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"Synthetic and Mechanistic Investigations on Copper Mediated C-N Bond Formation in Arylation Reactions"

PhD Synopsis

Submitted to

GUJARAT TECHNOLOGICAL UNIVERSITY

For the Degree

of

Doctor of Philosophy

In

Chemistry

By

Kamlesh Kumar Gurjar

(Enrollment No.: 139997672001)

Supervisor: Dr. Rajendra K Sharma Assistant Professor, DESM

Regional Institute of Education NCERT, Ajmer, Rajasthan

DPC Members

Dr. K H Chikhalia,

Professor, Department of Chemistry,

Veer Narmad South Gujarat University,

Surat

Dr. Sudhanshu Sharma,

Assistant Professor, Department of Chemistry,

IIT, Gandhinagar, Palaj, Gandhinagar.

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“Synthetic and Mechanistic Investigations on Copper Mediated C-N Bond Formation in Arylation Reactions.”

Graphical Abstract

I

NH

O

O

CuI

Ligand(N, N)

Cu

O

O

HN NH

NHC OO

Me

Me

O

K2CO3N

O

O

CuO

OC O

H2N

H2N

InactiveDFT studies

Direct observation of Cu(III) species in situ Uv-Vis and FTIR studies and

predicted by DFT

Cl

Nu-N+CuI/Ligand pair/Base

R

R

up to 99% yield>24 examples

Nu-NH

Imides,amides, amines Selective C-Cl and C-I activation

K2CO3/Toluene/110 o

C

3. Activation of aryl chloride in copper mediated C-N coupling reactions;a synthetic and theoritical (DFT) studies

1. Mechanistic-experimental and theoritical studies

2. Possible deactivation pathways of Cu(I) catalyst.

Cu(I)

Cu(II) + ICu(II) + Cu(0)

Generation of nucleophile ligated inert [Cu(Nu)2]- species

Carbonate ligation

+PhI

Cu(III) intermediate

Oxidation of Cu(I) in to Cu(II) through aryl free radical formationBase or ligand promoted

disproportionation of Cu(I)

3

Abstract

Although copper-catalyzed nucleophilic aromatic substitution reactions were discovered

more than a century ago by Ullmann and Goldberg but harsh temperature condition, use of

highly polar solvents and high loading of catalyst restricted their synthetic utility. In last two

decades, reaction was revitalized by introduction of bidentate ligands (N,N/N,O/O,O) to

lower down loading of copper and to achieve milder conditions.

Copper mediated C-heteroatom coupling have been developed as cheaper substitute of

expensive Pd/ligand system. Conversely to Pd-mediated cross coupling reactions, mechanism

of these reactions are poorly understood and cheaper arylchlorides are extremely poor

substrates. Moreover, causes of deactivation of copper catalyst during course of reaction are

not known. However, uncertainty about the behavior of copper/ligand system and awaiting

activation of cheaper aryl chlorides restricted the wider applications of copper catalyzed

reactions.

It has been reported in the literature that Cu-based coupling reactions are in some sense

unpredictable. In earlier attempts, to establish the mechanism, roles of ligand and base were

keenly investigated and widely used carbonate species was considered as a base. However,

actual intermediate species in the catalytic cycle could not be traced out.

In first phase of studies, in-situ spectroscopic (FTIR and Uv-Vis) experiments were designed

to find the intermediate species. Observations indicate, carbonate and phosphates which are

considered as base, actually are second ligands. Copper mediated C-N coupling reactions

follow oxidative addition reductive elimination (OA-RE) pathway through Cu(III) species

and carbonate/phosphate ligated octahedral Cu(III) are actual intermediate. Studies provide

direct spectroscopic evidences of actual Cu(III) intermediate species. Experimental results are

complimented with DFT studies.

In second phase of studies, detailed DFT studies were conducted to investigate deactivation

of copper catalyst. Various hypothesis proposed in literature, were investigated. DFT studies

were performed on more than 20 intermediate species. In present computational studies, it

was found that ligation of carbonate base to active copper species is actual reason for

deactivation and carbonate offers competitive ligation to nucleophile.

