants, is 12.2 kcal mol - 1 (to be compared with 8.1 kcal mol - 1 for TS H A T - O 2 ) and its free energy is 17.1 kcal

mol - 1 (11.4 kcal mol - 1 for TS H A T - O 2 ).

As for the previous

case, this pathway is disfavored. The final products (the iminium dichlorocuprate IX plus the by-products, HOO . and two water molecules from the SET) are located 7.0 kcal mol - 1 below all initial reactants in terms of energy and 17.1 kcal mol - 1 below in terms of free energy. The HAT to O 2 for N-phenyltetrahydroisoquinoline is illustrated in Scheme 10b and the study is limited to the transition structure TS a H A T - O 2 and the final products. The energy barrier (with respect to VI a + O 2 ) is 2.9 kcal mol - 1 (10.8 kcal mol - 1 above all initial reactants, i.e. N-PhTHiQ, I, and O 2 ) and the free energy barrier is 14.2 kcal mol - 1 (14.1 kcal mol - 1 above). The final products (the iminium dichlorocuprate IX a plus the by-products) are located 8.4 kcal mol - 1 below all initial reactants in terms of energy and 16.7 kcal mol - 1 below in terms of free energy. 18 ACS Paragon Plus Environment

Page 19 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 10. The mechanisms for the generation of the iminium dichlorocuprates by HAT to molecular oxygen (O 2 ) for triethylamine (a) or N-phenyltetrahydroisoquinoline (b). The figures show the most relevant bond distances in Ångstroms. 4. Hydroperoxyl Radical.

No matter what is generated from the reaction of O 2

(through the HAT as described above or after the oxidation of copper when 19 ACS Paragon Plus Environment


Page 20 of 49

regenerating the catalyst), HOO . is a species that could be present in the reaction environment.

It should be able to abstract a hydrogen atom from a reactive

radical-cation like VI (or VI a ) generating hydrogen peroxide as by-product (eq. 9). (CH 3 CH 2 ) 3 N . + CuCl 2 - + HOO . → [(CH 3 CH 2 ) 2 N=CHCH 3 ] + CuCl 2 - + H 2 O 2

eq. 9

The reaction mechanism is shown in Scheme 11a. The complex with VII H O O (the acceptor) is located 2.2 kcal mol - 1 below VI + HOO . in terms of energy (5.2 kcal mol - 1 above all initial reactants, i.e. NEt 3 , I, and HOO . ) and 10.0 kcal mol - 1 above VI + HOO . in terms of free energy (7.3 kcal mol - 1 ).

This species undergoes the

HAT through TS H A T - H O O with an energy barrier (with respect to VI + HOO . ) of 3.8 kcal mol - 1 (3.6 kcal mol - 1 above all initial reactants) and a free energy barrier of 11.3 kcal mol - 1 (8.1 kcal mol - 1 above). workers, 3 7 the HAT to HOO . is very fast.

As pointed out by Thiel and coIn our case too, it shows really low

barriers in terms of free energy. The product (VIII H O O ) of the HAT is a complex between the iminium dichlorocuprate and the radical hydroperoxide.

This species is located 51.6 kcal mol - 1

below VI + HOO . in terms of energy (44.2 kcal mol - 1 below all initial reactants) and 38.5 kcal mol - 1 below VI + HOO . in terms of free energy (41.7 kcal mol - 1 below). The final products (the iminium dichlorocuprate IX plus the by-products, H 2 O 2 and two water molecules from the SET) are located 38.2 kcal mol - 1 below all reactants in terms of energy and 46.2 kcal mol - 1 in terms of free energy.

The study was

extended also to N-phenyltetrahydroisoquinoline (Scheme 11b) limitedly to the transition structure TS a H A T - H O O and the final products. The energy barrier (with respect to VI a + HOO . ) is -6.0 kcal mol - 1 (1.8 kcal mol - 1 above all initial reactants, i.e. N-PhTHiQ, I, and HOO . ) and the free energy barrier is 6.4 kcal mol - 1 (6.4 kcal mol - 1 ). The final products (the iminium dichlorocuprate IX a plus the by-products) are located 39.6 kcal mol - 1 below all initial reactants in terms of energy and 45.8 kcal mol - 1 in terms of free energy.


Page 21 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 11. The mechanisms for the generation of the iminium dichlorocuprates by HAT to radical hydroperoxide (HO 2 . ) for triethylamine (a) or N-phenyltetrahydroisoquinoline (b). The figures show the most relevant bond distances in Ångstroms. 21 ACS Paragon Plus Environment


5. Hydrogen Peroxide.

Page 22 of 49

H 2 O 2 is sometimes added as oxidant but it can also be

generated (as HOO . ) by the HAT as described above or by the oxidation of copper when regenerating the catalyst. It is expected to be less reactive than O 2 or HOO . . However, we cannot rule out a role for this molecule a priori because of the reactivity of the radical-cations VI (or VI a ),.

The reaction generates a hydroxyl

radical and one water molecule, according to eq. 10. (CH 3 CH 2 ) 3 N . + CuCl 2 - + H 2 O 2 → [(CH 3 CH 2 ) 2 N=CHCH 3 ] + CuCl 2 - + HO . + H 2 O

eq. 10

The reaction mechanism is shown in Scheme 12. The complex with the acceptor (H 2 O 2 in this case), VII H 2 O 2 , is located 1.2 kcal mol - 1 below VI + H 2 O 2 in terms of energy (6.2 kcal mol - 1 above all initial reactants, i.e. NEt 3 , I, and H 2 O 2 ) and 9.2 kcal mol - 1 above VI + H 2 O 2 in terms of free energy (6.0 kcal mol - 1 above). This species undergoes the HAT through TS H A T - H 2 O 2 with an energy barrier (with respect to VI + H 2 O 2 ) of 14.1 kcal mol - 1 (21.5 kcal mol - 1 above all initial reactants) and a free energy barrier of 26.0 kcal mol - 1 (22.8 kcal mol - 1 above). Clearly, this pathway is not competitive with the previous ones, so we did not perform any calculations on N-phenyltetrahydroisoquinoline. The role of H 2 O 2 is probably limited to the oxidation of copper when regenerating the catalyst.

Scheme 12. The mechanisms for the generation of the iminium dichlorocuprates by HAT to hydrogenperoxide (H 2 O 2 ) for triethylamine. The figures show the most relevant bond distances in Ångstroms. 22 ACS Paragon Plus Environment

Page 23 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6. Hydroxyl Radical.

The last acceptor we considered is HO . .

As for the

previous ones, we presume that it can be generated by the decomposition of H 2 O 2 by the oxidation of copper when regenerating the catalyst.

Along with the

iminium dichlorocuprate, the HAT generates water (eq. 11). (CH 3 CH 2 ) 3 N . + CuCl 2 - + HO . → [(CH 3 CH 2 ) 2 N=CHCH 3 ] + CuCl 2 - + H 2 O

eq. 11

Any attempt to optimize the structure of a complex between VI and HO . or the transition structure for the HAT failed.

