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Chemical Reactions. Overview. Reactions in organic chemistry, review Problems in reaction chemistry Chemoinformatics methods Applications of reaction chemoinformatics to reaction chemistry problems Review questions. Overview. Reactions in organic chemistry, review

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Overview
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to reaction chemistry problems

  • Review questions

2


Overview1
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to reaction chemistry problems

  • Review questions

  • Chemicals – Reactions Relationship

  • Reaction Specification

  • Reaction Mechanisms

  • Reactivity Principles

  • Reaction Favorability

  • Reaction Classification

3


Chemicals rxns relationship

+

HBr

Chemicals – Rxns Relationship

  • Chemical Space

    • Chemicals are points in the space

    • Reactions are “vectors” describing how to reach new points from existing ones

  • Reactant Chemicals  Product Chemicals

  • Transformation that forms and breaks bonds

    • Rearrangement of electron configuration

4


Reaction specification

C2H5O- Na+

+ HBr

C2H5OH

70o C

Reaction Specification

  • Simplest reaction specification is a chemical equation indicating starting reactants and resultant products

  • For practical use and reproducibility, additional information is required:

    • Catalyst or other reagents

    • Reaction conditions (temperature, solvent, etc.)

    • Yield %, etc.

5


Reaction mechanisms
Reaction Mechanisms

  • Reactions are fundamentally rearrangements of electron configurations

  • Mechanisms describe the specific flow of electrons, the transient intermediates, and the final products

6


Mechanistic principles

+

Mechanistic Principles

  • Curved arrow diagrams

    • Depict flow of electrons, NOT atoms

    • Source must be electrons (bond, lone pair, radical)

    • Targets should be atoms / nuclei

7


Reactivity principles
Reactivity Principles

  • Broadly speaking, reactions are the transfer of electrons from

    • Electron-dense groups (nucleophiles) to

    • Electron-deficient ones (electrophiles)

8


Reactivity principles1

p

n

s

s

Reactivity Principles

  • Molecular orbitals

    • Distinct spaces around atoms that electrons reside in (high electron probability density)

    • Up to 2 electrons per orbital

    • Relative order of reactivity:

      • radicals (1e) >

      • n-orbital: Lone pairs >

      • p-orbital: Double / triple bonds >

      • s-orbital: Single bonds

9


Reaction favorability
Reaction Favorability

  • Thermodynamics

    • Eventually reactions will proceed to thermodynamic equilibrium, maintaining a steady state ratio of products : reactants

    • Keq: Equilibrium constant defining the stable ratio of products : reactants for a reaction under standard conditions (1 atmosphere, room temperature)

    • Larger value of Keq thus indicates greater favorability for a reaction

    • Given competing products, Keq can indicate major ones

10


Reaction favorability1
Reaction Favorability

  • Gibbs Free Energy

    • Keq is a function of DGo (and temperature)

    • DG: Difference between product and reactant (Gibbs) free energy

      • Negative DG is thus favorable

      • State function, measuring thermodynamic stability

      • DGo: DG under standard conditions

Keq = e-DGo/RT

DGo = -RT ln Keq

R = Universal gas constant

T = Absolute temperature

11


Reaction favorability2
Reaction Favorability

  • Enthalpy and Entropy contributors

    • G = H – TS

    • H: Enthalpy, primarily determined by strength of bonds broken and formed in a reaction

    • S: Entropy, measuring “randomness” of a system, with greater randomness being favorable

      • For most reactions, DS is small (esp. when Dn = 0), thus

      • Unless at very high temperatures, DH dominates TDS, thus

      • Calculating DH provides a good estimate for DG

12


Reaction favorability scoring
Reaction Favorability Scoring

  • Thermodynamics

    • DG = DH – TDS (Enthalpy & Entropy contribute)

    • Hess’ Law simplification

    • DHreaction = S(BDEbroken) – S(BDEformed)

    • BDE: Bond Dissociation Energy

      • Standard lookup values (kcal/mol)

        C-C : 83 C=O : 178

        C=C : 146 C≡N : 213

        C=N : 147 etc.

