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Substitusi Nukleofilik

1. The document discusses nucleophilic substitution (SN1 and SN2) reactions, where a nucleophile replaces a leaving group on a substrate. 2. It describes factors that determine the rate of these reactions, such as the nucleophilicity of the nucleophile, stability of the leaving group, and structure of the substrate. Tertiary substrates typically undergo SN1 while primary typically undergo SN2. 3. SN1 is a two-step reaction involving a carbocation intermediate, while SN2 is a single-step reaction with inversion of configuration.

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SUBSTITUSI NUKLEOFILIK
+ + REAKSI SUBSTITUSI Y menggantikan tempat X (Substitusi ) Y “menggantikan” X Satu gugus menggantikan gugus yang lain Y R X R Y X
SUBSTITUSI NUKLEOFILIK produk PENGGANTIAN NUKLEOFILIK nukleofil “menggantikan” gugus lepas. Disebut reaksi substitusi: Nu menggantikan X (berganti tempat). nukleofil substrat gugus lepas
APA YANG MEMBUAT SUATU NUKLEOFIL BAIK? APA ITU NUKLEOFIL? BASA? NUKLEOFILISITAS
Kebasaan ukuran kemampuan pereaksi untuk menerima sebuah proton dalam suatu reaksi asam-basa Nukleofilisitas ukuran kemampuan suatu pereaksi untuk menyebabkan terjadinya suatu reaksi substitusi
NUKLEOFIL DAN BASA PERBEDAAN DASAR Basa baik belum tentu Nukleofil baik, begitu sebaliknya HOWEVER : Parameter kinetik (kecepatan) Parameter thermodinamika (keseimbangan) Nukleofilisitas kebasaan Semua nukleofil adalah basa..... dan semua basa adalah nukleofil.
I Br Cl ROH HOH C ≡N OH OR HOH ROH Cl Br OH OR I C ≡N Urutan kebasaan Urutan nukleofilisitas Keterangan: semakin ke bawah semakin kuat
REAKSI SUBSTITUSI NUKLEOFILIK REAKSI ASAM-BASA (substitusi pada atom karbon) (Substitusi pada atom Hidrogen) Dapat dibandingkan dengan ….. REAKSI PENGGANTIAN
basa asam Asam konyugasi Basa kanyugasi nukleofil substrat produk Gugus lepas PERBANDINGAN SUBSTITUSI PENGGANTIAN PADA ATOM C PENGGANTIAN PADA ATOM H
R O R R ' C C R R ' C O O R NUKLEOFIL PEMILIHAN NUKLEOFIL UNTUK SINTESIS BERBAGAI SENYAWA ORGANIK: Nukleofil Produk R X R O H C N R R S H alkyl halides alcohols ethers nitriles esters alkynes thiols Senyawa ‘ ‘ R-Y + Nu R-Nu + Y
R ' N H R O R R NUKLEOFIL YANG TIDAK BERMUATAN Nukleofil Produk alcohols Senyawa O R H ethers R N H 2 amines amines O H H + R B r O H H R + + B r O H R O H H + H 3 O + + B r - - Under some circumstances water will react. ‘ ‘
Kedua reaksi kelihatan identik Dan mengikuti pola di atas Dua reaksi berikut.... Kenyataan, keduanya berbeda ! REAKSI “MIRIP” RBr + NaOH ROH + NaBr
DUA REAKSI MIRIP 1) 2) ( + some alkene by E1,E2 ) 55 o C 55 o C NaOH kons tinggi NaOH kons rendah KEC = k 2 [RBr] [NaOH] KEC = k 1 [RBr] RBr + NaOH ROH + NaBr
REAKSI 1 REAKSI S N 2
S N 2 bimolekular 55 o C k 2 = 0.022 liter/mole-sec substitusi nukleofilik bimolekular - kecepatan = k 2 [RBr] [NaOH]
Reaksi serentak (1 tahap) produk pereaksi  H E N E R G Y Ea S N 2 Keadaan transisi TS
REAKSI 2 REAKSI S N 1
lambat cepat 2 tahap; unimolekular 55 o C k 1 = 0.010 liter/mole-sec substitusi nukleofilik unimolekular alkene (via E1) also kecepatan = k 1 [RBr] S N 1
pereaksi produk Ea 1 Ea 2  H intermediet TS 2 TS 1 E N E R G Y step 1 step 2 karbokation REAKSI DUA TAHAP S N 1
55 o C Alkil halida primer Two similar reactions, different kinetics. RBr + NaOH ROH + NaBr Kecepatan = k 2 [RBr] [NaOH] S N 2 1) Kasus pertama