Inspection of the electronic structure

(mainly atomic charges) and some tests led to the conclusion that the electron affinity of the hydroxyl radical is high enough to oxidize Cu I to Cu I I in the dichlorocuprate moiety.

This SET yields a complex between a radical-cation

hydroxide and CuCl 2 which cannot further evolve. Therefore, we did not explore this pathway any further. The results reported above allow us to draw some preliminary conclusions. The electronic and free energies (all with respect to the reactants) of the most important structures along the pathways for the generation of the radical-cation and iminium dichlorocuprates from triethylamine (NEt 3 ) and N-phenyltetrahydroisoquinoline (N-PhTHiQ) are collected in Table 1. The comparison of the energy profiles (Figures 2 and 3) and of the energy values (Table 1) confirms that NEt 3 is a good model for N-PhTHiQ. Furthermore, we can see that the HAT to a second molecule of catalyst ( I ) is less competitive than to the molecular oxygen or to the hydroperoxyl radical (the free energies of TS H A T - C l and TS a H A T - C l are larger than that of the other TS H A T ). However, because the free energies of TS H A T - C l and TS a H A T - C l are not extremely high, a role for the catalyst in the HAT cannot be ruled out. This is the case when an alternative oxidant is absent as in the anaerobic experiments by Klussmann 2 3 where the catalyst was the only species available for this role (although high concentrations of I were required).



Page 24 of 49

Table 1. Electronic energies (∆E 0K ) and free energies (∆G 363K ) in kcal mole -1 of the most important structures along the pathways for the generation of the radical-cation and iminium dichlorocuprates from Triethylamine (NEt 3 ) and N-phenyltetrahydroisoquinoline (N-PhTHiQ). NEt 3

N-PhTHiQ

∆E 0K

∆G 363K

∆E 0K

∆G 363K

0.0

0.0

0.0

0.0

TS I I - I I I or TS a I I - I I I

6.2

14.4

3.3

12.8

VI or VI a + 2 H 2 O

7.4

-3.2

7.9

-0.1

15.1

18.2

14.0

18.7

3.2

-22.5

1.8

-22.0

8.1

11.4

10.8

14.1

-7.0

-17.1

-8.4

-16.7

3.6

8.1

1.8

6.4

-38.2

-46.2

-39.6

-45.8

Reactants a SET phase:

HAT by a second CuCl 2 (H 2 O) 2 : TS H A T - C l or TS a H A T - C l IX or IX a + X + HCl + 3 H 2 O HAT by O 2 : TS H A T - O 2 or TS a H A T - O 2 IX or IX a + HOO . + 2 H 2 O HAT by HOO • : TS H A T - H O O or TS a H A T - H O O IX or IX a + H 2 O 2 + 2 H 2 O

the amine + CuCl 2 (H 2 O) 2 , and a second CuCl 2 (H 2 O) 2 , O 2 , or HOO . depending on the reaction considered.

a

Tertiary amines candidate to the oxidative cross-coupling. Once the mechanism for the generation of the iminium dichlorocuprates was elucidated (Scheme 13), we extended the study to the panel of tertiary amines N i shown in Chart 1.

We calculated the relative energies and free energies of the

radical-cation dichlorocuprates ( VI i ) and of the iminium dichlorocuprates ( IX i plus the by-products of the HATs, i.e. X , HCl, HOO . , H 2 O 2 ). The results are collected in Table 2.


Page 25 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 13. General mechanism for the generation from the tertiary amine ( N i ) of the iminium dichlorocuprates ( IX i ) and passing through the radical-cation dichlorocuprates ( VI i ).

Chart 1. The tertiary amines ( N i ) used for the extended study.


The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

Page 26 of 49

Table 2. Electronic energies a (∆E 0K ) and free energies a (∆G 363K ) of the radical-cation dichlorocuprates ( VI i ) and of the iminium dichlorocuprates ( IX i ) generated from the tertiary amines ( N i , Chart 1), CuCl 2 (H 2 O) 2 ( I ), and the oxidants. Entry Amines N i

Ni + I →

N i + 2 I → IX i +

VI i + 2 H 2 O

N i + I + HOO . →

Ni + I + O2 →

CuCl•H 2 O + HCl + 3

IX i + HOO . + 2

+ H2O2 + 2

IX i

∆E 0K ∆G 363K

∆E 0K

2O ∆GH363K

∆E 0K

2O ∆GH363K

H 2 ∆E O 0K

∆G 363K

1

NMe 3

10.5

2.7

11.8

-11.6

1.62

-6.3

-29.6

-35.4

2

NEt 3

7.4

-3.2

3.2

-22.5

-7.0

-17.1

-38.2

-46.2

3

NiPr 3

2.4

-6.4

-4.8

-30.3

-15.0

-25.0

-46.1

-54.1

4

C 6 H 5 NMe 2

7.4

-0.4

17.4

-4.7

7.2

0.7

-24.0

-28.4

5

C 6 H 5 NEt 2

7.2

-0.7

7.6

-16.0

-2.6

-10.7

-33.8

-39.8

6

C 6 H 5 NiPr 2

6.3

-0.7

-0.8

-25.1

-11.0

-19.8

-42.2

-48.9

7

4-MeC 6 H 4 NMe 2

4.7

-3.4

16.2

-5.7

6.0

-0.4

-25.2

-29.5

8

C 6 H 5 CH 2 NMe 2

12.1

2.9

7.3

-17.6

-2.9

-12.2

-34.1

-41.3

9

C 6 H 5 CH 2 NEt 2

10.5

3.9

6.5

-16.8

-3.7

-11.5

-34.9

-40.5

10

C 6 H 5 CH 2 NiPr 2

6.3

1.1

6.0

-17.9

-4.2

-12.6

-35.4

-41.6

11

C 6 H 5 CH 2 N(Me)C 6 H 5

6.0

-1.7

8.0

-14.4

-2.2

-9.0

-33.4

-38.1

12

N-PhTHiQ

7.9

-0.1

1.8

-22.0

-8.4

-16.7

-39.6

-45.8

13

N-MeTHiQ

4.6

-3.0

7.6

-16.5

-2.6

-11.2

-33.8

-40.2

a

kcal mol -1 , all with respect to the reactants: amine N i + CuCl 2 (H 2 O) 2 and a second CuCl 2 (H 2 O) 2 or O 2 or HOO . .


Page 27 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


All VI i structures present most of the unpaired electron on the organic moiety. Their net total spin densities (see Supplementary Information, section 6) are all above 0.75. The organic moieties also present net total positive charges of 0.75 or more confirming their nature of radical-cation dichlorocuprates. From the inspection of Table 2, we can gain some insight into the effect of the substituents on the N atoms on the stability of the radical cation dichlorocuprate ( VI i ) and the iminium dichlorocuprate ( IX i ). The alkyl groups (entries 1-3 in Table 2) stabilize both VI i and IX i , with the isopropyl being the most stabilizing (independently of the oxidant used). This is not unexpected, since the carbocation formed is primary for NMe 3 , secondary for NEt 3 and tertiary for NiPr 3 . The same is true also for the differently-substituted anilines (entries 4-6). The phenyl ring has a less stabilizing effect than a third alkyl group (the free energy for the aliphatic amines is always lower than the corresponding one for the anilines). On the other hand, though, it can be seen that the addition of a phenyl ring does not affect the stability of the radical-cation ( VI i ) too much: there is a gain in stability only for C 6 H 5 NMe 2 (with respect to NMe 3 ), while the overall effect for the other two is destabilizing if compared to the corresponding aliphatic amines. Furthermore, there is no difference in either of the radical cations. Adding a para-substituent on the phenyl ring of C 6 H 5 NMe 2 (entry 7) seems not to affect the stability of the iminium ions generated, but it stabilizes (by 3 kcal mol 1)

the radical-cation.

