chemical reactions. 2 overview reactions in organic chemistry, review problems in reaction chemistry...

Chemical Reactions

2

Overview

• Reactions in organic chemistry, review

• Problems in reaction chemistry

• Chemoinformatics methods

• Applications of reaction chemoinformatics to reaction chemistry problems

• Review questions

3

Overview






– Chemicals – Reactions Relationship– Reaction Specification– Reaction Mechanisms– Reactivity Principles– Reaction Favorability– Reaction Classification

4

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

CH3

CH2CH3

Br

CH3

HBr+

5

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.

Br + HBrC2H5O- Na+

C2H5OH70o C

6

Reaction Mechanisms

• Reactions are fundamentally rearrangements of electron configurations

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

7

Mechanistic Principles

• Curved arrow diagrams– Depict flow of electrons, NOT atoms– Source must be electrons (bond, lone pair, radical)– Targets should be atoms / nuclei

O

Cl

N C- N

O-

Cl

N

O

Cl-

+

8

Reactivity Principles

• Broadly speaking, reactions are the transfer of electrons from – Electron-dense groups (nucleophiles) to – Electron-deficient ones (electrophiles)

9

H

N C

H

H

..

..

..

..

.. .

. .

.

n

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 >• -orbital: Double / triple bonds >• -orbital: Single bonds

N

H

H

H

10

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

11

Reaction Favorability• Gibbs Free Energy

– Keq is a function of Go (and temperature)

– G: Difference between product and reactant (Gibbs) free energy

• Negative G is thus favorable• State function, measuring thermodynamic stability• Go: G under standard conditions

Keq = e-Go/RTGo = -RT ln Keq

R = Universal gas constantT = Absolute temperature

12


• 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, S is small (esp. when n = 0), thus• Unless at very high temperatures, H dominates TS, thus• Calculating H provides a good estimate for G

13

Reaction Favorability Scoring• Thermodynamics

– G = H – TS (Enthalpy & Entropy contribute)

– Hess’ Law simplification– Hreaction = (BDEbroken) – (BDEformed)– BDE: Bond Dissociation Energy

• Standard lookup values (kcal/mol)C-C : 83 C=O : 178C=C : 146 C≡N : 213C=N : 147 etc.

• Kinetics– Much less data available

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

O

N

83 + 178 + 83 + 213

557

14


• Reaction Kinetics– Thermodynamics: How “far” a reaction will proceed– Kinetics: How “fast” a reaction will proceed

2 H2 + O2 2 H2O• Highly favorable G, 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…

15

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

Reaction Coordinate

Relative

Energy

Ea

G

Go = 1.4 kcal / mol ~ 10x Keq

Ea < 22 kcal / mol ~ Room temperature reaction

OH

H

H

H

Cl-

+OH

-Cl

H

H

H

C-

Cl

H

H

H

OH

16

Overview

• Reactions in organic chemistry, review– Reaction Classification

• Specific chemicals• Compatible functional groups• Reactant counts• Bond rearrangement patterns• Functional classification• Mechanism based

Mo

re

Ge

neral

More Informative

17

Reaction Classification/Organization

• Specific chemicals– acetic acid + methanamine N-methylacetamide

• Compatible functional groups– carboxylic acid + primary amine amide + water

NH2 R2 R1

NH

O

R2

R1

OH

O

OH2+ +

NH2

NH

O

OH

O

OH2+ +

18

Reaction Classification

• Reactant counts– Substitutionn = 0

– Additionn < 0

– Eliminationn > 0

CH3

CH2 CH3

Br

CH3

HBr+

NH2

NH

O

OH

O

OH2+ +

OH

H

OH2+

19

Reaction Classification• Bond rearrangement patterns

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

C

O

Cl

HNH

C

O

NH

Cl

H

NH

O

C

A B

C D

A B

C D

A B

C D

20

Reaction Classification• Bond rearrangement patterns

– 6 atom cyclic rearrangement covers ~25%A

F B

E CD

AF B

E CD

O

O

O

O

O

O

+

21

Reaction Classification

• Functional classification– Acid-catalyzed,

Electrophilic– Base-catalyzed,

Nucleophilic– Oxidation-

Reduction– Free-radical– Etc.