55 o C Alkil halida tersier Kecepatan = k 1 [RBr] S N 1 2) Kasus kedua
S N 2 conditions S N 1 conditions [OH-] tinggi [OH-] rendah enantiomer Campuran resemat R-(-)-2-bromooktana S-(+)-2-octanol Inversion sempurna Rasemisasi sempurna PERUBAHAN STEREOKIMIA [  ] D = +10.3 o [  ] D = - 36.0 o [  ] D = 0 o + R S R S
enantiomer MEKANISME S N 1 karbokation planar (S) (R) (R) 50% 50% campuran racemat serangan atas dan bawah secara bersamaan + sp2 - RASEMISASI
MEKANISME S N 2 Serangan Belakang Serangan nukleofilik Konfigurasi (R) Konfigurasi (S) C R H CH 3 H O : .. .. : O .. H .. INVERSI C H Br R CH 3 : : .. ..
Menemukan secara eksperiment bahwa: HUGHES AND INGOLD ca. 1940 Kebanyakan alkil halida primer bereaksi SN2 dengan orde reaksi kedua Kebanyakan alkil halida tersier bereaksi SN1 dengan orde reaksi pertama
 Nu: C X Nu: + C X + X Nu C   E R rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
 Nu: C X E R Nu: + C X + X Nu C   rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
C Nu  X E R Nu: + C X + X Nu C   rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
C Nu  X E R Nu: + + X Nu C   Terjadi inversi pada karbon “ serangan belakang” C X S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
 Nu: Review: S N 2 = Substitusi Nukleofilik Orde ke 2 C X Nu: + C X + X Nu C   E R reaktan produk
 Nu: C X E R Nu: + C X + X Nu C   Review: Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
C Nu  X E R Nu: + C X + X Nu C   Review: ΔG ‡ ΔG ° (equilibria) (rates) Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
LIKE POOL OR BILLIARDS 1) two balls at rest and touching 2) forceful shot directly on axis 3) straight-on collision 4) momentum transfer Nu Nu Nu X X X X CONCEPTUAL ANALOGY 1 Similar in concept to an attack from the back forcing the nucleophile to leave.
INVERSION OF AN UMBRELLA IN THE WIND Inversion of the umbrella is similar in concept to the inversion of an S N 2 atom. CONCEPTUAL ANALOGY 2
C H CH 3 R Br HO activated complex is trigonal planar (sp 2 ) (R)-configuration (S)-configuration configuration is inverted Ea HO C B partial bonding 2p THE INVERSION PROCESS sp 3 sp 3 sp 2 C R H CH 3 Br : C R H CH 3 HO : H O : .. ..
ACTIVATED COMPLEX FOR S N 2 C R H CH 3 Br HO trigonal planar (sp 2 ) 5 bonds to Carbon breaking forming … but the bonds to Br and OH are only half-formed and are not full bonds. NOT A STABLE SPECIES MIDPOINT OF THE REACTION
FAKTOR YANG MEMPENGARUHI SUBSTITUSI NUKLEOFILIK
NUCLEOPHILIC SUBSTITUTION Banyak Faktor Berpengaruh Terhadap Reaksi S N 1 dan S N 2 a) struktur b) atom yg digunakan c) konsentrasi d) Kekuatan basa a) struktur R, stereochemistry a) Keadaan X b) konsentrasi a) Pelarut b) Suhu c) pH SOME PARAMETERS : b) atom yg digunakan c) Kekuatan basa c) Kekuatan ikatan a) Kekuatan ikatan e) kelarutan f) ukuran d)  H
Factors that affect the rate of S N 2 reactions E R ΔG ‡
Factors that affect the rate of S N 2 reactions ΔG ‡ E R
Nukleofilisitas
Nukleofilisitas
If the atom type changes then nucleophilicity may not be determined by basicity.
If the atom type changes then nucleophilicity may not be determined by basicity. basicity basicity nucleophilicity nucleophilicity
Why are some species, such as H-S  and I  weak bases and strong nucleophiles. basicity nucleophilicity
Sulfur has polarizable electrons and can form strong bonds at long distances. The S N 2 Reaction is very sensitive to steric effects.
 