This is coherent with the experimental and computational

data on N-(4-methylphenyl)-tetrahydroisoquinoline collected by Chan, Todd, and co-workers. 3 8 When it comes to benzylamines (entries 8-10), one can see that each structure is different from the others by a value within 3-4 kcal mol - 1 , way below the accuracy of the computational approach used here. 4 2 Therefore, the structures are not too different from each other, and this is consistent with the idea that, since the carbocation is benzylic, the nature of the other substituents on the N atom is not as important as in other cases. However, if compared to the aliphatic amines, we can see that the benzyl group has a stabilizing effect only if it substitutes a methyl, while in every other case it is destabilizing. In the end, for N substituted tetrahydroisoquinolines (entries 12-13) we see that a phenyl ring stabilizes the iminium more than a methyl group, which in turn stabilizes the radical-cation more than phenyl. 27 ACS Paragon Plus Environment


Page 28 of 49

The comparison between the data for N-PhTHiQ and the other amines in Chart 1 and Table 2 suggests that NEt 3 , NiPr 3 , C 6 H 5 NEt 2 , C 6 H 5 NiPr 2 , C 6 H 5 CH 2 N(Me)C 6 H 5 , and N-MeTHiQ might be suitable substrates for the aerobic CuCl 2 -catalyzed dehydrogenative cross-coupling.

For these amines, the free energies of the

radical-cation dichlorocuprates and of the iminium dichlorocuprates generated by the HAT with O 2 (the expected main acceptor) are both negative. Experiments on the oxidative cross-coupling. In order to confirm the theoretical calculations, we chose NEt 3 , C 6 H 5 NEt 2 and C 6 H 5 NiPr 2 among the amines described above because they are commercially available.

Their cross-coupling reactions with some selected nucleophiles are

shown in Scheme 14. First, the model reaction between NEt 3 , nitromethane (very strong excess, 5 ml) and CuCl 2 (H 2 O) 2 was studied under different reaction conditions (Table 3). The reaction was performed in open air at room temperature (Table 3, entry 1) or heating at 90°C in the presence of 5 mol% (entry 2) or 15 mol% (entry 3) of CuCl 2 (H 2 O) 2 .

No oxidative coupling product ( XI ) was obtained.

Then, the

reaction was carried out under 1 atm of O 2 heating at 90°C (entry 4). Also in this case, no traces of XI were detected. So, we changed nucleophile (methyl malonate instead of nitromethane) but the reaction, also in this case, failed (entry 5). In

the

light

of

these,

we

proceeded

using

C 6 H 5 NEt 2 .

Its

reactions

with

nitromethane (very strong excess, 5 ml) in the presence of CuCl 2 (H 2 O) 2 were studied under different conditions.

Again, when the reaction was performed in

open air at room temperature (entry 6) or heating at 90°C (entry 7) in the presence of 5 mol% of CuCl 2 (H 2 O) 2 no oxidative coupling product ( XI b ) was obtained. Then, the reaction was carried out under 1 atm of O 2 heating at 50°C (entry 8). Also in this case, no traces of XI b were detected but when we increased the amount of CuCl 2 (H 2 O) 2 up to 15 mol% traces of the desired product XI b were detected on GC-MS analyses (entry 9).

Finally, with our delight, XI b was received in 45%

yield when reaction mixture was heated at 90°C for 24 hours (entry 10).

In a

collateral proof (entry 10, note d) the reaction was carried out using MeOH as a solvent in the presence of strong excess of CH 3 NO 2 (20 equivalents). The reaction time and the yield were virtually identical to the previous reaction.


Page 29 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 14. The oxidative cross-coupling NEt 3 , C 6 H 5 NEt 2 and C 6 H 5 NiPr 2 with some selected nucleophiles (see text).



Page 30 of 49

Table 3. Aerobic oxidative cross-coupling of tertiary amine with different nucleophiles Entry

1

Amine

N

Nu

CuCl2(H2O)2 Time (h) Temperature mol% (°C)

Products and yields (%)

MeNO2

5

24

r.t

-a

2

N

MeNO2

5

24

90

-a

3

N

MeNO2

15

24

90

-a

4

N

MeNO2

15

24

90

-b

5

N

15

24

90

-b

COOMe COOMe

6

N

MeNO2

5

24

r.t.

-a

7

N

MeNO2

5

24

90t

-a

8

N

MeNO2

5

24

50

-b

9

N

MeNO2

15

24

50

tracesb

10

N

N

MeNO2

15

24

90

NO2

XI b , 45b,c,d COOMe

11

N

COOMe COOMe

N

15

24

90

COOMe

XII b , 35b,c


Page 31 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


12

N

13

N

N

OSiMe

15

24

90

-b

15

24

90

-b

N

14

N

MeNO2

15

8

NO2

90 XI c , 35b,c

COOMe

15

N

COOMe COOMe

N

15

12

90

COOMe

XII c , 29b,c a

The reaction was carried out in open air; general conditons: 10 mmol of amine, strong excess of nucleophile, no solvent; b The reaction was carried under O2: general conditons: 10 mmol of amine, strong excess of nucleophile, no solvent; c Yield refers to pure and isolate product; d The reaction was carried out in MeOH (5 ml). The yield of XI b was 45%. In the light of these results and in order to further exploit the generality and the scope of this reaction, other nucleophiles namely methyl malonate (Table 3, entry 11), N-methylpirrole (entry 12) and (isopropenyloxy)trimethylsilane (entry 13) were tested. Only methyl malonate, reacted under the most favorable conditions, giving the oxidative coupling product XII b (35% yield). In order to explain why only some nucleophiles gave the desired product, we can refer to the reactivity scales developed by Mayr and co-workers. 4 3 - 4 6

The

nucleophilicity value of nitromethane 4 4 and dimethylmalonate 4 5 are, respectively, 20.71 and 20.22 (both refer to the corresponding anion), whilst the values of Nmethylpyrrole 4 6 and (isopropenyloxy)trimethylsilane 4 6 are, respectively, 5.85 and 5.41. So, it is evident that only strong nucleophiles can lead to positive results. In the end, C 6 H 5 NiPr 2 was investigated in the reactions with the strong nucleophile CH 3 NO 2 and methyl malonate (entries 14 and 15).

The calculations (Table 2)

indicate that the formation of the iminium dichlorocuprate from this aniline is one of the most exoergonic reactions.

