Formation and Reactivity of Nitrenes with Silver Catalysts for

C-H Bond Amination

Prasoon Saurabh Dr. Joe ScanlonRipon College

Experimental background:Why C-N bonds?

• Important in pharmacology and synthesizing natural products

• Synthetically very challenging

• Reaction of interestMorphine

Penicillin

C

H

C

N

Catalysts for the Formation of C-N Bonds

• Only intramolecular amination reactions

H2N

O

O CH

H

2 mol%AgNO3 and tBu3tpy

CH3CN 82°CPhI(OAc)2

Y. Cui, C He, Angew. Chem. Int. Ed. 2004, 43, 4210-4212.

[Ag2(tBu3tpy)2(NO3)]+Catalyst 1

• Intermolecular Reactions

• Cyclo-alkane Reactions

2 mol% CatPhI=NNs

CH2Cl2 50°C

+ PhI

+ PhI

2 mol% Cat PhI=NNs

CH2Cl2 50°C

L. Zigang, D. Capretto, R. Rahaman, C. He, Angew. Chem. Int. Ed. 2007, 46, 5184-5186.

[(Agbp)2OTf2H2O]

Catalyst 2

Benefits of using Ag catalysts for amination reactions

• Ag is readily available

• Ligands used are available commercially

• Able to react at a relatively low temperature

• Reacts with relatively inert C-H bonds in cyclo-alkanes

H2N

O

O CH

H

2 mol%AgNO3 and tBu3tpy

CH3CN 82°CPhI(OAc)2

Lower than boiling point of water[50°C for phenanthroline (phen)]

My research goals:• Generation of a model system of the disilver

catalysts to determine the mechanism of formation of nitrene

• Ag mediated generation of a nitrene• Singlet-triplet gaps for intermediate molecules and the

nitrene • Calculation of energy of formation of intermediates and

nitrene

• Monomer Vs Dimer form of catalysts Agtpy and Agphen

• Validation of truncation of ligands• [Ag2(tBu3tpy)2(NO3)]+ to Ag2tpy2(catalyst 1)• [(Agbathophen)2OTf2H2O] to Ag2phen2(catalyst

2)

Formation of Nitrene:• An organic compound containing nitrogen atom with 6 valence electron

around the nitrogen with general formula:

• Nitrenes are important reactive electrophilic intermediate in amination reaction

• For studying formation of nitrene (NTs), ethenediamine (L) is used as a model ligand for phenanthroline (phen).

• The similar ligand was used for a nickel complex as studied computationally by Cundari and Morello1.

Cundari T. R. ; Morello G. R. J. Org. Chem., 2009, 74 (15), pp 5711–5714

Ag-(L)Ag

L=ethenediamine

dhpe=1,2-bis-(dihydrophosphino)ethane

Theoretical Methods:

• Density Functional: B3LYP, M06L

• Basis sets used on all non-metal atoms: midi! and 6-31G(d)

• Stuttgart Dresden Dunning (SDD) basis set and effective core potential for Ag

Motivation: Cundari* Paper...

• Model ligand used was (dhpe=1,2-bis-(dihydrophosphino)ethane) which is similar system as Ag2phen2

• B3LYP/CEP-121G where CEP-121G being combined basis set for both core potential and valence electron

Lowest energy intermediate*: (dhpe)Ni-PhI=NTs

dhpe

*Cundari T. R. ; Morello G. R. J. Org. Chem., 2009, 74 (15), pp 5711–5714

Cundari Paper*

Intermediates

Products

*Cundari T. R. ; Morello G. R. J. Org. Chem., 2009, 74 (15), pp 5711–5714

•Cundari found that the lowest energy intermediate found have iodine and oxygen coordinated to the nickel and the iodine-nitrogen bond intact

Energy Diagram of Intermediates of Nitrene Formation for Ag(ethenediamine)+1

• Atoms in parenthesis are coordinated to silver• Solvation might show slightly different results (work in progress)• Similar structures and relative energies as found by Cundari’s nickel system

