This document provides a summary of computational organic chemistry methods for investigating molecular structures, properties, reactivities, and selectivities. It describes the basic concepts of molecular mechanics and quantum chemistry methods, including their advantages and limitations. Applications include determining molecular geometries and conformations, absolute configurations, electron distributions, acidities, and frontier molecular orbital energies to examine reactivity and selectivity. Combining computational methods with experiments allows more reliable investigations.

1. A Review on Computational Organic Chemistry: Basic Concepts and Applications By Isamu Katsuyama

2. Contents Introduction Basic Guide to Computational Chemistry Applications to Investigation of Molecular Structure and Property Applications to Investigation of Chemical Reactivity and Selectivity Future Direction

3. Introduction Role of Calculations Calculations are much like experiments in that both may be employed in two different ways: Data collection. Looking for the unusual.

4. 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

5. 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.

6. 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 .

7. 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

8. 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.

9. 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 .

10. 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.

11. 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

12. Relative Computation Times Methylcyclohexane (C 7 H 14 )‏ 14 2 pBP/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 )‏ f f MMFF94 ( MM )‏ Geometry Optimization Single-Point Energy Level of Calculation

13. Comparison of the Performance of Molecular Mechanics( MM ) and Quantum Methods( QM ) S= satisfactory; U= unsatisfactory Task MM Semi- Ab initio DFT Empirical HF Correlated Geometry S S S S S Transition-state - S S S S Geometry Conformation S U S S S Thermochemistry - U S S S

14. 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 , 4 th ed., Prentice hall, Englewood cliffs, NJ, 1991; P.W. Atkins and R.S. Friedman, molecular quantum mechanics , 3 rd ed., Oxford Univ. Press, oxford, 1997.

15. 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.

16. 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 .

17. Applications to Investigation of Molecular Structure and Property Investigation of Molecular Structure by use of MM and/or QM Geometry Absolute Configuration Investigation of Molecular Property (Electron Charge Distributions) by use of QM

18. Geometry (bond distance, angle, energy of molecules etc.)‏ Conformational Energy Differences in 1,3-Butadiene; Investigation of Order of Stability Investigation of Molecular Structure by use of MM and/or QM Dihedral angle 0  90  180 

19. 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

20. 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 )‏

21. Advantage and Disadvantage of X-ray and CD Method Advantage These methods have high reliability. Disadvantage These methods have limitation of application. Preparation of single crystal (X-ray)‏ Molecules where  -electron chromophores exist or can be introduced (CD method)‏

22. Advantages and Disadvantages of Total Synthesis Advantage This method has high reliability. Disadvantage Long Time Many Synthetic Organic Chemists

23. Advantages and Disadvantages of NMR (2D-NMR, 1D-NMR with Chiral Derivatizing Agents )‏ Advantage NMR is widely used and easy to perform. Disadvantage Low Reliability on Acyclic Systems as well as Macro cyclic Systems ( 2D-NMR )‏ Preparation of Derivatives by use of Chiral Derivatizing Agents ( Mosher’s Method etc. )‏

24. 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 .

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

26. The distance between H-2 and H-13 is 4.0 Å in 13( R )configuration . This is not consistent with information based on NOESY.

27. The distance between H-2 and H-13 is 2.4 Å in 13( S )configuration. This is consistent with information based on NOESY.

28. CD Spectrum Negative Cotton Effect - CD also supports 13( S )configuration.

29. 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…

30. 4-Aminopyridine: Where is the Basic Site ? Quantitative Investigation  H(A) = 193.6,  H(B) = 169.1 kcal/mol B is more stable than A , and thus the ring N is more basic.

31. Qualitative Investigation (Electrostatic Potential Map)‏ 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.

32. Imidazole: Where is the Basic Site ? The N-3 is negatively charged , and thus is the basic site . Electrostatic Potential Map

33. Acidities of Alcohols stronger stronger weaker weaker 15.5 Methanol 15.9 Ethanol 7.2 4-Nitrophenol 10.0 Phenol 12.4 2,2,2-Trifluoroethanol pKa’s (acidities)‏

34. 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).

35. Applications to Investigation of Chemical Reactivity and Selectivity (Investigation of Molecular Orbital by use of QM )‏ When there are more than one reagent, which reagent will react first ? 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 .

36. 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 , 2 nd . Ed., Cambridge University Press, 1979. T. A. Albright, J. K. et al., Orbital Interactions in Chemistry , Wiley, New York, 1985.

37. 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

38. Acrolein/BF 3 : What is the role of Lewis Acids ? Lewis acids are commonly used to accelerate chemical reactions; the BF 3 adduct of acrolein more rapidly undergoes nucleophilic attack than acrolein itself.

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

40. 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)‏

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

42. HOMO of the Enolate HOMO Map of the Enolate The color near red indicates minimum value, and the color near blue indicates maximum value of HOMO. The terminal carbon,where HOMO shape (value) is larger , generally reacts with electrophile .

43. Electrophilic Substitution of Indole; What should be favorite position for electrophilic attack ? HOMO map reveals that 3-position is the most likely site of electrophilic attack.

44. 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.

45. Nucleophilic Additions to Dioxanone Ring LUMO map for the axial face LUMO map for the equatorial face Nucleophililes preferentially attack from the axial face.

46. Nucleophilic Additions to Dithianone Ring LUMO map for the axial face LUMO map for the equatorial face Nucleophililes preferentially attack from the equatorial face.

47. Future Direction Calculation in Solution Although calculation in gas phase usually provide s 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.

48. 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).

49. 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 . Explosive developments in computer hardware and software

50. 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.