In fact, the yields of XI c and XII c were

comparable with those obtained using C 6 H 5 NEt 2 , but with lower reaction times (8 or 12 hours instead of 24 hours). 31 ACS Paragon Plus Environment


Page 32 of 49

The role of the complexation of the catalyst. Despite the favorable data reported in Table 2, the negative outcome of the experiments with NEt 3 suggested that we were probably ignoring something important.

In fact, we found out that we were neglecting the fact that

triethylamine is a good complexing agent, which can easily displace the water molecules from the CuCl 2 (H 2 O) 2 complex ( I ). described in Scheme 15.

These complexation reactions are

In the first one, triethylamine displaces one water

molecule from I generating the monoamino-complex XV . In the second one, two triethylamine displace two water molecules, thus generating the bisamino-complex XVI . Of course, this second reaction can also occur when XV reacts with another

molecule of triethylamine.

Scheme 15. The formation of the monoamino- ( XV ) and bisamino ( XVI ) complexes of CuCl 2 from triethylamine and CuCl 2 (H 2 O) 2 (I). These equilibria (equations 12 and 13) are possible for all amines and their energies and free energies are reported in Table 4. I + N i . → XV i + H 2 O

eq. 12

I + 2 Ni

eq. 13

→ XVI i + 2 H 2 O

With the only exceptions of the diisopropyl aniline and benzylamine (entries 6 and 10), the monoamino-complexes XV i or the bisamino-complexes XVI i (or both) are 32 ACS Paragon Plus Environment

Page 33 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the most stable forms of the catalyst. As one can see from Table 4, the bisaminocomplexes with NMe 3 , NEt 3 , and C 6 H 5 NMe 2 are particularly stable.

The main

factor that seems influences the stability of XV i and XVI i seems to be the steric hindrance. In fact, it seems that the larger the alkyls groups bound to the nitrogen, the less stable the amino-complexes. In some cases the copper ion is barely bound to the nitrogen atoms (see figures in the Supplementary Information, section 6). Table 4. Electronic energies a (∆E 0K ) and free energies a (∆G 363K ) of the complexes XV i and XVI i (see text) between the amines ( N i , Chart 1) and CuCl 2 (H 2 O) 2 ( I ). Entry Amines N i

Ni + I →

2 Ni + I →

XV i + H 2 O

XVI i + 2 H 2 O

∆E 0K ∆G 363K

∆E 0K ∆G 363K

1

NMe 3

-10.6

-8.0

-20.8

-13.7

2

NEt 3

-11.1

-7.8

-21.9

-11.3

3

NiPr 3

-8.1

-3.9

-12.5

-1.3

4

C 6 H 5 NMe 2

-5.2

-0.9

-10.8

-0.5

5

C 6 H 5 NEt 2

-7.2

-2.3

-10.9

-1.0

6

C 6 H 5 NiPr 2

-4.5

0.9

-7.7

1.7

7

4-MeC 6 H 4 NMe 2

-6.0

-1.0

-12.3

-2.7

8

C 6 H 5 CH 2 NMe 2

-12.0

-7.8

-21.1

-11.0

9

C 6 H 5 CH 2 NEt 2

-8.6

-1.1

-11.6

1.7

10

C 6 H 5 CH 2 NiPr 2

-3.3

3.5

-2.5

8.7

11

C 6 H 5 CH 2 N(Me)C 6 H 5

-8.8

-3.0

-14.8

-3.5

12

N-PhTHiQ

-7.7

-3.0

-12.7

-3.9

13

N-MeTHiQ

-5.7

-1.0

-8.3

1.0

If the complexes XV i or XVI i are more stable than I , the catalyst is not immediately available for the generation of the iminium dichlorocuprates.

I needs to be re-

generated by reversing the equilibria reported in eq. 12 and 13.

Taking into

account this new element, we included the most stable form of the catalyst (that could be either I , XV i , or XVI i ) in Figure 5 and Table 5, which collects the new recalculated energies for the same species reported in Table 2.



Page 34 of 49

Table 5. Electronic energies a (∆E 0K ) and free energies a (∆G 363K ) of the radical-cation dichlorocuprates ( VI i ) and of the iminium dichlorocuprates ( IX i ) generated from the tertiary amines ( N i , Chart 1), the catalyst (cat. i ) in its more stable form (see text), and the oxidants. Entry

Amines N i

N i + cat. i → VI i + 2 H 2 O

N i + 2 cat. i → IX i + X + HCl + 3 H 2 O

N i + cat. i + O 2 → IX i + HOO . + 2 H 2 O

N i + cat. i + HOO . → IX i + H 2 O 2 + 2 H 2 O

∆E 0K ∆G 363K

∆E 0K

∆G 363K

∆E 0K

∆G 363K

∆E 0K

∆G 363K

1

NMe 3

31.3

16.4

53.4

15.7

22.4

7.4

-8.8

-21.7

2

NEt 3

29.3

8.2

47.1

0.2

14.9

-5.8

-16.2

-34.9

3

NiPr 3

10.5

-2.5

11.5

-22.6

-6.8

-21.1

-38.0

-50.2

4

C 6 H 5 NMe 2

12.6

0.4

27.9

-2.9

12.4

1.5

-18.7

-27.6

5

C 6 H 5 NEt 2

14.4

1.6

21.9

-11.4

4.6

-8.4

-26.6

-37.5

6

C 6 H 5 NiPr 2

6.3

-0.7

-0.8

-25.1

-11.0

-19.8

-42.2

-48.9

7

4-MeC 6 H 4 NMe 2

17.1

-0.7

40.9

-0.3

18.4

2.3

-12.8

-26.8

8

C 6 H 5 CH 2 NMe 2

33.2

13.9

49.6

4.5

18.2

-1.2

-12.9

-30.3

9

C 6 H 5 CH 2 NEt 2

19.2

5.0

23.7

-14.6

4.9

-10.4

-26.3

-39.5

10

C 6 H 5 CH 2 NiPr 2

6.3

1.1

6.0

-17.9

-4.2

-12.6

-35.4

-41.6

11

C 6 H 5 CH 2 N(Me)C 6 H 5

20.7

1.8

37.5

-7.4

12.6

-5.6

-18.6

-34.6

12

N-PhTHiQ

20.6

3.9

27.3

-14.2

4.3

-12.8

-26.8

-41.9

13

N-MeTHiQ

10.3

-2.0

18.9

-14.5

3.0

-10.2

-28.2

-39.2

a

kcal mol -1 , all with respect to the reactants: amine N i + cat. i plus a second cat. i or O 2 or HOO . ). 34 ACS Paragon Plus Environment

Page 35 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5. Free energy profiles (∆G 363K , in kcal mol -1 ) for the generation of the iminium dichlorocuprates IX i from the amines (N i , see Chart 1), through the radical-cations dichlorocuprate VI i . The “Initial Reactants” include N i , CuCl 2 (H 2 O) 2 ( I ), and O 2 ; the “Effective Reactants” include N i , the most stable form of the catalyst ( I , XV i , or XVI i ) and O 2 (see also text, Table 6, and Scheme 12; by products are not shown). From the direct comparison of the energy values reported in Table 2 and Table 5 (or by Figure 5), we can see that the formation of the radical-cation and the iminium dichlorocuprates is always thermodynamically less favorable when taking 35 ACS Paragon Plus Environment


Page 36 of 49

into account the complexation of the catalyst and the amines. particularly evident for NMe 3 , NEt 3 and C 6 H 5 CH 2 NMe 2 .