The S N 2 Reaction is very sensitive to steric effects.
1. nucleophilicity of the nucleophile. Factors that affect the rate of S N 2 reactions E R  G ‡
Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. E R  G ‡  G ‡
Weak bases are good leaving groups in substitution reactions. pK a X 
The Halides. Nucleophilicity and leaving group abilities. increasing acidity increasing nucleophilicity increasing reactivity (substitution)
The Halides Iodine is both a good leaving group and a good nucleophile! increasing nucleophilicity increasing reactivity (substitution)
Factors that affect the rate of S N 2 reactions 1. nucleophilicity of the nucleophile. 2. stability of the leaving group. E R  G ‡
Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. E R  G ‡
Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. stronger bond  G ‡ E R  G ‡
Relative reactivity of alkyl substituted alkyl halides.
Relative reactivity of alkyl substituted alkyl halides.
Factors that affect the rate of S N 2 reactions 2. basicity of the leaving group. 1. basicity (nucleophilicity) of the nucleophile. structure of the substrate. alkyl group substitution. E R  G ‡
STRUKTUR SUBSTRAT S N 1
S N 1 - SUBSTRAT DAN KARBOKATION R-X R + + X - lambat R + + Nu - R-Nu cepat The better ion will have the lower energy pathway. Energi intermediet karbokation faktor penting untuk reaksi S N 1 3 o < 2 o < 1 o
SOLVOLYSIS tert-BUTIL BROMIDA acetone S N 1
1935: Hughes & Ingold SOLVOLYSIS t-BUTYL BROMIDA + H 3 O + + Br - tertiary
kecepatan relatif 1.0 1.7 45 RBr + H 2 O ROH + HBr 100% HCOOH kecepatan meningkat rel rate = rate CH 3 Br rate PENGARUH PENINGKATAN SUBSTITUSI - S N 1 methyl primary secondary tertiary Guess ? PENGARUH SUBSTRAT PADA KECEPATAN 10 8
HIPERKONYUGASI STABILITAS KARBOKATION
STABILITAS KARBOKATION HIPERKONYJUGASI C C H .. H H + R R elektron yang berdekatan ikatan C-H  membantu menstabilkan Muatan positif karbokation tertiary secondary primary << < Energi terendah Energi tertinggi REVIEW
STRUKTUR SUBSTRAT S N 2
S N 2 - SUBSTRAT C R Br : H O : .. .. R R large groups introduce steric hindrance C H Br : H H easy access no steric hindrance H O : .. ..
decreasing rate EFFECT OF DEGREE OF SUBSTITUTION - S N 2 methyl primary secondary tertiary EFFECT OF SUBSTRATE ON RATE 150 1 0.01 0.001 rel rate = rate EtBr rate
decreasing rate EFFECT OF BULKY SUBSTITUENTS - S N 2 NEOPENTYL slower than t -butyl ALL ARE PRIMARY ! ( substitution on the  carbon ) 17 1 0.03 3 x 10 -6 rel rate = rate EtBr rate    
STERIC HINDRANCE
isopropyl t -butyl neopentyl COMPARATIVE STERIC HINDRANCE
WILL NOT REACT - S N 2 backside attack is difficult Steric Hindrance
BENZYL SUBSTRATES
S N 2 increasing rate rel rate = rate EtBr rate
SUMMARY
S N 1 S N 2 tertiary methyl ** benzyl benzyl allyl allyl secondary primary primary secondary tertiary neopentyl Notice that benzyl and allyl are good for both S N 1 and S N 2 BEST WORST (fastest) (slowest) bridgehead bridgehead (bicyclic) (bicyclic) APPROXIMATE RATE ORDERS BEST (fastest) WORST (slowest) SUMMARY ** In S N 2 reactions benzyl is actually better than methyl, but allyl is not. For illustration purposes benzyl and allyl were grouped in the yellow box.
AND DON’T FORGET: S N 1 and S N 2 reactions occur only at sp 3 (tetrahedral) carbon atoms. yes no sp 3 sp 2 sp (attempted S N 2 reaction) (attempted S N 1 solvolysis) CH 3 CH 2 -C=CH-Br + H 2 O no reaction + NaCN no reaction acetone