  • Kinetics

    • Much less data available

83 + 178 + 83 + 213

557

13

http://www.cem.msu.edu/~reusch/OrgPage/bndenrgy.htm


Reaction favorability3
Reaction Favorability

  • Reaction Kinetics

    • Thermodynamics: How “far” a reaction will proceed

    • Kinetics: How “fast” a reaction will proceed

      2 H2 + O2 2 H2O

      • Highly favorable DG, but without a catalyst or flame, reaction proceeds so slowly as to essentially not occur

    • Measured by rate constants, but much less data exists

    • Based on relative stability of transition states…

14


Reaction favorability4

+

Reaction Favorability

  • Given infinite time, all reactions will reach thermodynamic equilibrium, but

  • Intervening, unstable intermediates in the pathway impose an activation energy (Ea) barrier

  • Given limited time and input energy, a reactions may only achieve kinetic equilibrium, settling into an energy local minimum between large Ea barriers

Relative Energy

Ea

DG

Reaction Coordinate

  • DGo = 1.4 kcal / mol ~ 10x Keq

  • Ea < 22 kcal / mol ~ Room temperature reaction

15


Overview2
Overview

  • Reactions in organic chemistry, review

    • Reaction Classification

      • Specific chemicals

      • Compatible functional groups

      • Reactant counts

      • Bond rearrangement patterns

      • Functional classification

      • Mechanism based

More General

More Informative

16


Reaction classification organization

+

+

+

+

Reaction Classification/Organization

  • Specific chemicals

    • acetic acid + methanamine  N-methylacetamide

  • Compatible functional groups

    • carboxylic acid + primary amine  amide + water

17


Reaction classification

+

+

+

HBr

+

Reaction Classification

  • Reactant counts

    • Substitution

      Dn = 0

    • Addition

      Dn < 0

    • Elimination

      Dn > 0

18


Reaction classification1

A B

C D

A B

C D

A B

C D

Reaction Classification

  • Bond rearrangement patterns

    • 4 atom bond swap covers ~50% of organic reactions

19


Reaction classification2

A

F B

E C

D

A

F B

E C

D

+

Reaction Classification

  • Bond rearrangement patterns

    • 6 atom cyclic rearrangement covers ~25%

20


Reaction classification3

H2SO4

Heat

+ HNO3

+ H2O

+

+

Na2Cr2O7

H2SO4

Reaction Classification

  • Functional classification

    • Acid-catalyzed,

      Electrophilic

    • Base-catalyzed,

      Nucleophilic

    • Oxidation-

      Reduction

    • Free-radical

    • Etc.

21


Reaction classification4
Reaction Classification

  • Mechanism-based

    • Sn1

    • Sn2

    • E1

    • E2

    • etc.

    • Most informative classification patterns, but

      • Reaction mechanisms often unknown

      • Mechanisms cannot be directly observed, can only be proposed and supported with exp. evidence

22


Overview3
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to reaction chemistry problems

  • Review questions

  • Storing / retrieving reaction information

  • Combinatorial chemistry / virtual chemical space

  • Reaction prediction / discovery

  • Chemical Synthesis

    • Reaction planning

    • Synthesis design (retrosynthesis)

23


Storing retrieving reactions
Storing / Retrieving Reactions

  • DB: Record and classify all reactions, including:

    • Reactants and products

    • Reaction conditions, catalysts, solvents, etc.

    • Literature references, lab notes, etc.

  • Search: Ability to query for information on all reactions that

    • Use an epoxide reactant

    • Produce an aromatic ring

    • Follow the Sn2 reaction mechanism

    • Use copper as a catalyst

    • Can be run at room temperature in aqueous solution

24


Combi chem virtual space
Combi Chem + Virtual Space

  • Combinatorial Chemistry

    • Given a collection of “building block” chemicals, combine them with reactions to produce a diverse set of new products

  • Virtual Chemical Space

    • Systems like ChemDB catalog all chemicals available for purchase from different vendors

    • “RChemDB” would store or allow on-the-fly searching of all chemicals indirectly (but easily) available by applying reactions to directly available chemicals

25


Reaction prediction discovery
Reaction Prediction / Discovery

  • Given a mixture of reactants and reaction conditions, predict the major products

NaOMe

D

?