NH2

NH

O

OH

O

OH2+ +

NO2

+ HNO3

H2SO4

Heat+ H2O

O

OH

OHNa2Cr2O7

H2SO4

22

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

OH- OH

H

H

H

Cl-

ClH

H

H

+OH

OH-

Cl

Cl-

23






Overview


• Problems in reaction chemistry– Storing / retrieving reaction information– Combinatorial chemistry / virtual chemical space– Reaction prediction / discovery– Chemical Synthesis

• Reaction planning• Synthesis design (retrosynthesis)

24

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

25

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

26

Reaction Prediction / Discovery

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

O

O

O

O

N

N

NH2NH

+ ?NaOMe

27

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 ?

28

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.

29

Chemical Synthesis• Series of reactions from starting reactants

to form a pathway to the final product

CH3

CHCH3

CH2

CH3

Br

CH3C-

NNa+CH3

CH3

N

H2 PdCaCO3 Quinolone

HBr

30

Reaction Planning

• Derive synthesis pathway given– Starting reactant– Target product– Available reagents / reactions

? ? ?

O

N

O

Cl

O

N O

31

Retrosynthesis

• Derive synthesis pathway given– Starting reactant pool– Target product– Available reagents / reactions

O

NH

N

O

SO

ON

N

N

N

? ? ?ChemicalVendorCatalog

32

Overview







• Chemoinformatics methods– SMILES Extensions

• Reaction SMILES• SMARTS• SMIRKS

– Quantum Mechanics

33

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

Br+ HBr

34

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

Br + HBrC2H5O- Na+

C2H5OH70o C

35

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)

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

36

SMILES Extensions

http://www.daylight.com/dayhtml_tutorials/languages/smarts/for complete rule list

SMARTS Description* Wildcard atom. Matches any atom

[C] Aliphatic (non-aromatic) carbons

[c] Aromatic carbons

[#6] Any carbons (aliphatic or aromatic)

[CH3] Terminal carbons (having exactly 3 hydrogens)

[+1] Any atom with a formal charge of +1

[OX2] Oxygen with degree 2 (exactly 2 neighbors)

[!#1] Any atom that is NOT hydrogen

[N,O,C-1] Nitrogen OR oxygen OR (carbon with –1 charge)

[N,O;+1] (Nitrogen OR oxygen) AND +1 charge

37

SMILES Extensions

SMARTS Description

[CH3]C(=O)[OH] Acetic acid

*C(=O)[OH] Any carboxylic acid

C(=O)O Any carboxylic acid or ester

C(=O)[F,Cl,Br,I] Any acid halide

[C+,B;X3] Carbocation or neutral boron

38

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/

39

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]

R1

O

OH

NH-R2H+

R1

O

+ H2O

NH-R2

1

2

9 3 7

8 4 5 10

1

2

7,8 3

9 4 5 10

40

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

BrOH

-OH

Br-

+

OH

Br-

+

41

Quantum Mechanics

• Capable of accurate predictions for– Chemical reactivity– Chemical stability Reaction favorability

• Requires significant computational power, unfeasible for large scale processing

42

Overview




• Applications of reaction chemoinformatics to organic chemistry problems

• Review questions– Reaction databases (storing / retrieving info)– Combinatorial chemistry / virtual chemical space– Reaction prediction / discovery– Synthesis design (retrosynthesis)



43

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

44

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

45

Reaction Prediction / Discovery

• Algorithm features needed– Hypothesis generating scheme– Thermodynamic scoring system– Kinetic scoring system– Known reactions database

O

O

O

O

N

N

NH2NH

+ ?NaOMe

46

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)