In third phase of studies, a normal and facile protocol has been developed for arylation of

imides, amides and amines, using cheaper aryl chlorides at 110 oC. This protocol involves

CuI and a pair of readily available simple diamine ligands to functionalize (Aryl) C-Cl bond.

It is not only a potential alternative of expensive Pd catalyst, but also cheaper substitute of

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costly aryl iodides. Current method provides powerful new synthetic strategy for selectively,

installation of two nucleophiles in chloroiodoarenes by successive activation of C-I/C-Br and

C-Cl bonds.

A catalytic cycle has been proposed for CuI/ligand pair promoted activation of C(aryl)-Cl

bond on the basis of DFT calculations. These observation indicate that reaction follows

oxidative addition-Reductive elimination and active catalytic species are tetracoordinated

Cu(I).

X

H-N/O/S-nucleophile+ CuI/Ligand

N/O/S-nucleophile

Base

Scheme 1 Ullmann-Goldberg reaction

State of the Art of Research Topic

Copper-mediated reactions are widely used in synthesis of polymers, bio-active molecules

and agro-chemicals.1–4 Arylation of amines, amides, imides and phenols has extensive

applications in synthetic organic chemistry and it has become an essential tool in modern

laboratories and industries.5

A survey of the literature6–14 reveals that mechanisms of copper catalyzed C-N coupling

reactions involving reactive aryl halides (ArBr and ArI) are mainly classified in four

categories (Scheme 2 and 3):

1. π−complex formation-Cu(I) forms π-coordinated complex with aryl halide to

facilitate the attack of nucleophiles.

2. σ−bond metathesis-formation of Cu(I) cyclic complex with nucleophile and aryl

halide.

3. Free radical substitution-single electron transfer (SET) and halogen atom transfer

(HAT) by involvement of Cu(I)/Cu(II) and radical intermediate.

4. Oxidative addition-reductive elimination (OA-RE) by involvement of Cu(III)

intermediate.

It is commonly accepted that Cu(I) species are the active catalytic species in coupling

reactions.6

5

Free radical substitution via Cu(I)/Cu(II) (SET and HAT) and oxidative addition-reductive

elimination (OA-RE) via Cu(I)/Cu(III) mechanisms are under debate for Cu-mediated

coupling reactions.6,10,15

LCuI-Nu

X

LCuI

XNu

Nu

+ LCuI-X

LCuI-Nu

X

1. π

-complex formation

2. σ-bond metathesis

X

NuCuIL

Nu

+ LCuI-X

Scheme 2 Previously suggested pathways for Ullmann coupling reactions

3. (a) Free radical single electron transfer (SET)

LCuI-Nu

X

LCuII-Nu

XNu

+ LCuI-X

3. (b) Free radical atom transfer (AT)

LCuI-Nu

X

LCuIINu

X

Nu

+ LCuI-X

4. Oxidative addition-reductive elimination

LCuI-Nu

X

Nu

X

Nu

+ LCuI-XCuIIIL

Scheme 3 Recently suggested pathways for Ullmann coupling reactions

Most of the computational and experimental studies indicate that Cu(I)/ligand facilitated N-

arylation reactions follow OA-RE pathway.7 Free radical mechanism was invoked many

times but discarded due to invalidated negative radical clock experiment and lack of

inhibition by radical scavengers. In 2010 Buchwald group,14 suggested free radical

mechanism on the basis of computational studies that short lived phenyl free radical remains

in a caged and therefore invalidate the radical clock test.

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Definition of the Problem

Present investigations are based on three problems-

1. Copper-mediated reactions are uncertain and not well understood like Pd-mediated

reactions and actual intermediate copper species are not well known.6,10

2. Deactivation of copper catalyst, during course of reactions.6,16–18

3. Limited substrate scope of Ullmann reaction e.g. activation of cheaper arylchlorides

remains challenge.19,20

Systematic experimental and computation studies were performed to find out solutions of

aforementioned problems.

Objective and Scope of Work

Objectives:

1. To investigate the reaction mechanism of Cu-mediated C-N cross coupling reactions

involving aryl iodide.

2. To investigate the deactivation of copper catalyst in modern Ullamann reaction.

3. To investigate the synthetic and mechanistic aspects of activation of commercially

available cheaper aryl chlorides in N-arylation reactions.