Intermediates Atoms in parenthesis are coordinated to silver (bond

length in Å and bond angles in degrees )

N(1) from NitreneN(2) from Liganda the product of the silver catalyst mediated nitrene formation

LAg(N)NTs LAg(3N)NTsa

Ag-N(1) 2.16 2.21Ag-N(2) 2.32 2.30Ag-O NA NA Ag-I NA NA

N(1)-Ag-N(2) 146.2 140.2N-Ag-O NA NA O-Ag-I NA NA

LAg(N)NTs[RE = -46.45 Kcal/mol]

* Ethene diamine (L)

LAg(3N)NTs[RE = -58.22 Kcal/mol]

Intermediates• Atoms in parenthesis are coordinated to silver

(Bond length in Å and bond angles in degrees )

LAg(O)(N)PhI=NTs LAg(I)IPh(O)3NTsb

Ag-N(1) 2.28 2.38Ag-N(2) NA 2.36Ag-O 2.13 2.30Ag-I NA 3.15

N(1)-Ag-N(2) NA NA N-Ag-O 167.1 102.2O-Ag-I NA 91.3

N(1) from NitreneN(2) from Ligandb the lowest relative energy intermediate of the silver catalyst

mediated nitrene formation reaction

* Ethene diamine (L)

LAg(I)IPh(O)3NTs[RE = -63.18 Kcal/mol]

LAg(O)(N)PhI=NTs[RE = -58.22 Kcal/mol]

3

Results: Singlet-Triplet Gap• In experimental study of Ag catalyst reaction pathways, phenyl

iodide nitrene [PhI-NTs] is one of the important precursors.

• For NTs, triplet is favored energetically over singlet by 9.6 kcal/mol

• However, optimizing a triplet PhI-NTs (nitrene precursor) leads to I-N bond breaking suggesting that it may not be the stable precursor

NTs

Model Ligand Vs Actual Ligand:

AgL AgPhen

Ag-N/Å 2.32 2.27

N-Ag-N/° 78.2 77.0

Uncoordinated

Coordinated NitreneLAg-NTs Agphen-NTs

Ag-N1/Ǻ 2.31 2.12

Ag-N2/Ǻ 2.37 2.19

Ag-N3/Ǻ 2.16 2.02

N1-Ag-N2/° 74.4 78.2

N1-Ag-N3/° 146.2 98.2

N2-Ag-N3/° 138.9 176.4

N1

N3

LAg-NTs

N2

Agphen

N1

N2

•The calculations validate ethenediamine as a model ligand for phen

Truncating the substituent Used in order to increase the speed of computational

process Truncated:

Removed tert-butyl from tBu3tpy to form tpy

Removed phenyl groups from bathophenanthroline (Bathphen) to form phenanthroline (phen)

tBu3tpy tpy

phenanthrolinebathophenanthroline

Proper truncation of substituent

To see if the truncating process is proper: Compare the desired bond lengths Decide if the model system is good

Optimized geometry for both monomers and dimers of Ag-coordinated with tBu3tpy and tpy ; bathophen and phen using B3LYP/midi! with SDD as effective core potential for Ag Bond distances and bond angles compared

Geometry: Results

Ag2Bathophen2 Ag2Phen2

Ag(1)-Ag(2) 2.69 3.06

Ag(1)-N(1) 2.19 2.27

Ag(1)-N(2) 2.19 2.27

Ag(2)-N(3) 2.19 2.27

Ag(2)-N(4) 2.19 2.27

Table: Comparing Bond lengths in Å for Batho-phen and phen

Ag2Bathaphen2

Ag2Phen2

Ag(1)

Ag(2)

Ag(1)Ag(2)

N(1)

N(4)

N(3)

N(2)

N(1)N(2)

N(4)N(3)

•It was found that Ag2Phen2 had stacked geometry while in Ag2Bathophen2 ligands were on the opposite side of the metals perhaps due to steric hindrance

