Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled “Nanozyme”

Dr. Kenneth RaymondBorn 1942; B. A. Reed College (1964); Ph. D. Northwestern University (1968); Alfred P. Sloan Research Fellow (1971-1973); Miller Research Professor (1977-1978, 1996, 2004); Guggenheim Fellow (1980-1981); Selected as one of the "Technology 100, 1981" by Technology Magazine; American Association for the Advancement of Science Fellow (1984); DOE Ernest O. Lawrence Award (1984); Lawrence Berkeley Laboratory Technology Transfer award (1988, 1991); Humboldt Research Award for Senior U.S. Scientists (1992); American Chemical Society Alfred Bader Award in Bioinorganic or Bioorganic Chemistry (1994); Erskine Fellow, University of Canterbury, New Zealand (1997); Elected to National Academy of Sciences (1997); Basolo Medal, Northwestern University (1997); Max-Planck-Institut fur Strahlenchemie "Frontiers in Biological Chemistry" Award (1997); Elected to the American Academy of Arts and Sciences (2001); Reed College Howard Vollum Award (2002); ACS Auburn Section G. M. Kosolapoff Award (2004); Izatt-Christensen Award in Macrocyclic Chemistry (2005); Joe L. Franklin Memorial Lectureship (2006); Paulo Fasella Lectureship (2006); UC Berkeley Chancellor's Professor, (2007-).

426 Pubs

126 Inorg Chem

113 JACS

21 Angew

The Cope Rearrangement

• 3,3 sigmatropic rearrangement• Aza Cope rearrangement

The Catalyst• M4L6

12- assembly• M = Ga3+ (Al3+, Fe3+); L = N,N’-bis(2,3-dihydroxybenzoyl)-

1,5-diaminonaphthalene• Racemic mixture of homochiral ΔΔΔΔ and ΛΛΛΛ

enantiomers• Anionic nature makes soluble in H2O, with hydrophobic

core• Water-labile cations (ketone-derived iminium ions,

diazonium, tropylium, phosphine-acetone adducts) are encapsulated

Enammonium synthesis

Basic Cope rearrangement of enammonium

1H NMR

• NMR in D2O

• Hi-res ES-TOF MS in H2O

Rate constantsCompound R kfree=(10-8 s-1) kencaps=(10-8 s-1) kencaps/kfree

2 H 62.4 237 4

3 Me 62.3 6200 100

4 Et 20.0 3670 184

5 n-Pr 19.5 1920 98

6 i-Pr 6.7 870 129

7 n-Bu 15.1 73 5

8 i-Bu 17.0 477 28

9 s-Bu 50.0 1150 23

R=Me has fastest encapsulation rate; zeroth order when >3 eq substrate; RLS = rearrangementrate depends on [host-bound substrate].

• Catalyzed reaction on the left; uncatalyzed on the right. ΔH‡ is more negative for the catalyzed reaction

• Entropy for catalyzed reaction is >20 J/mol more positive than for uncatalyzed

• Entropy-based rate increase

RS

hk

RTH

Tk Brate

‡‡

lnln

Michaelis-Menten in the house

Vmax = 1.2 x 10-4 mM.s-1

Km = 0.67 mM

kcat = 7.0 x 10-5 s-1

Vmax = ~1.05 x 10-4 mM.s-1

Km = >1.7 mM

kcat = ? x 10-5 s-1

The Emergence of a New Radical-Cationic Amino Acid Dynamics:

The Proton Patches ModelMatthew MacLennan

1 J. Mol. Struct. THEOCHEM0 Angew. Chem.0 JACS

Dr. Galina OrlovaRostov University, Russia, 1981-1998 (R. Minyaev)Southern Illinois University at Carbondale 1996/97 (S. Scheiner)University at Guelph 1998/2002 (J. D. Goddard)York University 2002/2004 (K.W.M. Siu, D.K. Bohme, A.C. Hopkinson)

42 Pubs10 J Phys Chem A5 JACS

Methodology

• Lowest energy conformers of neutral amino acid

• Geometry in Gaussian• Charge = +1; Multiplicity = 2 (ionization)• Run CPMD simulation to test

“Proton Scissors”12 AWFULLY

COMPLICATED STEPS

This fragmentation of C-N bond to give oxazolone cation and neutral fragment occurs at 31.3 kcal/mol. This size barrier is common with protonated species (between 30 and 40 kcal/mol). The fragmentation of any C-N or C-C bond in GGG is always preceded by proton transfer.

Fragments

+

+

Amino Acids

• Arginine

• Asparigine

• Aspartic Acid

• Threonine

• Tryptophan

Radical-Cationic Arginine (Arg+•)

Arg+•

0

2

4

6

8

10

12

0 100 200 300 400 500 600 700 800

Time (fs)

C-C

Bon

d Le

ngth

(Ang

stro

ms)

Arg+•

00.20.40.60.8

11.21.41.61.8

2

0 100 200 300 400 500 600 700 800

Time (fs)

N-H

Bon

d D

ista

nce

(Ang

stro

ms)

Radical-Cationic Asparigine (Asn+•)

Asn+•

00.20.40.60.8

11.21.41.61.8

22.2

0 100 200 300 400 500 600 700 800

Time (fs)

O-H

Bon

d Di

stan

ce (A

ngst

rom

s)

Asn+•

0

1

2

3

4

5

6

7

0 100 200 300 400 500 600 700 800

Time (fs)

C-C

Bond

Dis

tanc

e (A

ngst

rom

s)

Radical-Cationic Aspartic Acid (Asp+•)

Asp+•

0

1

2

3

4

5

6

7

0 100 200 300 400 500

Time (fs)

C-C

Bon

d D

ista

nce

(Ang

stro

ms)

Asp+•

0

1

2

3

4

5

6

0 100 200 300 400 500

Time (fs)

O-H

Bon

d Di

stan

ce (A

ngst

rom

s)

~124 fs

Radical-Cationic Threonine (Thr+•)

Radical-Cationic Tryptophan (Trp+•)

Summary• Radical-cationic amino acids do not obey the

“proton scissors” motif (Proton transfer before C-C bond cleavage); we see variety

• Arg+•, Asp+•, and Thr+• (conformer 2) show C-C bond cleavage before proton transfer

• Asn+• shows C-C bond cleavage and proton transfer occurring almost simultaneously

• Thr+•, Trp+• show C-C bond cleavage without any proton transfer

• Explanation for lack of IE potentials of amino acids