Scope of Work

A survey of the literature indicates that earlier studies have not been able to provide sufficient

experimental evidences in favour of oxidative addition-reductive elimination pathway for the

coupling reactions. However, on the basis of experimental and computational studies, several

research groups have proposed the involvement of Cu(III) intermediate and Cu(III) has been

demonstrated in electrochemical studies by Taillefer and Jutand group.9 Cu(III)I

demonstrated in predefined pincer complex by Stahl and co-workers.21 However, Cu(III)

intermediates could not be demonstrated through spectroscopic studies in the reaction of

typical coupling partners.

These studies could not explain the deacctivation of copper catalyst and consequently, higher

loading of ligand and copper.18 Notably, copper (5-10 mol%) and ligand (10-20 mol%)

loading is relatively higher than the Pd/ligand loading in Buchwald-Hartwig reaction.20

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Methodology of Research

Extensive experimental studies were conducted to solve the aforementioned problems and

these results were well complimented with theoretical studies (Density functional

calculations).

a. Synthetic-Experimental studiesb. Mechanistic investigation-

1. To investigate reaction mechanism of Cu-mediated C-N cross coupling reactions and investigate the actual intermediate copper species.

Experimental (In situ Uv-Vis andFTIR spectroscopic studies) andComputational (DFTcalculations)

2. To investigate the deactivation of copper catalyst. Computational studies

3. To investigate the activation of cheaper arylchlorides

MethodProblem

(DFT calculations)

Computational (DFT) studies

Figure 1 Methodology used in solving the problem

1. To investigate the mechanistic aspects of reaction, in situ FTIR and Uv-Vis

spectroscopic studies were conducted. Experimental electronic and vibrational spectra

were compared with theoretical spectra to get approval of involved intermediate

species (Figure 1).

2. During investigation of mechanism it was noticed that carbonate play triple role in

process and thus to explore these finding DFT studies were conducted. These studies

unveiled that carbonate species are responsible for deactivation of copper catalyst.

3. CuI/ligand pair protocol has been developed for activation of long awaited aryl

chlorides. DFT studies have also been conducted to investigate the role of second

ligand.

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Results

1. Mechanistic studies on Ullmann type C-N coupling reactions involving aryl

iodides22

L2Cu-NNu

PhI

L2Cu

Ph

I

NNu

L2CuI

NuNH, CO32-

I-

OA

RE

PhNNu

L2=

L2Cu-HNNu

PhI

L2Cu

I

L2CuCO3

NuNH

OA

RE

PhNNu

L2CuPh

NuNH

O

OC O

CO32-

I-

CO32-

HNNH CH3H3C

(a) (b)

HNNu

Ph

Base

Figure 2 OA-RE mechanism pathways (a) Previously suggested (b) proposed catalytic cycle in current study (NuNH= amides and imides).

CuN

NH

Me

Me

-107.85

O

OC O

TSRE

+1.07

+N

O

H

inert species

Reductive elimination

CuIII

PhHN

O

O NHPyHNC O 1 TSRE

Figure 3 Free energy gap of various intermediates in catalytic cycles in toluene at 298 K. Transition state (TS) for reductive elimination (without deprotonation of nucleophile).

1.1. It was noticed that oxidative addition can proceed without presence of base or in

presence of sub-mol amount of base (Figure 2, 3 and 4).

1.2. Deprotonation of nucleophile is not necessary for oxidative addition.

1.3. Species appears in oxidative addition in presence of base and in absence of base

are different and they show different electronic spectra.

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1.4. In situ FTIR studies revealed that carbonate act as ligand in process and

facilitates reductive elimination.

1.5. These reactions follow oxidative addition-reductive elimination pathways.

1.6. It was also noticed that carbonate ligand is competitor ligand of nucleophile.

Role of carbonate ligated Cu(I) and Cu(III) species were proposed in

mechanism.23

(a)

CuIII

PhHN

O

O NHPyHNC O

1

Figure 4 Electronic spectrum (simulated and experimental) of species 1, b. FTIR spectrum of bidentate carbonate in species 1 (calculated values are shown in bracket).