IS THE NUCLEOPHILE IMPORTANT IN BOTH S N 1 AND S N 2 REACTIONS ?
Nucleophiles are unimportant in an S N 1 reaction; they are not involved in the rate-determining step. S N 1 rate = K 1 [RX] The nature of a nucleophile is only important to an S N 2 reaction. S N 2 rate = K 2 [RX][Nu] NUCLEOPHILES IMPORTANCE IN S N 1 AND S N 2 REACTIONS
WHAT IS A GOOD NUCLEOPHILE ? S N 2 REACTIONS
C R Br : R R WHAT IS THE IDEAL NUCLEOPHILE ? no way ! bad STERIC PROBLEMS Smaller is better ! LARGE SMALL S N 2 REACTIONS For an S N 2 reaction the nucleophile must find the back lobe of the sp 3 hybrid orbital that the leaving group is bonded to. good Y : : .. .. : .. .. X : -
:C N: SMALL SPHERES ROD OR SPEAR SHAPED EXPECTED “IDEAL” NUCLEOPHILES :N N N: - - - - - + etc. These types should be able to find the target ! azide cyanide Generally this idea is correct. .. :F: .. :Cl: .. ..
F Cl Br I 1.36 A 1.81 A 1.95 A 2.16 A - - - - smallest ion and we would expect the smallest one (fluoride) to be the best nucleophile, … .. however, that is not usually the case. OUR NAÏVE EXPECTATION We would expect the halides to be good nucleophiles: ionic radii:
F - 5 x 10 2 Cl - 2.3 x 10 4 Br - 6 x 10 5 I - 2 x 10 7 slowest fastest k CH 3 -I + NaX CH 3 -X + NaI Rate = k [CH 3 I] [X - ] RELATIVE RATES OF REACTION FOR THE HALIDES MeOH * MeOH solvates like water but dissolves everything better. EXPERIMENTAL RESULTS S N 2
SOLVATION Solvation reverses our ideas of size.
F - 120 Kcal / mole - gas phase F - H O H water solution H O H HEAT OF SOLVATION H O H H O H F - (g) F - (aq) HEAT OF SOLVATION SOLVATED ION ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER The interaction between the ion and the solvent is a type of weak bond. Energy is released when it occurs. Solvation lowers the potential energy of the nucleophile making it less reactive.
F Cl Br I 1.36 A 1.81 A 1.95 A 2.16 A HALIDE IONS Heats of solvation in H 2 O - 120 - 90 Kcal / mole - 65 - - - - increasing solvation - 75 SMALL IONS SOLVATE MORE THAN LARGE IONS smallest ion larger n smaller n IONIC RADIUS X(H 2 O) n -
WATER AS A SOLVENT polar OH bonds Water is a polar molecule. Negative on the oxygen end, and positive on the hydrogen end. It can solvate both cations and anions.
SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES solvent shell - - ...smaller solvent shell ...escapes easily … more potential energy BETTER NUCLEOPHILE I F - - “ Effective size” is larger. H O H H O H H O H H O H H O H H O H H O H H O H H O H H O H Heavy solvation lowers the potential energy of the nucleophile. It is difficult for the solvated nucleophile to escape the solvent shell. This ion is less reactive.
PROTIC SOLVENTS water methanol ethanol amines Water is an example of a “protic” solvent. Protic solvents are those that have Protic solvents can form hydrogen bonds and can solvate both cations and anions. O-H, N-H or S-H bonds.
In protic solvents the larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potential energy. Since the solvent shell is smaller in a larger ion it can more easily “escape” from the surrounding solvent molecules during reaction. There is more potential energy. LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTS THREE FACTORS ARE INVOLVED : 1 2 3 The larger ions are thought ( by some ) to be more “polarizable”. see the next slide …..