+

26


Knowledge vs principle based
Knowledge vs. Principle-based

  • Knowledge-based

    • If a reaction database was available, predicting the course of a reaction could just be a matter of finding it (or an analog) in the database

  • Knowledge-based limitations

    • Requires construction of the database of many different known reaction profiles to achieve any degree of generalization

    • DB driven approach would be unlikely to discern competing cases. For example,

      • carboxylic acid + amine  amide

      • carboxylic acid + alcohol  ester

      • carboxylic acid + amino-alcohol  ?

27


Knowledge vs principle based1
Knowledge vs. Principle-based

  • Principle-based

    • Predict or derive reactions based on general principles of reactivity

    • Much more flexible and powerful

    • Entails the ability to discover new reaction profiles that may not be in known in any DB

  • Principle-based limitations

    • Complex reactivity can be very difficult to predict

    • Confounding factors of solvent effects, catalysts, etc.

28


Chemical synthesis
Chemical Synthesis

  • Series of reactions from starting reactants to form a pathway to the final product

H2 Pd

CaCO3 Quinolone

HBr

29


Reaction planning

?

?

?

Reaction Planning

  • Derive synthesis pathway given

    • Starting reactant

    • Target product

    • Available reagents / reactions

30


Retrosynthesis

?

?

?

Retrosynthesis

  • Derive synthesis pathway given

    • Starting reactant pool

    • Target product

    • Available reagents / reactions

Chemical

Vendor

Catalog

31


Overview4
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to reaction chemistry problems

  • Review questions

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • SMILES Extensions

    • Reaction SMILES

    • SMARTS

    • SMIRKS

  • Quantum Mechanics

32


Smiles extensions

+ HBr

SMILES Extensions

  • Reaction SMILES

    • Reaction equation denoted with delimiters

      • “.” separates distinct molecules

      • “>>” separates reactants from products

        CCC(Br)(C)C>>CC=C(C)C.Br

33


Smiles extensions1

C2H5O- Na+

+ HBr

C2H5OH

70o C

SMILES Extensions

  • Reaction SMILES

    • Catalyst, solvent or other chemicals may be added between the “>>” delimiters

    • No natural space to specify non-molecular info such as temperature, yield %, etc.

      CCC(Br)(C)C>CC[O-].[Na+].CCO>CC=C(C)C.Br

34


Smiles extensions2
SMILES Extensions

  • SMARTS

    • “Regular expressions” for molecules

    • SMILES are SMARTS strings, but

    • SMARTS strings can describe more general matching criteria, such as

      • Atom types

      • Bond types

      • Logical operators (and, or, not)

35

http://www.daylight.com/dayhtml_tutorials/languages/smarts/


Smiles extensions3
SMILES Extensions

36

http://www.daylight.com/dayhtml_tutorials/languages/smarts/

for complete rule list



Smiles extensions5
SMILES Extensions

  • SMIRKS

    • Reaction profile describing reactants and how to transform them into respective products

    • Combination of

      • Reaction SMILES

      • SMARTS

      • Atom Mapping

    • Generally must be manually specified. Limited work done to automatically derive reaction profile from specific examples

http://www.daylight.com/dayhtml_tutorials/languages/smirks/

38


Smiles extensions6

1

O

1

O

8 4 5 10

7,8 3

H

NH-R2

+

+ H2O

2

2

9 3 7

R1

OH

9 4 5 10

R1

NH-R2

SMILES Extensions

  • Atom Mapping

    • Necessary to map reactant to product atoms

    • Proper transform requires balanced stoichiometry

      • Hydrogens generally must be explicitly specified

Carboxylic acid + [O:1]=[C:2]([*:9])[O:3][H:7].

Primary amine  [H:8][N:4]([*:10])[H:5]>>

Amide + [O:1]=[C:2]([*:9])[N:4]([*:10])[H:5].