47

Reaction Prediction Example

Blue: HOMOs / NucleophilesRed: LUMOs / Electrophiles

H O-

CH3

CCl

O

0

CH3C

Cl

O-

OH

+7

CH3 C

OH

O

Cl-

-17.5

48

CH

CH Br-

O+

H

H

H+300

Reaction Prediction ExampleCH

CH

Blue: HOMOs / NucleophilesRed: LUMOs / Electrophiles

O H

H

H Br

CH

CH

0

Br

O H

H

-30

CH-

CH

Br

O+

H

H

H+415

CH2

CH+

O H

HBr-

+315

Br-

O+

H

H+300

OH

H Br

-25

49

Retro-Synthesis Tree• Apply retro reactions towards available starting reactants

OH

OH

StartingMaterial

OH

OH

O

O

OH

OH

Br

Dead End

Dead End

O

O

Starting Material

OH OH

50

Existing Approaches

• Retrosynthetic– Interactive: LHASA, SECS– Non-Interactive: SYNCHEM

• Forward: SST, CHIRON

• Formal: IGOR, WODCA, SYNGEN

• Reaction Prediction: CAMEO, EROS

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

51 Virtual Chemical Space

Target StructureNothing directly similar in

DB

NH

N

O

NH

O

O

N

NH

O

NH2

N

O

O

O

O

NO

O

N

N

O

O

N

O

O

N

O

O NH

N

N

N

NN

NN

N

N

NN

N

N

N

N

2. Search DB for items similar to components

1. Apply retro reaction to find possible components

Retro Diels-Alder

+

N

ONH

52

NH

O

O

N

NH

O

NH2

N

O

O

O

O

NO

O

N

N

O

O

N

O

O

N

O

O NH

N

N

N

NN

NN

N

N

NN

N

N

N

N

Forward Diels-Alder

+

O

NH N

ON O

N

O

O

NH N

O

O

N N

O

O

N N

O

Target Structure

NH

N

O

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

53

Reaction Discovery and Retrosynthesis

• Synergy between:1. Chemical DB

2. Reaction DB

3. Reaction mechanism

4. Search algorithms (chemical and reactions)

– Address combinatorial challenges

54

Docking and Drug Discovery

55

Reaction Prediction / Discovery• Discover reaction profiles by general principles• Generic 4 atom reaction profile covers about

50% of all known organic reactions

C

O

Cl

HNH

C

O

NH

Cl

H

NH

O

C

A B

C D

A B

C D

A B

C D

56

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

O Cl

NH2

O

Cl

NH

CH4

O

NH Cl

C

O

Cl

HNH

+

Diels-Alder

N N+

N-

N N

N+

Azide + Alkyne

aromatic cyclization

57

Reaction Favorability Scoring• Thermodynamics

– G = H – TS (Enthalpy & Entropy contribute)

– Hess’ Law simplification– Hreaction = (BDEbroken) – (BDEformed)– BDE: Bond Dissociation Energy

• Standard lookup values (kcal/mol)C-C : 83 C=O : 178C=C : 146 C≡N : 213C=N : 147 etc.

• Kinetics– Much less data available

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

O

N

83 + 178 + 83 + 213

557

58

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

59

Pseudo-Mechanistic Reactions• Applying general electron-shifting rules on

the intermediates provides significant power and chemically intuitive results

O- H+O H O

-

H+

O

60

Azide + Alkyne Example

R1 N N+ N-

R2 C CR3

R1 N+ N N-

R2 C- C+

R3

R1 NN N

C CR2

R3-38.9 kcal / mol

61

Diels-Alder Example

C CC C

C C

C- CC+ C

C- C+

C CC+ C-

C- C+

-40 kcal / mol

62

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)

63

Synthesis Design (Retrosynth)

ComponentsStarting Reactants

Reagents w/ Reaction Profiles

Synthesis Problem

64

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

65

Overview








66

Review: Reactivity Principles• For each molecule, what is the most

reactive (lone or bond) pair of electrons?

