CHM443 Stereocatalysis Opposite stereoselectivity in the prolinecatalyzed Mannich and Aldol reaction

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CHM443Stereocatalysis Opposite
stereoselectivity in the proline-catalyzed
Mannich and Aldol reactions

• Computational investigation

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Reference
Org. Lett., 5 (8), 1249 -1251, 2003. Origins of
Opposite Absolute Stereoselectivities in
Proline-Catalyzed Direct Mannich and Aldol
Reactions S. Bahmanyar and K. N. Houk
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Potential Energy Surfaces Energy as a function
of geometry

• Polyatomic molecule
• N-degrees of freedom
• N-dimensional potential energy surface

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PES Extrema (Stationary Points)

• Minima
• 1st deriv (gradient) equals zero in all
  directions
• 2nd deriv positive in all directions
• Global vs. local
• Saddle Point
• Transition state
• 2nd deriv negative in one direction, positive in
  others
• Hilltop
• 2nd deriv negative in more than one direction

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Locating PES Extrema

• Algorithms
• Minimize energy (local minima)
• Minimize gradient (transition state)
• Specialized methods
• Convergence criteria
• Force (DE/Dr) 0
• Displacement (Dr) 0
• Indicated in output file

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Optimization - minimization

• From starting point,
• Compute slope
• If slope ? 0, take step in the direction of the
  slope
• If slope 0, stop

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Optimization in N-dimensions

• Initial guess geometry

Compute energy and gradient
Check for convergence gradient, displacement
yes
Done
no
Update geometry
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Gaussian Input for optimization

• RHF/6-31G(d) Opt Test
• RHF/6-31G(d) C2OH4 vinyl alcohol optimization
• 0,1
• C
• C 1 CC
• H 2 CH 1 CCH
• O 1 CO 2 CCO 3 OCCH
• H 4 OH 1 HOC 2 CCOH
• H 1 CH 2 HCC 3 HCCO
• H 2 CH 2 HCC 4 HCCO
• CC 1.309
• CH 1.090

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Gaussian Output

• Item Value Threshold Converged?
• Maximum Force .000246 .000450 YES
• RMS Force .000083 .000300 YES
• Maximum Displacement .001383 .001800 YES
• RMS Displacement .000544 .001200 YES
• Predicted change in Energy -2.370307D-07
• Optimization completed.
• -- Stationary point found.

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General Strategies

• A good starting geometry is essential
• For large molecules, pre-optimize using a lower
  level of theory
• When a job fails
• Read the output file to determine why
• Look at the final geometry
• Although every molecule is different, past
  experience will help guide your calculations

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Locating Transition States

• Difficult! Finding 1 point in 103N-6
• Opt(TS,CalcFC,NoEigenTest)
• Minimize gradient
• Must have a good starting point
• OptQST2
• Morph reactants and products
• Must provide both structures
• Atoms must have same numbering!

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For Optimization

• Assumption molecule at a
• frozen point on PES
• Find stationary point
• (where slope 0)
• 1st derivative with respect to nuclear
  coordinates
• Minimum or maximum?
• 2nd derivative with respect to nuclear
  coordinates
• However molecules do not
• maintain fixed positions
• vibrating

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Molecular Vibrations

• A molecule has 3N-6 vibrational degrees of
  freedom
• Vibrations arises from a parabolic potential
  energy surface
• Transition states have imaginary (negative)
  frequencies

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Molecular Vibrations
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Molecular Vibrations
Normal Modes of CF4
n1 (A1) - Symmetric Stretch908 cm-1
n3 (F2) - Asymmetric Stretch1283 cm-1
n2 (E) - Symmetric Bend434 cm-1
n4 (F2) - Asymmetric Bend631 cm-1
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Harmonic Oscillator in 2-D

• Energy levels
• Compute 2nd derivatives (force constants)
• Compute harmonic vibrational frequencies

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Zero-point energy

• Compute equilibrium structure
• Zero-point energy minimum energy a molecule can
  possess

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Gaussian Input for Frequencies
key word
route section

• PM3/3-21G Opt Freq
• PM3/3-21G formaldehyde optimization
• 0,1
• C
• O 1 CO
• H 1 CH 2 HCO
• H 1 CH 2 HCO 3 D1
• CO 1.275
• CH 1.090
• HCO 120.0
• D1 180.0

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Frequency calculations

• Must always be on an optimized structure
• Opt job then Freq job
• Or Opt Freq in same job
• Must always be with the same method/basis set as
  the optimization

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IR and Raman spectra

• Raman
• Square of derivative of polarizabilities with
  respect to nuclear coordinates
• depolarizability ratios
• scattering activities

• IR
• Square of derivative of dipole moment with
  respect to nuclear coordinates
• frequencies
• intensities

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Computational Experiment using Gaussian03 suit
of programs and WebMo interface
Before you begin
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First set of calculations
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Second set of calculations
Mannich
Aldol
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1. Building the Reactant Structures
C. Go to stereocatalysis and use each isomer
structure for your first two jobs.
A. Open editor in Build Molecule window
B. Click on Build and go to Choose Fragments
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2. Job Options
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Edit Job Options !
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3. Evaluating Results
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Your Report