This trend is

The only notable

exceptions are C 6 H 5 NiPr 2 and C 6 H 5 CH 2 NiPr 2 . For a better comparison with the experimental results, we calculated also the transition structures of the key steps for the generation of the iminium dichlorocuprates for the two anilines (C 6 H 5 NEt 2 and C 6 H 5 NiPr 2 respectively). The reaction schemes are reported in Scheme 16 and Scheme 17.

Scheme 16. The mechanism for the generation of the iminium dichlorocuprate IX b from C 6 H 5 NEt 2 . The figures show the most relevant bond distances in Ångstroms.


Page 37 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 17. The mechanism for the generation of the iminium dichlorocuprate IX c from C 6 H 5 NiPr 2 . The figures show the most relevant bond distances in Ångstroms.



Page 38 of 49

Table 6. Electronic energies a (∆E 0K ) and free energies a (∆G 363K ) of the key structures for the generation of the radical-cations and iminium dichlorocuprates from Triethylamine (NEt 3 ), N-phenyltetrahydroisoquinoline (N-PhTHiQ), N,N-diethylaniline (C 6 H 5 NEt 2 ), and N,N-diisopropylaniline (C 6 H 5 NiPr 2 ).

Reactants b

NEt 3

N-PhTHiQ

C 6 H 5 NEt 2

C 6 H 5 NiPr 2

∆E 0K ∆G 363K

∆E 0K ∆G 363K

∆E 0K ∆G 363K

∆E 0K ∆G 363K

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

TS i I I - I I I

28.1

25.7

16.0

16.7

11.1

14.9

3.5

13.5

VI i + 2 H 2 O

29.3

8.6

20.6

3.9

14.4

1.6

6.3

-0.7

TS i H A T - O 2 (+ 2 H 2 O) IX i + HOO . + 2 H O

30.0

22.7

23.5

18.1

21.4

20.4

16.1

19.6

14.9

-5.8

4.3

-12.8

4.6

-8.4

-11.0

-19.8

2

a

kcal mol -1 , all with respect to the reactants;

b

the amine, the catalyst in its more stable form (see text) and O 2 as hydrogen acceptor.


Page 39 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6. Free energy profiles (∆G 363K , in kcal mol -1 ) for the generation of the iminium dichlorocuprate IX i from Triethylamine (NEt 3 ), N-phenyltetrahydroisoquinoline (NPhTHiQ), N,N-Diethylaniline (C 6 H 5 NEt 2 ), and N,N-Diisopropylaniline (C 6 H 5 NiPr 2 ). The reactants include the amine (N i ), the most stable form of the catalyst ( I , XV i , or XVI i ) and O 2 (see also text, Table 6, and Scheme 12; by products are not shown). Table 6 includes the electronic and free energies of the transition structures for the first desolvation (TS i I I - I I I ) and for the HAT to O 2 , (TS i H A T - O 2 ), the radical-cation dichlorocuprates ( VI i ), and the iminium dichlorocuprates ( IX i ) for NEt 3 , N-PhTHiQ, C 6 H 5 NEt 2 and C 6 H 5 NiPr 2 .

The values take into account the most stable form of

the catalyst ( I , XV i , or XVI i ). The free energy profiles are shown in Figure 6. The energies of the key points for the generation of IX from NEt 3 are considerably higher than those reported for the other amines (see Table 1). This explains why the experiments failed with this species. C 6 H 5 NEt 2 , C 6 H 5 NiPr 2 and N-PhTHiQ can all undergo cross-coupling reactions with strong nucleophiles. In fact, they show energies of about the same magnitude. Although not with large differences, the energies of the TSs of C 6 H 5 NiPr 2 are lower than that of C 6 H 5 NEt 2 .

By contrast, the energies of the iminium

dichlorocuprate of C 6 H 5 NiPr 2 are substantially lower than that of C 6 H 5 NEt 2 . In the end, both results are confirmed by the experiments, which report a faster crosscoupling reaction for diisopropylaniline. 39 ACS Paragon Plus Environment


Page 40 of 49

Computational Details Given the size of the molecules under investigation (24 non-hydrogen atoms for the largest structure analyzed), Density Functional Theory (DFT) 4 7 - 4 9 was the most accurate method that we could afford.

Given the presence of a metal, the

choice of exchange-correlation (xc) functional and basis set needs to be carefully considered. 5 0 After a benchmark study (see below), we decided to use the M06-L functional of Zhao and Truhlar. 5 1

The basis set we chose for H and C was the

Dunning’s cc-pVDZ 5 2 and the aug-cc-pVDZ for N and O. In order to take into account relativistic effects for copper, we decided to use the SBKJC Effective Core Potential (ECP) with the associated basis set. 5 3 To reduce the computational effort, we chose the same ECP and basis set for chlorine as well. 5 4 During the course of the reaction, some species might show di-radical character. Therefore, we used the spin-unrestricted formalism 5 5 which

allows a correct

picture in such cases, and the single point energy values were then corrected using to Yamaguchi's formula. 5 6 - 5 8

Most of the reactions have been performed in neat

conditions, i.e. using one reactant as solvent without a co-solvent.

In our case,

either nitromethane or methanol could be used. Since the reactions gave the same yields (see below) in both cases, and the two species have almost the same dielectric constant (32.6 for methanol, 36.6 for nitromethane), were introduced the solvent

effects

in

our

calculations

using

the

universal

Solvation

Model

Density. 5 9 , 6 0 The nature of the critical points was characterized using vibrational analysis 6 1 , 6 2

which

also

provided

the

thermodynamic

data

at

363.15

K

(corresponding to the experimental condition of 90 °C). Free energy values have been converted from the gas phase to the 1M standard state at 1 atm. 6 3 All calculations have been performed using the Gaussian 09 6 4 quantum package. Atomic net charges and spin have been computed by Natural Population Analysis. 6 5

Figures

4

and

pictures

of

the

molecular

structures

in

the

Supplementary Information were obtained with the graphical program Molden. 6 6 Benchmark study.

As we mentioned in the previous section, the choice of an

exchange-correlation functional was not straightforward due to the presence of the copper atom. Another complication is represented by the fact that we also need to choose an ECP for copper and chlorine.