Water [H:7][O:3][H:8]

39


Smiles extensions7

+

+

SMILES Extensions

  • Atom mapping implies mechanism

    • Two feasible mechanisms for reaction below

    • Ambiguity without at least atom mapping

  • Atom mapping still lacks a complete mechanistic description analogous to “curved arrow” diagram

40


Quantum mechanics
Quantum Mechanics

  • Capable of accurate predictions for

    • Chemical reactivity

    • Chemical stability  Reaction favorability

  • Requires significant computational power, unfeasible for large scale processing

41


Overview5
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to organic chemistry problems

  • Review questions

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to organic chemistry problems

  • Reaction databases (storing / retrieving info)

  • Combinatorial chemistry / virtual chemical space

  • Reaction prediction / discovery

  • Synthesis design (retrosynthesis)

42


Reaction databases
Reaction Databases

  • Storage

    • Specific reactions can be recorded with reaction SMILES

    • More general mechanistic reaction profiles can be stored with SMIRKS

  • Retrieval

    • Search by reactant or product is same as usual chemical structure search

    • Search by bonds that change focuses on reaction centers to find similar classes

43


Reaction databases1
Reaction Databases

  • Most repositories with thousands of records, some may have millions

    - CASREACT - Beilstein

    - ChemInform RX - ChemReact

  • Generally poor consistency and completion of

    • Balanced reaction stoichiometry

    • Atom mapping / mechanistic description

    • Reaction conditions, etc.

  • Not publicly available or difficult to access

44


Reaction prediction discovery1
Reaction Prediction / Discovery

  • Algorithm features needed

    • Hypothesis generating scheme

    • Thermodynamic scoring system

    • Kinetic scoring system

    • Known reactions database

NaOMe

D

?

+

45


Reaction prediction approximation
Reaction Prediction Approximation

  • Find electron donors (nucleophile) and electron acceptors (electrophile) using rules and rank them

  • Compute all possible intermediates

  • Rank by Enthalpy (+Enthropy)

  • Recurse

  • Stopping rule (drop in delta G)

46


Reaction prediction example

+7

-17.5

Reaction Prediction Example

0

47

Blue: HOMOs / Nucleophiles

Red: LUMOs / Electrophiles


Reaction prediction example1

0

+300

+315

+415

+300

-25

-30

Reaction Prediction Example

48

Blue: HOMOs / Nucleophiles

Red: LUMOs / Electrophiles


Retro synthesis tree

Dead End

Starting

Material

Dead End

Starting Material

Retro-Synthesis Tree

  • Apply retro reactions towards available starting reactants

49


Existing approaches
Existing Approaches

  • Retrosynthetic

    • Interactive: LHASA, SECS

    • Non-Interactive: SYNCHEM

  • Forward: SST, CHIRON

  • Formal: IGOR, WODCA, SYNGEN

  • Reaction Prediction: CAMEO, EROS

50

Todd, M. H. (2004). "Computer-Aided Organic Synthesis." Chemical Society Reviews(34): 247-266.


Virtual chemical space

Target Structure

Nothing directly similar in DB

Retro Diels-Alder

Virtual Chemical Space

1. Apply retro reaction to find possible components

2. Search DB for items similar to components

51


Chemical reactions

Forward Diels-Alder

Target Structure

3. Reapply forward reaction to components to generate theoretical products that should be similar to the original target

4. 160 unique products resulted with similarity scores ranging in [0.247, 0.860],

14 with similarity score > 0.80

52


Reaction discovery and retrosynthesis
Reaction Discovery and Retrosynthesis

  • Synergy between:

    • Chemical DB

    • Reaction DB

    • Reaction mechanism

    • Search algorithms (chemical and reactions)

  • Address combinatorial challenges

53



Reaction prediction discovery2

A B

C D

A B

C D

Reaction Prediction / Discovery

  • Discover reaction profiles by general principles

  • Generic 4 atom reaction profile covers about 50% of all known organic reactions

A B

C D

55


Generic reaction profile issues

  • Diels-Alder

+

Generic Reaction Profile Issues

  • Still, a screening or ranking method is needed to filter many unrealistic reactions proposed

  • More sophisticated profiles are not covered without more knowledge based profiles

56


Reaction favorability scoring1
Reaction Favorability Scoring

  • Thermodynamics

    • DG = DH – TDS (Enthalpy & Entropy contribute)

    • Hess’ Law simplification

    • DHreaction = S(BDEbroken) – S(BDEformed)

    • BDE: Bond Dissociation Energy

      • Standard lookup values (kcal/mol)

        C-C : 83 C=O : 178

        C=C : 146 C≡N : 213

        C=N : 147 etc.