2. Deactivation of copper catalyst - a theoretical investigation

Following possible reasons of deactivation of copper catalyst have been discussed in the

literature, (i) generation of nucleophile ligated inert [Cu(Nu)2]- species,24 (ii) base or ligand

promoted disproportionation of Cu(I),18 (iii) oxidation of Cu(I) in to Cu(II) through aryl free

radical formation25 and (iv) formation of carbonate ligated inert species.22

Results reveals that formation of carbonate ligated inert species [L1CuCO3]- are actual

reason of deactivation. Our DFT studies23 indicate that formation of [L1CuNHAc] is favored

by -41.29 kcal/mol free energy (Scheme 4). Interestingly, the ligation of CO32- is more

favored (∆G=-43.41 kcal/mol) than ligation of AcNH- (∆G=-41.29 kcal/mol). Actually,

carbonate and nucleophile (AcNH-) are competitor ligands. Formation of active catalytic

species [L1CuNHAc] is slightly unfavoured over formation of inert speccies [L1CuCO3]-

(∆G=2.12 kcal/mol). Excess carbonate prevents the formation of active catalytic species.

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K[L1CuCO3] + AcNH2 L1CuNHAc + KHCO3

L1CuI + AcNH2 + K

2CO3 L1CuNHAc+ KI + KHCO3

L1CuI + K2CO3 K[L1CuCO3] + KI

H[L1CuCO3] + AcNHK

-27.43 kcal/mol

-27.34 kcal/mol

-0.89 kcal/mol

K[L1CuCO3] + AcNH2 12 kcal/mol

L1CuCO3AcNH2 + L1CuNHAc HCO3+ 2.12 kcal/mol

L1CuAcNH2 CO3-2+ + L1CuNHAc HCO3

-+ -41.29 kcal/mol

L1Cu CO3-2 L1CuCO3

+ -43.41 kcal/mol

Scheme 4 Role of carbonate in deactivation of Cu(I), computed free energy for various possible paths.

3. Activation of aryl chlorides-synthetic and mechanistic studies 3.1. Synthetic studies

We have developed a simple CuI/ligand pair protocol for C-N coupling reactions involving

aryl chlorides and phthalimide (Scheme 5). Protocol has also been found satisfactory for aryl

amines. Moreover, low cost of CuI and commercial availability of diamine ligands expected

to make this method attractive for industries and academia. In view of the difference in

reactivity of C-Cl and C-Br, we explored a new synthetic approach to install two different

nucleophiles by sequential activation of C-Br and C-Cl bonds. The proposed synthetic

method can be further explored for the synthesis of important bio-active molecules, e.g.

imatinib and acetaminophen.

3.2. Mechanistic studies

NH2

Investigated other nucleophiles

R1N NH2

Pd/ligand

base+ NuHBuchwald Hartwig reaction ArCl Ar-Nu

CONH2

NH

O

O

5 mol% CuI, 110 oC/ 16 h 10 mol% L1,10 mol% L2

+N

O

O1.5 eq 1 eq

toluene/K2CO3 (1 eq.)

Cl

R R

This work

yield up to 98%23 examples

Scheme 5 Investigated protocol

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Extensive DFT studies were performed to investigate free radical (SET and HAT) and OA-

RE pathway. Insight into mechanism of coupling reaction involving aryl chlorides and imides

have been investigated. Radical clock test and DFT studies indicate that reaction follows OA-

RE pathway. Catalytic cycle has been proposed for arylation of imide. Species 1c are actual

catalytic species in present case.

[Cu(L1)2] [Cu(L2)2]

[Cu(L1)(Nu)]

1a 1b

1e[Cu(Nu)2]

1f

[CuL1]1d

[Cu(L1)(L2)]1c

In presence of single ligand (L1 or L2) Additional CCS in presence of two ligands (L1 and L2)

L1/L2Cu(I)Insoluble

Figure 5 Possible copper catalytic species (CCS)

∆G=49

2.34 2.5

1.81

1.99

2.1

3.06

TSOAc TSRE

TSHAc

3.4

1.92 2.78

2.14

TSHAe

1.93.25

TSHATb

TSHATf

2.991.86

2.381.82

TSOAe

TSOAb

2.2 2.5

1.85

∆G=16

∆G=61.7

∆G=63 ∆G=54

∆G=82.4 ∆G=56.4∆G=54.3

Figure 6 DFT calculated Gibb’s free energy (∆G) and optimised geometries of transition states in

different paths (OA=oxidative addition, HAT=halogen atom transfer)

