A Review on Computational Organic Chemistry: Basic Concepts and Applications

By Isamu Katsuyama

Contents

1. Introduction 2. Basic Guide to Computational Chemist

ry3. Applications to Investigation of Molecul

ar Structure and Property4. Applications to Investigation of Chemic

al Reactivity and Selectivity5. Future Direction

1. Introduction 2. Basic Guide to Computational Chemist

ry3. Applications to Investigation of Molecul

ar Structure and Property4. Applications to Investigation of Chemic

al Reactivity and Selectivity5. Future Direction

1. Introduction

Role of Calculations

Calculations are much like experiments in that both may be employed in two different ways:

1. Data collection.

2. Looking for the unusual.

Calculations can be performed on unstable molecules and reaction transition states; Experiments are very difficult on such molecules and can not be performed on transition states.

Calculations are becoming less and less costly; Experiments are becoming more and more costly.

　 Advantages of Calculations

Advantages of Calculations (Cont.)

Calculations are safe; Experiments are sometimes dangerous.

Calculations are now easy to perform; Experiments are sometimes more difficult.

Calculations are now performed by not only computational chemists but also experimental chemists.

Disadvantages of Calculations

The cost of calculations increases rapidly with molecular size; The cost of experiments is generally independent of the molecular size.

Calculations sometimes yield different results depending on the employed model; Experiments usually provide only one result.

1. Basic Guide to Computational Chemistry

Molecular mechanics (MM) methods Quantum mechanics (QM) methods Semi-empirical Ab Initio Hartree-Fock Ab Initio correlated (Møller-Plesset) Density functional

Differences Between Molecular Mechanics and

Quantum Methods

Molecular mechanics are restricted to the description of equilibrium structure and conformation.

Quantum methods also provide information about non-equilibrium forms, e.g., transition states, and about electron charge distributions.

Differences Between Molecular Mechanics and Quantum Methods

(Cont.)

Molecular mechanics are based on use of experimental information (=parameters), and thus can not be applied outside the range of parameterization.

Quantum methods are not based on use of experimental information, and thus can be applied to areas where there is little or no prior experience.

Differences Between Molecular Mechanics and Quantum Methods

(Cont.)

Molecular mechanics methods are much less costly than even the simplest quantum methods such as semi-empirical methods.

Range of Molecular Mechanics and Quantum

Methods

Method Range (heavy atoms)

Molecular Mechanics > 1000

Semi-Empirical < 200

Ab initio Hartree-Fock(HF) < 50

Ab initio Correlated < 20

Density Functional (DFT) < 100

Relative Computation Times

142pBP/DN* (DFT)

.06

8

54-

f

1

7

100

AM1 (Semi-Empirical)

HF/3-21G (Ab initio)

HF/6-31G* (Ab initio)

MP2/6-31G*

(Ab initio Correlated)

ffMMFF94 (MM)

Geometry Optimization

Single-Point EnergyLevel of Calculation

Methylcyclohexane (C7H14)

Comparison　of　the　Performance　of　Molecular　Mechanics(MM)　and　Quantum　

Methods(QM)

Task 　 　 　 MM Semi- Ab initio DFT

　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 　 　 　 Empirical HF Correlated

Geometry S S S S S

Transition-state - 　 S S S SGeometry

Conformation S U S S S Thermochemistry - 　 　 　 U S S S

S= satisfactory; U= unsatisfactory

References of MM and QM

Review of MM: U. Burkert and N. L. Allinger, molecular mechanics, ACS monograph 177, American chemical society, Washington D.C., 1982.

Reviews of basic QM: I. N. Levine, quantum chemistry, 4th ed., Prentice hall, Englewood cliffs, NJ, 1991; P.W. Atkins and R.S. Friedman, molecular quantum mechanics, 3rd ed., Oxford Univ. Press, oxford, 1997.

Review of semi-empirical methods: T. Clark, A handbook of computational chemistry, Wiley, new York 1986.