Therefore, we decided to test the xc

functionals together with the ECPs, and thus identifying which one works best in our case. As mentioned in the previous section, the basis set for H, C, N, and O is 40 ACS Paragon Plus Environment

Page 41 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Dunning’s cc-pVDZ (augmented only for N and O), and it has been used here as well. We decided to analyze the performance of 11 different density functionals: five of them (BB95, BLYP, M06-L, mPW91, TPSS) are local, six of them (B3LYP, CAMB3LYP, M06, M06-2X, PBE0, TPSSh) are hybrids with different percentages of Hartree-Fock (HF) exchange (20, 19, 27, 54, 25 and 10% respectively). They were all tested together with five different ECPs: LANL2DZ, LANL08f, SBKJC, Stuttgart and Stuttgart+3f. The reactions used as reference are reported in equations 14 to 16. Only equation 14 was studied in the gas phase, equations 15 and 16 were studied in aqueous solution. Cu + → Cu + + + e -

eq. 14

2 Cu + + Cl 2 → 2 Cu + + + 2 Cl -

eq. 15

4 Cu + + O 2 + 4 HCl → 4 Cu + + + 2 H 2 O + 4 Cl -

eq. 16

After a careful analysis of the results obtained for reaction 14, we noticed that only four functionals (M06-2X, M06-L, PBE0 and TPSSh) performed in a satisfactory way.

From the results gathered on reaction 15, we further excluded

TPSSh, and from the analysis of the results for equation 16, we excluded M06-2X and PBE0, leaving M06-L as functional of choice for this study.

A detailed

analysis of equations 14-16 is reported in the Supplementary Information, Section 1. After that, we focused our attention only on the performance of M06-L with the different ECPs: we noted that the two Los Alamos ECPs (LANL2DZ and LANL08f) gave approximately the same results, and the same is true for the two Stuttgart ECPs. Neither of the two “families” of ECPs is as accurate as the SBKJC potential, though, and it became our choice throughout the rest of this study.

Experimental Section For the experiments, analytical grade reagents and solvents were used and reactions were monitored by GC, GC-MS and TLC. Petroleum ether (PE) refers to the fraction boiling in the range 40–70 °C. Room temperature is 20–25 °C. Mass 41 ACS Paragon Plus Environment


Page 42 of 49

spectra were recorded on an HP 5989B mass selective detector connected to an HP 5890 GC, cross-linked methyl silicone capillary column.

1H

NMR and

13C

NMR

spectra were recorded on a on Jeol ECZR spectrometer at 600 and 150 MHz respectively.

All reagents were purchased from Sigma-Aldrich or Alfa-Aesar.

Structures and purity of all the products obtained in this research were confirmed by their spectral (NMR, MS, IR) data. Satisfactory microanalyses were obtained for all new compounds.

Conclusions In this study, we demonstrated that the aerobic copper-catalyzed crosscoupling between a tertiary amine ( N i ) and a reactive nucleophile starts with the generation of an iminium from N i . process

is

initiated

dichlorocuprate

by

( VI i )

the

through

When using CuCl 2 (H 2 O) 2 ( I ) as catalyst, this

oxidation the

of

the

desolvation

reorganization) 4 1 , 4 2 that reduces Cu I I to Cu I .

amine of

the

to

a

copper

radical ion

cation (solvent

The second phase consists in a

Hydrogen Atom Transfer (HAT) from VI i to a suitable acceptor generating the iminium dichlorocuprate ( IX i ). The acceptor can be a second molecule of catalyst I or molecular oxygen. I plays a role in the HAT when other acceptors are absent. 3 1 We found out that O 2 is the main acceptor in the HAT under aerobic condition, opposing the claim that its only role is the regeneration of the catalyst through the re-oxidation of Cu I to Cu I I . Another suitable acceptor is HOO . , which is generated by O 2 in the HAT or in the regeneration of the catalyst. 3 7 The molecular structure of the amines influences the stability of the intermediates VI i and IX i mainly through the electronic effects of the groups bound to the

nitrogen atom (stabilization of the unpaired electron in VI i and of the positive charges on VI i and IX i ).

The steric hindrance of the alkyl groups bound to the

nitrogen atom has an important role, but it acts through an indirect effect.

The

amines can in fact displace one or two water molecules from the aquo-complex of CuCl 2 forming XV i and XVI i thus affecting the availability of the catalyst.

The

amino-complexes remove I (the active form of the catalyst) from the reaction environment. For the reaction to proceed, I must be regenerated by reversing the equilibria.

Of course, this increases the energies of all species involved in the

reactions for almost all the amines taken into account here. As shown in Figure 5, in

most

cases

thermodynamically

the

formation

favored

but

of

the

that

iminium of

their


dichlorocupates precursors

( IX i )

is

radical-cation

Page 43 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


dichlorocupates ( VI i ) is not. In most cases the complexation of the catalyst by the amines makes it less available, but we also showed that the stability of these complexes is mainly influenced by the dimension of the substituent on the N atom. This is particularly evident for the non-hindered methyl-amines which complex copper in a more efficient way than any other amine tested in this work. Interestingly, the N-phenyl ring does not affect the stability of VI i too much (see Table 2) unless an electro-donating group is present in the para position. 3 8 By contrast, the phenyl group in the anilines makes them less basic, and it slightly reduces the stability of the copper complexes.

Thus, the catalyst is more

available. By taking into account all of these effects, only some tertiary amines seem suitable substrates for the cross-coupling reaction catalyzed by CuCl 2 (H 2 O) 2 : triisopropylamine (NiPr3), N,N-diethylaniline (C 6 H 5 NEt 2 ), N,N-diisopropylaniline (C 6 H 5 NiPr 2 ), benzyldiisopropylamine (C 6 H 5 CH 2 NiPr 2 ), N-benzyl-N-methylaniline (C 6 H 5 CH 2 N(Me)C 6 H 5 ),

N-phenyltetra-hydroisoquinoline

(N-PhTHiQ),

and

N-

methyltetrahydroisoquinoline (N-MeTHiQ). Some of them have been tested experimentally in order to confirm the theoretical calculations. The experimental results reported here on C 6 H 5 NEt 2 , C 6 H 5 NiPr 2 , and NEt 3 (that was used in the wider computational study), are consistent with the computational results. As predicted, the two anilines give rise to cross-coupling with two highly reactive

nucleophiles

(nitromethane,

CH 3 NO 2

and

dimethylmalonate,

H 2 C(COOMe) 2 ) while NEt 3 is inert. The cross-coupling of the two anilines yielded 4 new molecules: XI b from C 6 H 5 NEt 2 and CH 3 NO 2 ;

XII b from C 6 H 5 NEt 2 and H 2 C(COOMe) 2 ;

XI c from

C 6 H 5 NiPr 2 and CH 3 NO 2 ; XII c from C 6 H 5 NiPr 2 and H 2 C(COOMe) 2 .

All these

molecules have been fully characterized (see Supplementary Information, section 8 for H- and

1 3 C-NMR

spectra).

Supporting Information. Details on the benchmark calculations phase (including the list of authors for reference 64) and on the choice of the model substrate for the extensive PES analysis; calculated absolute and relative electronic and free energies; relevant group spin and net charges; pictures of the calculated structures; representative experimental condition, physical properties and H- and

1 3 C-NMR

spectra of products XI b , XII b , XI c , and XII c . .