  • Kinetics

    • Much less data available

83 + 178 + 83 + 213

557

57

http://www.cem.msu.edu/~reusch/OrgPage/bndenrgy.htm


Pseudo mechanistic reactions
Pseudo-Mechanistic Reactions

  • More generalized, pseudo-mechanistic reaction modeling with the introduction of “intermediates”

  • Model breaking a bond by separating charge, representing bond electrons moving to one atom

  • Closing the intermediates is then just a matter of matching + and - charges

A B

C D

A+ B-

C- D+

A B

C D

58


Pseudo mechanistic reactions1

O- H+

O H

O

O

-

H+

Pseudo-Mechanistic Reactions

  • Applying general electron-shifting rules on the intermediates provides significant power and chemically intuitive results

59


Azide alkyne example

R1NN+N-

R2 C C R3

R1N

NN

R1N+NN-

C C

R2 R3

R2 C- C+ R3

Azide + Alkyne Example

-38.9 kcal / mol

60


Diels alder example

C- C

C+ C

C- C+

C C

C+ C-

C- C+

Diels-Alder Example

C C

C C

C C

-40 kcal / mol

61


Reactivity principles2
Reactivity Principles

  • Rather than trying all possible bond rearrangement combinations, can use reactivity principles to predict

  • For example, frontier molecular orbital theory can find the

    • Highest Occupied Molecular Orbital (HOMO)

    • Lowest Unoccupied Molecular Orbital (LUMO)

62


Synthesis design retrosynth
Synthesis Design (Retrosynth)

  • Components

    • Starting Reactants

    • Reagents w/ Reaction Profiles

  • Synthesis Problem

63


Synthesis design retrosynth1
Synthesis Design (Retrosynth)

  • Synthesis problem generator

    • Tutorial for students

    • Test base for retro-synthesis algorithm

  • Algorithm features needed

    • Knowledge base of reactions

    • Retro-reaction application

    • Heuristic to guide search

64


Overview6
Overview

  • Reactions in organic chemistry, review

  • Problems in reaction chemistry

  • Chemoinformatics methods

  • Applications of reaction chemoinformatics to organic chemistry problems

  • Review questions

  • Applications of reaction chemoinformatics to organic chemistry problems

  • Review questions

65


Review reactivity principles

.

.

.

.

.

.

.

.

Review: Reactivity Principles

  • For each molecule, what is the most reactive (lone or bond) pair of electrons?

  • Recall the relative order of molecular orbital reactivity

  • n-orbitals (lone pairs) >

  • p-orbitals (double / triple bonds) >

  • s-orbitals (single bonds)

Lone pairs win in general, though no lone pair is available in the last molecule (the nitrogen has already been protonated). In that case, the p-orbital (double bond) supercedes the s-orbitals of all the single bonds

66


Review reaction favorability
Review: Reaction Favorability

  • For the reaction energy diagram, suppose A = B = 2.8 kcal / mol

  • Would you expect the reaction to proceed at room temperature?

  • At thermodynamic equilibrium, what ratio of products : reactants would you expect?

  • Which of the following would shift the equilibrium closer to 50:50 ratio?

Relative Energy

A

B

Reactant Intermediate Product

Reaction Coordinate

  • Adding a catalyst

  • Heating the reaction mixture

  • Raising the universal gas constant

  • None of the above

67


Review reaction favorability1
Review: Reaction Favorability

  • For the reaction energy diagram, suppose A = B = 2.8 kcal / mol

  • Yes, expect the reaction to proceed at room temperature because

    Ea = A < 22 kcal /mol

  • At equilibrium, expect products : reactants ratio = Keq ~ 100:1

    10x Keq ~ 1.4 kcal / mol DG = B

  • Shifting the equilibrium ratio…

Relative Energy

A

B

Reactant Intermediate Product

Reaction Coordinate

  • Adding a catalyst: No, this lowers Ea, but DG is unchanged.