Review of Hartree-Fock and Møller-Plesset models: W.J. Hehre, L. Radom, P.V.R. Schleyer and J.A. Pople, Ab Initio molecular orbital theory, Wiley, new York 1986.

Reviews of density functional theory: R.G. Parr and W. Yang, density functional theory of atoms and molecules, oxford Univ. Press, oxford, 1989; J.K. Labanowski and J.W. Andzelm, eds., Density functional methods in chemistry, Spriger-Verlag, new York, 1991.

Widely Used Software Packages for MM, QM

Chem3D (CambridgeSoft, Corp. www.camsoft.com : Mac, PC)

Gaussian (Gaussian, Inc. www.gaussian.com : Unix, PC)

MOPAC (Fujitsu CCS www.winmopac.com : Unix, PC)

Sybyl (Tripos, Inc. www.tripos.com : Unix) SPARTAN (Wavefunction, Inc.: Unix, Mac,

PC)

Each software has different user interface, operating feature, price, manual and so on.

1. Applications to Investigation of Molecular Structure and Property

Investigation of Molecular Structure by use of MM and/or QM

a. Geometryb. Absolute Configuration Investigation of Molecular

Property (Electron Charge Distributions) by use of QM

a. Geometry (bond distance, angle, energy of molecules etc.)

Conformational Energy Differences in 1,3-Butadiene; Investigation of Order of Stability

H

H

H

H

H

H

H

H

H

H

s-cis twisted

H

H

s-trans

I. Investigation of Molecular Structure by use of MM and/or QM

Dihedral angle 0 90 180

Relation between Dihedral Angle and Relative Conformer Energy in 1,3-Butadiene

s-trans

s-cis

twisted

Order of stability: s-trans > s-cis > twisted

a. Absolute Configuration

Physical Methods X-ray Crystallography CD Spectroscopy

Chemical Methods Total Synthesis NMR Spectroscopy (2D-NMR, 1D-NMR with Chiral

Derivatizing Agents such as Mosher’s Method)

Computational Chemistry (MM and/or QM)

Advantage and Disadvantage of X-ray and CD Method

AdvantageThese methods have high reliability.

DisadvantageThese methods have limitation of

application. Preparation of single crystal (X-ray) Molecules where -electron chromophores

exist or can be introduced (CD method)

Advantages and Disadvantages of Total Synthesis

Advantage

This method has high reliability.

Disadvantage Long Time Many Synthetic Organic Chemists

Advantages and Disadvantages of NMR (2D-NMR, 1D-NMR with Chiral

Derivatizing Agents　)

AdvantageNMR is widely used and easy to perform.

Disadvantage Low Reliability on Acyclic Systems as well as

Macrocyclic Systems (2D-NMR) Preparation of Derivatives by use of Chiral

Derivatizing Agents (Mosher’s Method etc.)

Advantages and Disadvantages of Computational Chemistry

Advantage

This method does not require preparation of specific samples in contrast to X-ray and Mosher’s method etc.

Disadvantage

This method requires combination with another method such as NMR.

QM has limitation of molecular size.

Determination of Absolute Configuration in A Macrocyclic System by a Combination of Computational Chemistry and Another Method

O

O OH

O

O OH

CH3

OHSeO2

at room temp.

Sarcophine

13

HMBC20

O

O OH

H OH

NOESY

2

?(R)

The distance between H-2 and H-13 is 4.0 Å in 13(R)configuration.O

O OH

H OH

(R) configration This is not consistent with informationbased on NOESY.

O

O OH

H OH

(S) configuration

The distance between H-2 and H-13 is2.4 Å in 13(S)configuration.

This is consistent with informationbased on NOESY.This is consistent with informationbased on NOESY.

CD Spectrum O

O OH

H O

O

Cl

(S)

Negative Cotton Effect

-

CD also supports 13(S)configuration.CD also supports 13(S)configuration.