Acknowledgments. This work was supported by Università di Torino (Local Funding 2016). P. M. is grateful to Dr. Roberto Peverati for helpful suggestions. 43 ACS Paragon Plus Environment


Page 44 of 49

References. 1. Qin, Y.; Zhu, L.; Luo, S. Organocatalysis in inert C−H bond functionalization. Chem. Rev., 2017, 117, 9433‒9520. 2. Tsang, A. S. K.; Park, S. J. ; Todd, M. H. Mechanisms of cross-dehydrogenative-coupling reactions in From C-H to C-C bonds: cross-dehydrogenative-coupling (Ed.: C.-J. Li), The Royal Society of Chemistry, 2015, chap. 11, pp. 254‒294. 3. Li, C.-J. Cross-Dehydrogenative Coupling (CDC): Exploring C-C bond formations beyond functional group transformations. Acc. Chem. Res., 2009, 42, 335‒344. 4. Lim C.-J.; Li, Z. Green chemistry: The development of cross-dehydrogenative coupling (CDC) for chemical synthesis. Pure Appl. Chem., 2006, 78, 935‒945. 5. Yeung, C. S.; Dong, V. M. Catalytic dehydrogenative cross-coupling: forming carboncarbon bonds by oxidizing two carbon-hydrogen bonds. Chem. Rev., 2011, 111, 1215‒1292. 6. Zhang, C.; Tanga, C.; Jiao, N. Recent advances in transition-metal catalyzed reactions using molecular oxygen as the oxidant. Chem. Soc. Rev., 2012, 41, 3464‒3484. 7. McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation. Chem. Soc. Rev., 2011, 40, 1885–1898. 8. Yamaguchi, J.; Itami, K.; Yamaguchi, A. D. C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960– 9009. 9. Qin, Y.; Lv, J.; Luo, S. Catalytic asymmetric α-C(sp3)–H functionalization of amines. Tetrahedron Letters, 2014, 55, 551–558. 10. Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.; Lou, H. Practical metal‐free C(sp3)–H functionalization: construction of structurally diverse α‐substituted N‐benzyl and N‐allyl carbamates. Angew. Chem. Int. Ed. 2014, 53, 3904–3908. 11. Cheng, M.-X.; Yang, S.-D. Recent Advances in the enantioselective oxidative α-C–H functionalization of amines. Synlett 2017, 28, 159–174. 12. Szatmári, I.; Sas, J.; Fülöp, F. C-3 Functionalization of indole derivatives with isoquinolines. Curr. Org. Chem. 2016, 20, 2038–2054. 13. Jones, K. M.; Klussmann, M. Oxidative coupling of tertiary amines: scope, mechanism and challenges. Synlett, 2012, 23, 159‒162. 14. Subramanian, P.; Rudolf, G. ; Kaliappan, K. P. Recent Trends in copper-catalyzed C‒H amination routes to biologically important nitrogen scaffolds . Chem. Asian J., 2016, 11, 168‒192. 15. Leonard, N. J; Leubner, G. W. Reactions of nitroparafins with pseudo bases related to dihydroisoquinolinium hydroxide. J. Am. Chem. Soc., 1949, 71, 3408‒3411 16. Murahashi, S.; Komiya, N.; Terai, H. Ruthenium-catalyzed oxidative cyanation of tertiary amines with hydrogen peroxide and sodium cyanide. Angew. Chem. Int. Ed. Engl., 2005, 44, 6931‒6933 44 ACS Paragon Plus Environment

Page 45 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


17. Li, Z.; Li, C.-H. CuBr-Catalyzed Efficient Alkynylation of sp3 C‒H bonds adjacent to a nitrogen atom. J. Am. Chem. Soc., 2004, 126, 11810‒11811. 18. Shen, Y.; Li, M.; Wang, S.; Zhan, T.; Tan, Z.; Guo, C.-C. An efficient copper-catalyzed oxidative Mannich reaction between tertiary amines and methyl ketones. Chem. Commun., 2009, 953‒955. 19. Yoo, W. J.; Li, C. J. Cross-dehydrogenative coupling reactions of sp3-hybridized C‒H bonds Top. Curr. Chem., 2010, 292, 281‒302. 20. Ratnikov, M. O.; Doyle, M. P. Mechanistic investigation of oxidative Mannich reaction with tert-butyl hydroperoxide. The role of transition metal salt. J. Am. Chem. Soc., 2013, 135, 1549‒1557. 21. Tsang, A. S.-K. ; Jensen, P.; Hook, J. M.; Hashmi, A. S. K.; Todd, M. H. An oxidative carbon‒carbon bond-forming reaction proceeds via an isolable iminium ion. Pure Appl. Chem., 2011, 83, 655‒665. 22. Murata, S.; Miura, M.; Nomura, M. Iron-catalysed oxidation of N,N-dimethylaniline with molecular oxygen. J. Chem. Soc., Chem. Commun., 1989, 116‒118. 23. Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. Iron-catalyzed oxidation of 4-substituted N,N-dimethylanilines with molecular oxygen in the presence of benzoyl cyanide. Bull. Chem. Soc. Jpn., 1993, 66, 1297‒1298. 24. Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Copper-catalyzed aerobic oxidative C‒H functionalizations: trends and mechanistic insights. Angew. Chem. Int. Ed., 2011, 50, 11062‒11087. 25. Baslé, O.; Li, C.-H. Copper catalyzed oxidative alkylation of sp3 C‒H bond adjacent to a nitrogen atom using molecular oxygen in water. Green Chem., 2007, 9, 1047‒1050. 26. Yoo, W.-J.; Correia, C. A.; Zhang, Y.; Li, C.-H. Oxidative alkylation of cyclic benzyl ehers with malonates and ketones using oxygen as the terminal oxidant. Synlett. 2009, 1, 138‒142. 27. Huang, L.; Niu, T.; Wu, J.; Zhang, Y. Copper-catalyzed oxidative cross-coupling of N,Ndimethylanilines with heteroarenes under molecular oxygen. J. Org. Chem., 2011, 76, 1759‒1776. 28. Shi, Z.; Zhang, C.; Tanga, C.; Jiao, N. Recent advances in transition-metal catalyzed reactions using molecular oxygen as the oxidant. Chem. Soc. Rev., 2012, 41, 3381‒3430. 29. Gulzar, N.; Schweitzer-Chaput, B.; Klussmann, M. Oxidative coupling reactions for the functionalisation of C‒H bonds using oxygen. Catal. Sci. Technol., 2014, 4, 2778‒2796. 30. Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Farès, C.; Klussmann, M. Mechanistic studies on a Cu-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline: structure of intermediates and the role of methanol as a solvent. J. Am. Chem. Soc. 2011, 133, 8106‒8109. . 31. Boess, E.; Schmitz, C.; Klussmann, M. A Comparative mechanistic study of Cu-catalyzed oxidative coupling reactions with N-phenyltetrahydroisoquinoline. J. Am. Chem. Soc. 2012, 134, 5317‒5325.



