Base MetalStarting

Materials

Major 1st

Complex

Major

Transition

State

Major 2nd

Complex

Major

Products

Starting

Materials

Minor 1st

Complex

Minor

Transition

State

Minor 2nd

Complex

Minor

Products

no metal 0.00 4.20 3.09 -23.81 -27.73 0.00 4.82 0.93 -23.95 -25.26

Li 0.00 -7.19 3.14 -31.43 -19.93 0.00 -7.48 -0.84 -29.14 -19.94

no metal 0.00 -0.60 -1.94 -7.78 -7.45 0.00 -1.67 -1.40 -8.16 -4.98

Na 0.00 -3.10 3.03 -3.16 -0.10 0.00 -4.47 0.78 -3.66 -0.26

K 0.00 -1.11 2.99 -2.86 -1.60 0.00 -2.90 0.77 -8.24 -1.85

MECHANISM

Computational Studies of Intramolecular

Spiroether Synthesis from Peroxy EnolatesLi Fan and Keith T. Kuwata

Department of Chemistry, Macalester College, Saint Paul, MN 55105

BACKGROUND

OBJECTIVES● Explore intramolecular mechanisms of ether synthesis with computational

methods by locating potential transition state structures

● Study the influence of different reagents on reaction rates and equilibria

● Consider the effect of solvents on reaction rates and equilibria

● Previous studies on ether synthesis: ring-closing mechanism for synthesis of

spiroethers and spiroketals with enantioselectivity1

● Synthetic strategy: attack of nucleophilic carbon on electrophilic oxygen

● Lab experimentation: successful synthesis of oxaspirodecanone (n=2, n=3) 2

METHODS● Molecule of interest: 2-(methylperoxypropyl)-hexanone

● Reagents: M-diisopropylamine (M = no metal, Li) and M-tert-butoxide (M = no

metal, Na, K)

● Solvents: no solvent, THF

● B3LYP/6-31G(d) geometry optimization and vibrational frequencies

calculations

● B3LYP/6-31+G(d,p) molecular energy calculations

● Enthalpy: sum of the thermal correction term from B3LYP/6-31G(d) calculation

and the electronic energy from B3LYP/6-31+G(d,p) calculation

● Energy: sum of the zero-point energy from B3LYP/6-31G(d) calculation and the

electronic energy from B3LYP/6-31+G(d,p) calculation

● Reaction enthalpy, activation energy, equilibrium constant3, relative rates of

reactions

Step 1

Enolate

Formation

Step 2

Cyclization;

Cleavage of

peroxy O-O

bond

RESULTS

CONCLUSIONS

ACKNOWLEDGEMENTS

BIBLIOGRAPHY

● The proposed mechanism is validated with all related transition state structures located.

● Diisopropylamine reagents undergo more exothermic reactions than tert-butoxide reagents.

● Alkali metals add to exothermicity via interactions with electronegative atoms. The effect weakens with increasing atom size.

● THF has a stronger stabilizing effect on starting materials and products than on transition state structures.

● Minor reactions have lower reaction barriers and thus are preferred kinetically; thermodynamic selectivity varies for specific

reagents.

FUTURE WORK

● Professor Keith T. Kuwata, Macalester College

● Professor Patrick H. Dussault, University of Nebraska-Lincoln

● David Soro, Qifan Xiao and Tristan Truttmann, Macalester College

● Department of Chemistry, Macalester College

● National Science Foundation (1464914)

● Leonard Summer Research Fund

[1] Meth-Cohn, O.; Moore, C.; Taljaard, H. C. Journal of the Chemical Society, Perkin Transactions 1: Organic

and Bio-Organic Chemistry (1972-1999) (1988), (9), 2663-74 CODEN: JCPRB4; ISSN:0300-922X.

[2] (a) Willand-Charnley, R. W.; Puffer, B. W.; Dussault, P. H. J. Am. Chem. Soc. 2014, 136, 5821-5823. (b) Kyasa,

S.; Meier, R. N.; Pardini, R. A.; Truttmann, T. K.; Kuwata, K. T.; Dussault, P. H. J. Org. Chem., 2015, 80

(24), 12100–12114.

[3] Alvarez-Idaboy, J. R.; Mora-Diez, N.; Vivier-Bunge, A., A Quantum Chemical and Classical Transition State

Theory Explanation of Negative Activation Energies in OH Addition to Substituted Ethenes. J.

Am. Chem. Soc. 2000, 122, 3715-3720.

● Re-optimize the geometries of transition state structures and complexes with the presence of solvents

● Explore energetics of the cyclization step with minor products from the first step (kinetic enolates)

● Consider alternative calculation methods for the two negatively charged systems to achieve better approximations

● Calculate equilibrium constants for each step of the reactions, especially for the rate determining step

Figure 2. Relative enthalpies (kcal/mol) of optimized structures in the two-step mechanism.

Table 1. Relative enthalpies (kcal/mol) of structures in step-1 reactions which form thermodynamic (major) and kinetics (minor) enolates, with THF.

Table 2. Relative enthalpies (kcal/mol) of structures in cyclization reactions from the major products of step 1, without solvent or with THF.

Figure 1. Synthesis of a spiroether through an SN2 reaction followed by the cleavage of

peroxy functional group. (Image courtesy Dussault et. al.)

Thermo-

dynamic

Enolate

Metal

No Solvent THF

Starting

Materials

1st

Complex

Transition

State

2nd

ComplexProducts

Starting

Materials

1st

Complex

Transition

State

2nd

ComplexProducts

no metal 0.00 4.84 6.20 -36.55 -26.49 0.00 4.52 9.46 -38.69 -45.86

Li 0.00 -12.96 -12.49 -75.05 -51.53 0.00 -1.39 0.40 -62.93 -56.37

Na 0.00 -9.25 -8.79 -66.81 -47.40 0.00 -0.17 1.27 -56.21 -53.74

K 0.00 -5.92 -4.87 -61.54 -47.54 0.00 0.19 2.30 -55.02 -52.30