• Investigation of Molecular Property (Electron Charge Distributions) by use of QM

Electrostatic Potential Atomic Charges Dipole Moment Enthalpy, Entropy, and Free Energy Salvation Energy etc.

Investigation of Basicity (Proton Affinity), Acidity, and More…Investigation of Basicity (Proton Affinity), Acidity, and More…

4-Aminopyridine: Where is the Basic Site ?

Quantitative InvestigationN

NH2

H(A) = 193.6, H(B) = 169.1 kcal/mol

B is more stable than A, and thus the ring N is more basic. B is more stable than A, and thus the ring N is more basic.

N

NH2

N

NH3+

NH+

NH2

+ H2O + H3O+ + H2O

A B

Qualitative Investigation (Electrostatic Potential Map)

N

NH2

The ring N is more negatively charged, and thus is likely to be more basic.The ring N is more negatively charged, and thus is likely to be more basic.

Colors near red represent more negative charge, while colors near blue represent more positive charge. Colors near red represent more negative charge, while colors near blue represent more positive charge.

Imidazole: Where is the Basic Site ?

N

NH

1

3

The N-3 is negatively charged, and thus is the basic site. The N-3 is negatively charged, and thus is the basic site.

Electrostatic Potential Map

Acidities of Alcohols

15.5Methanol

15.9Ethanol

7.24-Nitrophenol

10.0Phenol

12.42,2,2-Trifluoroethanol

pKa’s (acidities)

stronger

stronger

weaker

weaker

CH3CH2OH CF3CH2OH

OHO2NOH

Electrostatic Potential (ESP) Map for the Alcohols

ESP map shows that the acidic sites are positively charged, and it reflects the relative acidities (light vs. dark blue). ESP map shows that the acidic sites are positively charged, and it reflects the relative acidities (light vs. dark blue).

• Applications to Investigation of Chemical Reactivity and Selectivity (Investigation of Molecular Orbital by use of QM)

a. When there are more than one reagent, which reagent will react first ?

b. When a molecule contains multiple reactive sites, which site will react first ?

Examination of frontier molecular orbital (HOMO and LUMO) is an important method because most chemical reactions involve electron movement between them.

Examination of frontier molecular orbital (HOMO and LUMO) is an important method because most chemical reactions involve electron movement between them.

References of Frontier Molecular Orbital　(FMO) Theory and Reaction

I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, New York, 1976.

K. Fukui, Theory of Orientation and Stereoselection, Springer, Berlin, 1975.

T. L. Gilchrist and R. C. Storr, Organic Reactions and Orbital Symmetry, 2nd. Ed., Cambridge University Press, 1979.

T. A. Albright, J. K. et al., Orbital Interactions in Chemistry, Wiley, New York, 1985.

• Investigation of Chemical Reactivity

A reagent with the highest HOMO energy will give its electrons most easily and thus be the most reactive donor.

A reagent with the lowest LUMO energy should be able to accept electrons most easily and thus be the most reactive accepter.

Examination of FMO Energies

Acrolein/BF3: What is the role of Lewis Acids ?

Lewis acids are commonly used to accelerate chemical reactions; the BF3 adduct of acrolein more rapidly undergoes nucleophilic attack than acrolein itself.

H

O

H

H

H H

O

H

H

H

BF3

Acrolein Acrolein/BF3

Lewis acid complexation reduces the energy of LUMO on acrolein, making it more accessible to the HOMO on nucleophile.

Lewis acid complexation reduces the energy of LUMO on acrolein, making it more accessible to the HOMO on nucleophile.

H

O

H

H

H H

O

H

H

H

BF3

HOMO nucleophile

acrolein/BF3

acroleinLUMO

smaller gap(more reactive)

OrbitalEnergy

LUMO Energy -0.19 eV -2.01 eV

a. Investigation of Chemical Selectivity

The regions where LUMO shape (value) is large will be reactive sites toward attack by a nucleophile.