POLARIZABILITY Polarizability assumes larger ions are able to easily distort the electons in their valence shell, and that smaller ions cannot. C Br The distortion of large ions is easier because the orbital clouds are more diffuse. The nucleophile “flows” into the reactive site. VERY HYPOTHETICAL
If everything else is equal, the stronger base is the better nucleophile . BASICITY This principle shows up in a period, where atoms do not vary appreciably in size, and solvate to similar extents. OH - is a better nucleophile than F -
NUCLEOPHILICITY TRENDS IN PROTIC SOLVENTS
OBSERVED NUCLEOPHILICITY TRENDS H 2 O OR OTHER “ PROTIC ” SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII basicity more solvation, larger effective size, lower potential energy basicity
MeOH RELATIVE RATES OF SOME NUCLEOPHILES CH 3 -I + Nu: CH 3 -Nu + I - Rate = k [CH 3 I] [X - ] F- 5 x 10 2 CH 3 COO- 2 x 10 4 Cl- 2.3 x 10 2 C 6 H 5 O- 5.6 x 10 5 N 3 - 6 x 10 5 Br- 6 x 10 5 CH 3 O- 2 x 10 6 CN- 5 x 10 6 I- 2 x 10 7 C 6 H 5 S- 8 x 10 9 CH 3 OH 1.0 NH 3 3.2 x 10 5 (CH 3 ) 2 S 3.5 x 10 5 C 6 H 5 NH 2 5 x 10 5 C 6 H 5 SH 5 x 10 5 these are the good nucleophiles, but watch out, some are strong bases (solvolysis is faster) S N 2 CHARGED NEUTRAL
APROTIC SOLVENTS
APROTIC SOLVENTS dimethylsulfoxide dimethylformamide hexamethylphosphoramide acetone acetonitrile if scrupulously free of water + - - + APROTIC SOLVENTS DO NOT HAVE OH, NH, OR SH BONDS “ DMSO” “ DMF” “ HMPA” They do not form hydrogen bonds.
APROTIC SOLVENTS SOLVATE CATIONS, BUT NOT ANIONS (NUCLEOPHILES) The nucleophile is “ free” (unsolvated), and therefore is small and not hindered by a solvent shell. - - + + crowded
S O H H DIMETHYLSUFOXIDE density - electrostatic potential plot space-filling
X - DIMETHYLFORMAMIDE nucleophile is “free” (unsolvated)
OBSERVED NUCLEOPHILICITY APROTIC SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII The direction of the red arrow ( COLUMNS ) represents a different order than in protic solvents. basicity decreasing ionic size
WHY NOT ALWAYS USE APROTIC SOLVENTS FOR S N 2 ? Mostly, it is a matter of expense. Water, ethanol, methanol and acetone are much cheaper, especially water. Water “free” Methanol $14.70 / L Ethanol $15.35 / L Acetone $16.60 / L DMSO $47.50 / L DMF $33.75 / L HMPA $163.40 / L Cheapest grades available, Aldrich Chemical Co., 2000.
SOLVENTS WHAT ARE GOOD SOLVENTS FOR S N 1 AND S N 2 ?
S N 1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. R-X R + + X - rate-determining step solvation of both ions speeds the ionization S N 1 SOLVENTS = POLAR Carbocation ions
S N 2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile. C R Br : : .. .. R R X : smaller is better ! SMALL, UNSOLVATED S N 2 SOLVENTS = NONPOLAR OR POLAR-APROTIC
overall polarity NONPOLAR POLAR POLAR PROTIC SOLVENTS POLAR APROTIC SOLVENTS S N 2 NONPOLAR SOLVENTS S N 1
SOLVENT MIXTURES
SOLVENT MIXTURES ARE VERY COMMON Alkyl halides don’t dissolve in water, but dissolve in most organic solvents. Nucleophile salts don’t dissolve in most organic solvents, but dissolve in water. RX NaX soluble in EtOH soluble in H 2 O miscible solvents Both dissolve in a mixed solvent.
EXCEPTIONS NaX Dissolve in polar-aprotic organic solvents: DMF, DMSO, HMPA. NaI and NaCN dissolve in acetone, but NaCl and NaBr do not
CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY S N 1 S N 2 BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT THE BOTTOM LINE The nucleophile is not involved in the rate-determining step. The nucleophile is involved in the rate-determining step.