Page 46 of 49

32. Scott, M.; Sud, A.; Boess, E.; Klussmann, M. Reaction progress kinetic analysis of a coppercatalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline J. Org. Chem. 2014, 79, 12033‒12040. 33. Baslé, O.; Borduas, N.; Dubois, P.; Chapuzet, J. M.; Chan, T.-H.; Lessard, J.; Li, C.-J. Aerobic and electrochemical oxidative cross-dehydrogenative-coupling (CDC) reaction in an imidazolium-based ionic liquid. Chem. Eur. J., 2010, 16, 8162‒8166. 34. Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Copper-catalyzed oxidative direct cyclization of N-methylanilines with electron-deficient alkenes using molecular oxygen. J. Org. Chem., 2011, 76, 6447‒6451. 35. Wang, T.; Schrempp, M.; Berndhauser, A.; Schiemann, O.; Menche, D. Efficient and general aerobic oxidative cross-coupling of THIQs with organozinc reagents catalyzed by CuCl2: proof of a radical intermediate. Org. Lett., 2015, 17, 3982‒3985. 36. Cheng, G.-J; Song, L.-J.; Yang, Y.-F.; Zhang, X.; Wiest, O.; Wu, Y.-D. Computational studies on the mechanism of the copper-catalyzed sp3-C‒H cross-dehydrogenative coupling reaction. ChemPlusChem, 2013, 78, 943‒951. 37. Boess, E.; Wolf, L. M.; Malakar, S.; Salamone, M.; Bietti, M.; Thiel, W.; Klussmann, M. Competitive hydrogen atom transfer to oxyl- and peroxyl radicals in the Cu-catalyzed oxidative coupling of N-aryl tetrahydroisoquinolines using tert-butyl hydroperoxide. ACS Catal., 2016, 6, 3253‒3261. 38. Tsang, A. S.-K.; Stephen, A.; Hashmi, K.; Comba, P.; Kerscher, M.; Chan, B.; Todd, M. H. N-aryl groups are ubiquitous in cross-dehydrogenative couplings because they stabilize reactive intermediates. Chem. Eur. J. 2017, 23, 9313–9318. 39. Peterson, S. W.; Levy, H. A. Proton positions in CuCl2·● 2H2O by neutron diffraction. J. Chem. Phys., 1957, 26, 220. 40. Silverstein, T. P. Marcus Theory: Thermodynamics can control the kinetics of electron transfer reactions. J. Chem. Educ., 2012, 89, 1159‒1167. 41. Marcus, R. A. (1992) “Rudolph A. Marcus - Nobel Lecture”. Nobelprize.org. June 24, 2010; http://nobelprize.org/nobel_prizes/chemistry/laureates/1992/marcus-lecture.html. 42. Mardirossian, N.; Head-Gordon, M. Thirty years of density functional theory in computational chemistry: an overview and extensive assessment of 200 density functionals. Mol. Phys., 2017, 115, 2315‒2372. 43. Mayr, H.; Ofial, A. R. Do general nucleophilicity scales exist? J. Phys. Org. Chem., 2008, 21, 584‒595. 44. Bug, T.; Lemek, T.; Mayr, H. Nucleophilicities of nitroalkyl Anions. J. Org. Chem., 2004, 69, 7565‒7576. 45. Lucius, R.; Loos, R.; Mayr, H. Kinetic Studies of carbocation - carbanion combinations: key to a general concept of polar organic reactivity. Angew. Chem., Int. Ed., 2002, 41, 91‒95.


Page 47 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


46. Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.;. Irrgang, B; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. Reference scales for the characterization of cationic electrophiles and neutral nucleophiles. J. Am. Chem. Soc., 2001, 123, 9500‒9512. 47.

Jensen, F. Introduction to computational chemistry, John Wiley & Sons, New York, 1999.

48. Parr, R. G.; Yang, W. Density functional theory of atoms and molecules, Oxford University Press, 1989. 49. Kohn, W.; Becke, A. D.; Parr, R. G. Density functional theory of electronic structure. J. Phys. Chem., 1996, 100, 12974‒12980. 50. Jiang, Y.-Y.; Man, X.; Bi, S. Advances in theoretical study on transition-metal-catalyzed C‒H activation. Sci. China Chem., 2016, 59, 1448‒1466. 51. Zhao, Y.; Truhlar, D. G. A new local density functional for main-group thermochemistry, transition metal bonding, thermochemical kinetics, and noncovalent interactions. J. Chem. Phys., 2006, 125, 194101/1‒18. 52. Dunning, Jr., T. H. Electron affinities of the first‐row atoms revisited. Systematic basis sets and wave functions. J. Chem. Phys., 1989, 90, 1007‒1023. 53. Stevens, W. J.; Krauss, M.; Basch, H.; Jasien, P. G. Relativistic compact effective potentials and efficient, shared-exponent basis sets for the third-, fourth-, and fifth-row atoms. Can. J. Chem., 1992, 70, 612‒630. 54. Stevens, W. J.; Basch, H.; Krauss, M. Effective potentials and multiconfiguration wave functions in quantum Monte Carlo calculations. J. Chem. Phys., 1984, 81, 6026. 55. Goldstein, E.; Beno, B.; Houk, K. N. Density functional theory prediction of the relative energies and isotope effects for the concerted and stepwise mechanisms of the Diels−Alder reaction of butadiene and ethylene. J. Am. Chem. Soc., 1995, 118, 6036‒6043. 56. Yamanaka, S.; Kawakami, T.; Nagao, K.; Yamaguchi, K. Effective exchange integrals for open-shell species by density functional methods. Chem. Phys. Lett., 1994, 231, 25‒33. 57. Yamaguchi, K.; Jensen, F.; Dorigo, A.; Houk, K. N. Spin correction procedure for unrestricted Hartree-Fock and Møller-Plesset wavefunctions for singlet diradicals and polyradicals Chem. Phys. Lett., 1988, 149, 537‒542. 58. Cramer, C. J.; Dulles, F. J.; Giesen, G. J.; Almlof, J. Density functional theory: excited states and spin annihilation. Chem. Phys. Lett., 1995, 245, 165‒170. 59. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B, 2009, 113, 6378‒6396. 60. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Performance of SM6, SM8, and SMD on the SAMPL1 Test set for the prediction of small-molecule solvation free energies. J. Phys. Chem. B, 2009, 113, 4538‒4543. 61. Foresman, J. B.; Frisch, A. Exploring chemistry with electronic structure methods, Gaussian, Pittsburgh, 1996. 47 ACS Paragon Plus Environment


62.

Page 48 of 49

McQuarrie, D. A. Statistical Thermodynamics, Harper and Row, New York, 1973.

63. Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Use of solution-phase vibrational frequencies in continuum models for the free energy of solvation. J. Phys. Chem. B, 2011, 115, 14556‒14562. 64. Gaussian 09, Revision A.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al Gaussian 09, Gaussian, Inc., Wallingford, CT, 2009. 65. Reed, A. E.; Weinstock, R. B.; Weinhold, F. W. Natural population analysis. J. Chem. Phys., 1985, 83, 735‒746 66. Schaftenaari, G.; Noordik, J. H. Molden: a pre- and post-processing program for molecular and electronic structures. J. Comput.-Aided Mol. Des., 2000, 14, 123‒134.


Page 49 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC Graphic


Aerobic CuCl2-Catalyzed Dehydrogenative Cross-Coupling of Tertiary

Recommend Documents