NH3+O....

O....

Recall the relative order of molecular orbital reactivity• n-orbitals (lone pairs) > • -orbitals (double / triple bonds) > • -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 -orbital (double bond) supercedes the -orbitals of all the single bonds

67

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? Reactant Intermediate Product

Reaction Coordinate

Relative

Energy

A

B

a. Adding a catalystb. Heating the reaction mixturec. Raising the universal gas constantd. None of the above

68

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 G = B

• Shifting the equilibrium ratio…

Reactant Intermediate Product

Reaction Coordinate

Relative

Energy

A

B

a. Adding a catalyst: No, this lowers Ea, but G is unchanged. Free energy is a state function. Catalyst only accelerates reaction

b. Heating the reaction mixture: Yes, Keq depends on G and temperature.Higher temperature provides more energy to maintain less stable state

Keq = e-Go/RT

69

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?

OH

OH

Bond BDEH—H 104

C—C 83

C=C 146

C—O 85

C—H 99

O—H 111

O—O 35

OH OH2+

OH

O

H2+OH

OH+

70

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?

OH

OH

Bond BDEH—H 104

C—C 83

C=C 146

C—O 85

C—H 99

O—H 111

O—O 35

OH OH2+

OH

O

H2+OH

OH+

(O—H + O—H) – (O—O + H—H) =

(111 + 111) – (35 + 104) =

+83

(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

71

Review: Reaction Classification• Which reactions can NOT be classified into the 4

atom bond rearrangement pattern?A—B + C—D A—C + B—D

CH3

CH2

CH3

Br

CH3

+ HBr

Br + HBrC2H5O- Na+

C2H5OH70o C

NH2

NH

O

OH

O

OH2+ +

NO2

+ HONO2

H2SO4

Heat

+ H2O

+

O

OH

OHNa2Cr2O7

H2SO4

72

Review: Reaction Classification• Which reactions can NOT be classified into the 4

atom bond rearrangement pattern?A—B + C—D A—C + B—D

CH3

CH2

CH3

Br

CH3

+ HBr

Br + HBrC2H5O- Na+

C2H5OH70o C

NH2

NH

O

OH

O

OH2+ +

NO2

+ HONO2

H2SO4

Heat

+ H2O

+

O

OH

OHNa2Cr2O7

H2SO4

73

Review: Reaction SMILES

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

O OOH

2

(50% yield)

10% NaOH, H2O

5o C

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

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

74

Review: SMARTS• For each SMARTS pattern, indicate which

molecules it will find at least one match in.

OH

OH

O

O

Cl

O

O

O

OH

O

N

O-

Cl

# SMARTS

1 C#C

2 C(=O)O

3 *C(=O)[OH]

4 C(=O)[F,Cl,Br,I]

5 [#8X1]

6 [X3]=[!O]

7 [c]

75

Review: SMARTS• For each SMARTS pattern, indicate which

molecules it will find at least one match in.

OH

OH

O

O

Cl

O

O

O

OH

O

N

O-

Cl

# SMARTS

1 C#C

2 C(=O)O

3 *C(=O)[OH]

4 C(=O)[F,Cl,Br,I]

5 [#8X1]

6 [X3]=[!O]

7 [c]

235

6

7 45

256

5 15

76

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]

OH OH

Br

OH

+ HBr

Br

+ H2OH

+ H2 X

No reaction! Reactant does not match the SMIRKS reactant pattern. No [H:3] attached to [C:1]

Br

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

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

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

Hydrobromination, Alkene

Hydrogenation, Alkyne

Hydrogenation, Alkene

Dehydration

+ H2O

77

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

Br

Br

OH

OH

OH

78

Review: RetrosynthesisBr

Br

OH

+ 2 HBr Halogenation

Dehydration

Hydrogenation, Alkyne

+ H2O

OH+ H2

Available Starting Material

79


• Enthalpy determination– Hf: “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

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