The regions where HOMO shape (value) is large will be reactive sites toward attack by a electrophile.

Examination of FMO Shape (Value)

Ester Enolate: Where is the reactive site ?

The site where HOMO shape (value) is larger will be more reactive toward attack by a electrophile.

The site where HOMO shape (value) is larger will be more reactive toward attack by a electrophile.

The ester enolate has two possible sites, which may react with electrophiles; the anion and the terminal carbon.

CH2

CO

CH2CH3

O

EH2C

CO

CH2CH3

O-

H2CC

OCH2

CH3

OE

E E

H2CC

OCH2

CH3

O-

HOMO of the Enolate HOMO Map of the Enolate

The color near red indicatesminimum value, and the color near blue indicatesmaximum value of HOMO.

The color near red indicatesminimum value, and the color near blue indicatesmaximum value of HOMO.

The terminal carbon,where HOMO shape (value) is larger, generally reacts with electrophile.The terminal carbon,where HOMO shape (value) is larger, generally reacts with electrophile.

Electrophilic Substitution of Indole; What should be favorite position for electrophilic attack ?

NH

2

34

5

6

7

HOMO map reveals that 3-position is the most likely site of electrophilic attack. HOMO map reveals that 3-position is the most likely site of electrophilic attack.

Stereochemistry of Nucleophilic Additions to Carbonyl Compounds

Cyclohexanones has two possible faces, which may undergo nucleophilic attack; the axial and the equatorial face.

The face where LUMO shape (value) is larger will be more reactive toward attack by a nucleophile.

The face where LUMO shape (value) is larger will be more reactive toward attack by a nucleophile.

XX

Oaxial

equatorial

Nu

Nu

X=CH2, O, S

Nucleophilic Additions to Dioxanone Ring

LUMO map forthe axial face

LUMO map for the equatorial face

Nucleophililes preferentially attack from the axial face.Nucleophililes preferentially attack from the axial face.

OO

Oaxial

equatorial

Nu

Nu

Nucleophilic Additions to Dithianone Ring

SS

Oaxial

equatorial

Nu

Nu

LUMO map for the axial face

LUMO map for the equatorial face

Nucleophililes preferentially attack from the equatorial face.Nucleophililes preferentially attack from the equatorial face.

1. Future Direction

I. Calculation in Solution Although calculation in gas phase

usually provides a reliable account, it in solution is still unsatisfactory for investigation of some tasks.

The development of several methods is in progress for the calculation in solution.The development of several methods is in progress for the calculation in solution.

References of Recently Developed Methods for Calculation in Solution

Supramolecular method: A. Abotto et al., J. Am. Chem. Soc., 119, 11255 (1997).

MC and MD method: M. Aida et al., Chem. Phys. Lett., 292, 474 (1998).

QM/MM method: J. Gao et al., J. Am. Chem. Soc., 115, 9667 (1993).

RISM-SCF method: H. Sato et al., J. Chem. Phys., 105, 1546 (1996).

I. Extension of Application Field of Computational Organic Chemistry

MM and QM calculations have been used mainly in the field of investigation of molecular structure and chemical reaction so far.

They have recently begun to be widely applied in not only organic chemistry but also biochemistry and closely related fields such as drug design.

They have recently begun to be widely applied in not only organic chemistry but also biochemistry and closely related fields such as drug design.

Explosive developments in computerhardware and software

References of Drug Design by use of QM

R. R. Squires et al., J. Phys. Chem. A, 102, 9072 (1998). J. Hoffner et al., J. Am. Chem. Soc., 120, 376 (1998). P. R. Schreiner, ibid., 120, 4184 (1998).

Quantum chemical calculations (QM) are expected to become an important method for drug design in the future.

Quantum chemical calculations (QM) are expected to become an important method for drug design in the future.

N

R1

R3

R2

R1

R2