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In this document
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Introduction to nucleophilic substitution reactions, highlighting the concept of one substituent replacing another in molecular structures.

Discussion on the factors defining a good nucleophile, including basicity and nucleophilicity, and the distinctions between them.

Ranking of nucleophiles and bases based on their efficiency in substitution reactions on carbon and hydrogen atoms.

Criteria for choosing nucleophiles in organic synthesis, distinguishing between similar reactions and their outcomes.

Comparison of bimolecular (SN2) and unimolecular (SN1) nucleophilic substitution mechanisms including their kinetics.

Analysis of stereochemical outcomes in SN1 and SN2 mechanisms, including inversion and racemization phenomena.

Discussion on various factors that impact nucleophilic substitution reactions, including structure, solvent and basicity.

Insights on how the type of atom and its basicity influence nucleophilicity, including examples and trends.

Analysis of halides' abilities as nucleophiles and their roles as leaving groups in nucleophilic substitution.

Overview of the relative reactivity of alkyl substituted halides in relation to their structural properties.

Discussion on factors affecting reaction rates in solvolysis, correlating substrate stability with reaction speed.

Investigating the influence of substituent size and steric hindrance on the rate of SN2 reactions.

Summary highlights differences between SN1 and SN2 reactions, addressing substrate effects and ideal conditions.

Clarification of nucleophile significance in SN1 and SN2 reactions exploring how they influence reaction mechanisms.

Defining criteria for ideal nucleophiles in SN2 processes emphasizing size and steric issues.

Discussion on how solvation influences nucleophilicity and reactivity, particularly among small ions.

Comparison of protic and aprotic solvents, detailing their roles in SN1 and SN2 reactions and solvation effects.

Review of solvent mixtures used in nucleophilic substitution emphasizing their practical application.

Discussion on how various nucleophiles interact with carbohydrates, impacting rate-determining steps.

