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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
• 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
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
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, 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 Favorability
• 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
• 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
• 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
• 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
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
• Reactions in organic chemistry, review
• Problems in reaction chemistry
• Chemoinformatics methods
• 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)
• Chemoinformatics methods
• Applications of reaction chemoinformatics to organic chemistry problems
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
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
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
• 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
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
Reaction Favorability
• 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