Geometry: Results

[Ag2(tpy)2NO3]+ Experimental M06-L/midi!Ag(1)-Ag(2) 2.84 2.95

Ag(1)-N(1) 2.29 2.32

Ag(1)-N(2) 2.45 2.46

Ag(1)-N(3) 2.24 2.35

Ag(1)-N(5) 2.45 2.37

Ag(2)-N(4) 2.27 2.31

Ag(2)-N(6) 2.27 2.56

Ag(2)-O(1) 2.33 2.12

Ag(2)-O(2) 2.72 2.28

Table: Comparing bond length in Å between experimental and theoretical values

N and O from NO3-

Further characterization• From earlier geometry calculations we find that Ag-Ag

bond is shorter in Ag2tpy2 than Ag2phen2

• To see if formation of Ag-Ag is possible in Ag2phen2 compared to Ag2tpy2, bond order (BO) calculations were performed in both the monomers and dimers of the Agtpy and Agphen.

• To compare the strength of disilver and Ag-N bonds, similar BO calculations were performed for the Ag-bathaphenalthroline and [Ag2tpy2(NO3)]+

Bond OrdersAg2phen2 Ag2bathophen2 Agphen Agbathphen

Ag1-Ag2 0.72 0.82 NA NA

Ag1-N1 0.39 0.35 0.35 0.28

Ag1-N2 0.39 0.35 0.35 0.28

Ag2-N3 0.39 0.35 NA NA

Ag2-N4 0.38 0.35 NA NA

N1N2

Agphen

Ag1

N2

Ag1

N1

Agbathphen

Ag1Ag

2

N2

N1

N3

N4

Ag2bathophen2

Ag1

Ag2

N2N1

N4

N3

Ag2phen2

Bond orders for Ag-Ag and Ag-N in monomers and dimers of AgPhen and AgBathphen

Bond OrdersAgtpy Ag2tpy2 [Ag2tpy2(NO3)]

+

Ag1‐Ag2 NA 0.75 0.69Ag1‐N1 0.28 0.29 0.30Ag1‐N2 0.28 0.29 0.23Ag1‐N3 0.27 NA 0.14Ag2‐N4 NA 0.29 0.27Ag2‐N5 NA 0.29 0.25Ag2‐N6 NA 0.18 0.29Ag2‐N3 NA NA 0.28Ag2‐N2 NA NA 0.12Ag1‐O1 NA NA 0.42Ag1‐O2 NA NA 0.53

Bond orders for Ag-Ag and Ag-N in monomers and dimers of Agtpy; [Agtpy2(NO3)]+

[Ag2tpy2(NO3)]+

Ag1

N1

N2

N3

Ag2

N2

Ag1

N1

N6 N3

N4

N5

O1

O2

Agtpy

Ag2tpy2

Ag1Ag2

N4

N6

N1 N5

N2

Conclusion• Ethenediamine does a good job as a model ligand for

phenanthroline.

• Desired product LAg3NTs is not the lowest energy species so perhaps the reaction goes through an intermediate.

• Three intermediates were found with LAg(I)IPh(O)3NTs being the lowest with RE = -63.18 Kcal/mol

• Truncated ligands could be used instead of actual ligands for reducing computation time with similar results

• Disilver bond length was found to be longer Ag2phen2 in than in Ag2tpy2

• Disilver bond order was 0.75 Ag2tpy2 in compared to 0.72 in Ag2phen2

Next Steps

Find transition states between the intermediate and nitrene reactants

Perform the actual amination step

Solvation calculations

Molecular Orbital Analysis

Natural Bond Order calculations

Acknowledgement

• Dr. Joseph Scanlon

• Dr. Masanori IIumura

• Dr. Dean Katahira

• Dr. Colleen Byron

• Rachel Van den Berg

• Ripon College Chemistry Department

• Midwest Undergraduate Computational Chemistry Consortium (MU3C)

• Minnesota Supercomputing Institute

• Everyone for their supports.