Substitusi Nukleofilik

  • 1.
  • 2.
    + + REAKSISUBSTITUSI Y menggantikan tempat X (Substitusi ) Y “menggantikan” X Satu gugus menggantikan gugus yang lain Y R X R Y X
  • 3.
    SUBSTITUSI NUKLEOFILIK produkPENGGANTIAN NUKLEOFILIK nukleofil “menggantikan” gugus lepas. Disebut reaksi substitusi: Nu menggantikan X (berganti tempat). nukleofil substrat gugus lepas
  • 4.
    APA YANG MEMBUATSUATU NUKLEOFIL BAIK? APA ITU NUKLEOFIL? BASA? NUKLEOFILISITAS
  • 5.
    Kebasaan ukuran kemampuanpereaksi untuk menerima sebuah proton dalam suatu reaksi asam-basa Nukleofilisitas ukuran kemampuan suatu pereaksi untuk menyebabkan terjadinya suatu reaksi substitusi
  • 6.
    NUKLEOFIL DAN BASAPERBEDAAN DASAR Basa baik belum tentu Nukleofil baik, begitu sebaliknya HOWEVER : Parameter kinetik (kecepatan) Parameter thermodinamika (keseimbangan) Nukleofilisitas kebasaan Semua nukleofil adalah basa..... dan semua basa adalah nukleofil.
  • 7.
    I Br ClROH HOH C ≡N OH OR HOH ROH Cl Br OH OR I C ≡N Urutan kebasaan Urutan nukleofilisitas Keterangan: semakin ke bawah semakin kuat
  • 8.
    REAKSI SUBSTITUSI NUKLEOFILIKREAKSI ASAM-BASA (substitusi pada atom karbon) (Substitusi pada atom Hidrogen) Dapat dibandingkan dengan ….. REAKSI PENGGANTIAN
  • 9.
    basa asam Asam konyugasi Basa kanyugasi nukleofil substrat produk Gugus lepas PERBANDINGAN SUBSTITUSI PENGGANTIAN PADA ATOM C PENGGANTIAN PADA ATOM H
  • 10.
    R O RR ' C C R R ' C O O R NUKLEOFIL PEMILIHAN NUKLEOFIL UNTUK SINTESIS BERBAGAI SENYAWA ORGANIK: Nukleofil Produk R X R O H C N R R S H alkyl halides alcohols ethers nitriles esters alkynes thiols Senyawa ‘ ‘ R-Y + Nu R-Nu + Y
  • 11.
    R ' NH R O R R NUKLEOFIL YANG TIDAK BERMUATAN Nukleofil Produk alcohols Senyawa O R H ethers R N H 2 amines amines O H H + R B r O H H R + + B r O H R O H H + H 3 O + + B r - - Under some circumstances water will react. ‘ ‘
  • 12.
    Kedua reaksi kelihatanidentik Dan mengikuti pola di atas Dua reaksi berikut.... Kenyataan, keduanya berbeda ! REAKSI “MIRIP” RBr + NaOH ROH + NaBr
  • 13.
    DUA REAKSI MIRIP1) 2) ( + some alkene by E1,E2 ) 55 o C 55 o C NaOH kons tinggi NaOH kons rendah KEC = k 2 [RBr] [NaOH] KEC = k 1 [RBr] RBr + NaOH ROH + NaBr
  • 14.
    REAKSI 1 REAKSI S N 2
  • 15.
    S N 2bimolekular 55 o C k 2 = 0.022 liter/mole-sec substitusi nukleofilik bimolekular - kecepatan = k 2 [RBr] [NaOH]
  • 16.
    Reaksi serentak (1tahap) produk pereaksi  H E N E R G Y Ea S N 2 Keadaan transisi TS
  • 17.
    REAKSI 2 REAKSI S N 1
  • 18.
    lambat cepat 2tahap; unimolekular 55 o C k 1 = 0.010 liter/mole-sec substitusi nukleofilik unimolekular alkene (via E1) also kecepatan = k 1 [RBr] S N 1
  • 19.
    pereaksi produk Ea1 Ea 2  H intermediet TS 2 TS 1 E N E R G Y step 1 step 2 karbokation REAKSI DUA TAHAP S N 1
  • 20.
    55 o CAlkil halida primer Two similar reactions, different kinetics. RBr + NaOH ROH + NaBr Kecepatan = k 2 [RBr] [NaOH] S N 2 1) Kasus pertama
  • 21.
    55 o CAlkil halida tersier Kecepatan = k 1 [RBr] S N 1 2) Kasus kedua
  • 22.
    S N 2conditions S N 1 conditions [OH-] tinggi [OH-] rendah enantiomer Campuran resemat R-(-)-2-bromooktana S-(+)-2-octanol Inversion sempurna Rasemisasi sempurna PERUBAHAN STEREOKIMIA [  ] D = +10.3 o [  ] D = - 36.0 o [  ] D = 0 o + R S R S
  • 23.
    enantiomer MEKANISME SN 1 karbokation planar (S) (R) (R) 50% 50% campuran racemat serangan atas dan bawah secara bersamaan + sp2 - RASEMISASI
  • 24.
    MEKANISME S N2 Serangan Belakang Serangan nukleofilik Konfigurasi (R) Konfigurasi (S) C R H CH 3 H O : .. .. : O .. H .. INVERSI C H Br R CH 3 : : .. ..
  • 25.
