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Home , Nitrene

Formation and Reactivity of Nitrenes with Silver Catalysts for C-H Bond Amination

Prasoon Saurabh Dr. Joe Scanlon Ripon College Experimental background: Why C-N bonds?

• Important in pharmacology and synthesizing natural products

• Synthetically very challenging

• Reaction of interest Morphine H N C C

Penicillin Catalysts for the Formation of C-N Bonds

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

• Only intramolecular amination reactions

H 2 mol% H2N O CH AgNO3 and tBu3tpy

CH3CN 82°C PhI(OAc) O 2

Y. Cui, C He, Angew. Chem. Int. Ed. 2004, 43, 4210-4212. Catalyst 2

• Intermolecular Reactions

2 mol% Cat PhI=NNs [(Agbp)2OTf2H2O] CH2Cl2 50°C + PhI

• Cyclo- Reactions

2 mol% Cat PhI=NNs + PhI CH2Cl2 50°C

L. Zigang, D. Capretto, R. Rahaman, C. He, Angew. Chem. Int. Ed. 2007, 46, 5184-5186. Benefits of using Ag catalysts for amination reactions • Ag is readily available • used are available commercially • Able to react at a relatively low temperature

H 2 mol% H2N O CH AgNO3 and tBu3tpy

CH3CN 82°C PhI(OAc) O 2

• Reacts with relatively inert C-H bonds in cyclo- 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 atom with 6 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 for phenanthroline (phen).

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

L=ethenediamine

Ag dhpe=1,2-bis-(dihydrophosphino)ethane Ag-(L) Cundari T. R. ; Morello G. R. J. Org. Chem., 2009, 74 (15), pp 5711–5714 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

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

*Cundari T. R. ; Morello G. R. J. Org. Chem., 2009, 74 (15), pp 5711–5714 Cundari Paper* •Cundari found that the lowest energy intermediate found have iodine and oxygen coordinated to the nickel and the iodine-nitrogen bond intact

Intermediates

Products

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

LAg(N)NTs LAg(3N)NTsa Ag-N(1) 2.16 2.21 Ag-N(2) 2.32 2.30 Ag-O NA NA Ag-I NA NA LAg(N)NTs N(1)-Ag-N(2) 146.2 140.2 [RE = -46.45 Kcal/mol] N-Ag-O NA NA O-Ag-I NA NA

* Ethene diamine (L)

(1) N from Nitrene LAg(3N)NTs N(2) from Ligand [RE = -58.22 Kcal/mol] a the product of the silver catalyst mediated nitrene formation 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 2.38 Ag-N(2) NA 2.36 3 Ag-O 2.13 2.30 Ag-I NA 3.15

N(1)-Ag-N(2) NA NA N-Ag-O 167.1 102.2 LAg(I)IPh(O)3NTs O-Ag-I NA 91.3 [RE = -63.18 Kcal/mol] * Ethene diamine (L)

N(1) from Nitrene N(2) from Ligand b the lowest relative energy intermediate of the silver catalystLAg(O)(N)PhI=NTs [RE = -58.22 Kcal/mol] mediated nitrene formation reaction 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 NTs

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

•The calculations validate ethenedLigand:iamine as a model ligand for phen Uncoordinated AgL AgPhen N2 Ag-N/Å 2.32 2.27 N1 N-Ag-N/° 78.2 77.0

Coordinated Nitrene LAg-NTs Agphen-NTs

Ag-N1/Ǻ 2.31 2.12 Agphen

Ag-N2/Ǻ 2.37 2.19

Ag-N3/Ǻ 2.16 2.02 N2

N1-Ag-N2/° 74.4 78.2 N3 N1 N1-Ag-N3/° 146.2 98.2

N2-Ag-N3/° 138.9 176.4 LAg-NTs Truncating the substituent

 Used in order to increase the speed of computational process

 Truncated:

 Removed tert-butyl from tBu3tpy to form tpy

tpy tBu3tpy

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

phenanthroline bathophenanthroline 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 N(4) Table: Comparing Bond lengths in Å for Batho-phen and phen N(3) Ag(2) (1) Ag2Bathophen2 Ag2Phen2 Ag (2) N N(1) Ag(1)-Ag(2) 2.69 3.06

Ag(1)-N(1) 2.19 2.27 Ag2Bathaphen2 Ag(1)-N(2) 2.19 2.27 N(2) Ag(2) N(3) Ag(2)-N(3) 2.19 2.27 Ag(1)

Ag(2)-N(4) 2.19 2.27 N(1)

•It was found that Ag2Phen2 had stacked geometry while N(4) in Ag2Bathophen2 ligands were on the opposite side of the metals perhaps due to steric hindrance Ag2Phen2 Geometry: Results

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

+ [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

(2) (1) - Ag -O 2.33 2.12 N and O from NO3 Ag(2)-O(2) 2.72 2.28 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 Orders Bond orders for Ag-Ag and Ag-N in monomers and dimers of AgPhen and AgBathphen Ag1

Ag2phen2 Ag2bathophen2 Agphen Agbathphen N2 Ag1-Ag2 0.72 0.82 NA NA N1

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 Agphen

N N2 3 Ag N 1 4 Ag Ag 2 1 N N N 4 1 1 N N Ag 3 2 2

N 2 N Ag 1 1

Agbathphen Ag2phen2 Ag2bathophen2 Bond Orders

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

+ Agtpy Ag2tpy2 [Ag2tpy2(NO3)] 5 N1 N Ag1‐Ag2 NA 0.75 0.69 Ag1‐N1 0.28 0.29 0.30 Ag1‐N2 0.28 0.29 0.23 Ag2 1 N6 Ag Ag1‐N3 0.27 NA 0.14 2 2 4 N Ag ‐N NA 0.29 0.27 N4 Ag2‐N5 NA 0.29 0.25 Ag2‐N6 NA 0.18 0.29 Ag2‐N3 NA NA 0.28 Ag2‐N2 NA NA 0.12 Ag1‐O1 NA NA 0.42 Ag2tpy2 Ag1‐O2 NA NA 0.53

O1

N3 O2 N1 N2 Ag 1 N1 N 2 Ag1 N6 N3 N 4 Ag 2 N 5 Agtpy + [Ag2tpy2(NO3)] 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 Department

• Midwest Undergraduate Computational Chemistry Consortium (MU3C)

• Minnesota Supercomputing Institute

• Everyone for their supports.