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Cl

[CuI(L1)(L2)]

PhClCuI(L1)(L2)]

PhCuIIICl

(L1)(L2)]

K2CO3 + NuH

KHCO3 + KCl

PhCuIIINu

(L1)(L2)]PhNu

1c

2c

3c

4c

RE

OA

(2η complex)

Figure 7 proposed catalytic cycle

Comparison Outcomes of research work

Achievements with respect to objectives

1. In situ spectroscopic studies were

conducted and broader role of base has

been proposed in catalytic cycle

Studies22 have been published in peer

reviewed international journal

ChemCatChem (impact factor-4.8).

Importance of studies recognised by

scientific community. (07 citation received

within a year)

2. Actual reason of deactivation of copper

catalyst have been proposed on the

basis of DFT studies

Recently, studies23 have been published in

peer reviewed and scopus indexed

international journal Asian journal of

chemistry.

3. Activation of aryl chlorides-general

and facile protocol have been

developed. Mechanism also has been

investigated

Manuscript is reviewed in RSC Chemcomm

(impact factor-6.13). Revised full article is

under consideration in Tetrahedron (impact

factor-2.65), Elsevier.

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Conclusion

Respective objectives has been achieved. The proposed catalytic cycle is expected to

contribute for further investigation on mechanistic aspects of these reactions. The novel

protocol for activation of aryl chlorides has also been successful in installing two distinct

nucleophiles on the substrate by successive C-Br and C-Cl bond activation therefore, it can

be further investigated for synthesis of molecules of industrial importance. Current protocol

opens scope for C-S, C-O and C-N coupling using aryl chlorides.

Original Contribution by the Thesis

Two full articles have already been published in international peer reviewed (Scopus

indexed) journals and one more manuscript is under process of publication in the reputed

international journal. Other original findings and outcomes of the PhD work will also be

published in the Journal of international repute.

Publications

1. Gurjar KK, Sharma RK. Mechanistic Studies of Ullmann-Type C–N Coupling Reactions: Carbonate-Ligated Copper(III) Intermediates. ChemCatChem. 2017;9(5):862-869. doi:10.1002/cctc.201601174 (impact factor-4.8). Citation-08+1 (including one self-citation).

2. Gurjar KK, Sharma RK. Theoretical investigations on deactivation of copper catalytic species in Ullmann cross coupling reactions. Ajchem. 2018;30(6):1401-1404. doi:10.14233/ajchem.2018.21381

3. Gurjar KK, Sharma RK , Activation of C(aryl)-Cl bond activation in Ullmann C-N coupling; is under consideration in Journal of Catalysis, Elsevier, (Impact factor-6.9).

Presentation at National Conference

1. Gurjar KK, Sharma RK. Green Synthesis of p-Substituted Phenyl amines via Copper

Mediated CN Coupling of Isoindole-1,3-dione and Aryl halides. International

Conference on Recent Trends in Chemical Sciences, held at Department of Chemistry,

Govt. College, Banswara during January,18-19, 2016,.

2. Gurjar KK, Sharma RK. Green Synthesis of Aniline by C-N coupling of ammonia

surrogates and aryl halides in different Cu catalytic systems. National Seminar on

Frontiers at Chemistry Allied Sciences Interface, held at Department of Chemistry,

University of Rajasthan, Jaipur during March,13-14, 2015.

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3. Gurjar KK, Sharma RK.,Green synthesis of Phenyl amines by Cu-mediated Ullmann

Goldberg C-N coupling of ammonia surrogates and aryl halides. National Conference on

Green Chemistry held at Department of Chemistry, Govt. PG College, Dausa. During

December,15-16,2014.

UGC Minor Research Project

This work has been financially supported by University Grant Commission, India.

Patents (if any): Nil

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23. Gurjar KK, Sharma RK. Theoretical investigations on deactivation of copper catalytic species in Ullmann cross coupling reactions. Ajchem. 2018;30(6):1401-1404. doi:10.14233/ajchem.2018.21381

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