    • Free energy is a state function. Catalyst only accelerates reaction

  • Heating the reaction mixture: Yes, Keq depends on DG and temperature.

    • Higher temperature provides more energy to maintain less stable state

68

Keq = e-DGo/RT


Review reaction prediction

+

+

+

Review: Reaction Prediction

  • Using the provided bond dissociation energies (BDE), which of the products do you predict is most likely for a reaction between the reactants?

69


Review reaction prediction1

+

+

+

Review: Reaction Prediction

  • Using the provided bond dissociation energies (BDE), which of the products do you predict is most likely for a reaction between the reactants?

(O—H + C—C) –

(C—O + C—H) =

(111 + 83) –

(85 + 99) =

+10

(O—H + C=C) –

(C—O + C—H + C—C) =

(111 + 146) –

(85 + 99 + 83) =

-10

(O—H + O—H) –

(O—O + H—H) =

(111 + 111) –

(35 + 104) =

+83

70


Review reaction classification

C2H5O- Na+

+ HBr

C2H5OH

70o C

+

+

+ HBr

H2SO4

Heat

+ HONO2

+H2O

Na2Cr2O7

H2SO4

Review: Reaction Classification

  • Which reactions can NOT be classified into the 4 atom bond rearrangement pattern?

    A—B + C—D  A—C + B—D

71


Review reaction classification1

C2H5O- Na+

+ HBr

C2H5OH

70o C

+

+

+ HBr

H2SO4

Heat

+ HONO2

+H2O

Na2Cr2O7

H2SO4

Review: Reaction Classification

  • Which reactions can NOT be classified into the 4 atom bond rearrangement pattern?

    A—B + C—D  A—C + B—D

72


Review reaction smiles
Review: Reaction SMILES

  • What features in the reaction below can NOT be specified with reaction SMILES?

10% NaOH, H2O

5o C

2

(50% yield)

CC=O.CC=O>[Na]O.O>CC(O)CC=O

Could not specify “10%,” reaction temperature or yield

73


Review smarts
Review: SMARTS

  • For each SMARTS pattern, indicate which molecules it will find at least one match in.

74


Review smarts1

2

3

5

6

7

4

5

2

5

6

1

5

5

Review: SMARTS

  • For each SMARTS pattern, indicate which molecules it will find at least one match in.

75


Review smirks

+ H2

+ H2

+ H2O

Review: SMIRKS

  • Apply each SMIRKS string to the respective starting reactants below to generate a product

[C:1]=[C:2].[H:3][Br:4]>>[H:3][C:1][C:2][Br:4]

Hydrobromination, Alkene

[C:1]#[C:2].[H:3][H:4]>>[H:3][C:1]=[C:2][H:4]

+ HBr

Hydrogenation, Alkyne

[C:1]=[C:2].[H:3][H:4]>>[H:3][C:1][C:2][H:4]

Hydrogenation, Alkene

[H:3][C:1][C:2][O:4][H:5]>>[C:1]=[C:2].[H:3][O:4][H:5]

Dehydration

X

No reaction! Reactant does not match the SMIRKS

reactant pattern. No [H:3] attached to [C:1]

76


Review retrosynthesis
Review: Retrosynthesis

  • Using the SMIRKS defined reactions and starting materials in this and the previous slide, come up with a synthesis pathway for the boxed target molecule

77


Review retrosynthesis1

Halogenation

Dehydration

Hydrogenation, Alkyne

+ H2

Review: Retrosynthesis

+ 2 HBr

+ H2O

Available Starting Material

78


Reaction favorability5
Reaction Favorability

  • Enthalpy determination

    • DHf: “Heat of formation.” State function indicating the heat / energy produced accompanying formation of a substance from its constituent elements in standard states (room t, 1 atmosphere)

      Formation equation for carbon dioxide:

      C(solid, graphite) + O2(gas)  CO2(gas)

    • Only relative values have meaning, “constituent elements in standard state” is an arbitrary zero point

79