    Menemukan secara eksperimentbahwa: HUGHES AND INGOLD ca. 1940 Kebanyakan alkil halida primer bereaksi SN2 dengan orde reaksi kedua Kebanyakan alkil halida tersier bereaksi SN1 dengan orde reaksi pertama
  • 26.
     Nu: CX Nu: + C X + X Nu C   E R rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
  • 27.
     Nu: CX E R Nu: + C X + X Nu C   rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
  • 28.
    C Nu X E R Nu: + C X + X Nu C   rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
  • 29.
    C Nu X E R Nu: + + X Nu C   Terjadi inversi pada karbon “ serangan belakang” C X S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
  • 30.
     Nu: Review:S N 2 = Substitusi Nukleofilik Orde ke 2 C X Nu: + C X + X Nu C   E R reaktan produk
  • 31.
     Nu: CX E R Nu: + C X + X Nu C   Review: Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
  • 32.
    C Nu X E R Nu: + C X + X Nu C   Review: ΔG ‡ ΔG ° (equilibria) (rates) Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
  • 33.
    LIKE POOL ORBILLIARDS 1) two balls at rest and touching 2) forceful shot directly on axis 3) straight-on collision 4) momentum transfer Nu Nu Nu X X X X CONCEPTUAL ANALOGY 1 Similar in concept to an attack from the back forcing the nucleophile to leave.
  • 34.
    INVERSION OF ANUMBRELLA IN THE WIND Inversion of the umbrella is similar in concept to the inversion of an S N 2 atom. CONCEPTUAL ANALOGY 2
  • 35.
    C H CH3 R Br HO activated complex is trigonal planar (sp 2 ) (R)-configuration (S)-configuration configuration is inverted Ea HO C B partial bonding 2p THE INVERSION PROCESS sp 3 sp 3 sp 2 C R H CH 3 Br : C R H CH 3 HO : H O : .. ..
  • 36.
    ACTIVATED COMPLEX FORS N 2 C R H CH 3 Br HO trigonal planar (sp 2 ) 5 bonds to Carbon breaking forming … but the bonds to Br and OH are only half-formed and are not full bonds. NOT A STABLE SPECIES MIDPOINT OF THE REACTION
  • 37.
    FAKTOR YANG MEMPENGARUHI SUBSTITUSI NUKLEOFILIK
  • 38.
    NUCLEOPHILIC SUBSTITUTION BanyakFaktor Berpengaruh Terhadap Reaksi S N 1 dan S N 2 a) struktur b) atom yg digunakan c) konsentrasi d) Kekuatan basa a) struktur R, stereochemistry a) Keadaan X b) konsentrasi a) Pelarut b) Suhu c) pH SOME PARAMETERS : b) atom yg digunakan c) Kekuatan basa c) Kekuatan ikatan a) Kekuatan ikatan e) kelarutan f) ukuran d)  H
  • 39.
    Factors that affectthe rate of S N 2 reactions E R ΔG ‡
  • 40.
    Factors that affectthe rate of S N 2 reactions ΔG ‡ E R
  • 41.
  • 42.
  • 43.
    If the atomtype changes then nucleophilicity may not be determined by basicity.
  • 44.
    If the atomtype changes then nucleophilicity may not be determined by basicity. basicity basicity nucleophilicity nucleophilicity
  • 45.
    Why are somespecies, such as H-S  and I  weak bases and strong nucleophiles. basicity nucleophilicity
  • 46.
    Sulfur has polarizableelectrons and can form strong bonds at long distances. The S N 2 Reaction is very sensitive to steric effects.
  • 47.
  • 48.
    The S N2 Reaction is very sensitive to steric effects.
  • 49.
    1. nucleophilicity ofthe nucleophile. Factors that affect the rate of S N 2 reactions E R  G ‡
  • 50.
    Factors that affectthe rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. E R  G ‡  G ‡
  • 51.
    Weak bases aregood leaving groups in substitution reactions. pK a X 
  • 52.
    The Halides. Nucleophilicity and leaving group abilities. increasing acidity increasing nucleophilicity increasing reactivity (substitution)
  • 53.
    The Halides Iodineis both a good leaving group and a good nucleophile! increasing nucleophilicity increasing reactivity (substitution)
  • 54.
    Factors that affectthe rate of S N 2 reactions 1. nucleophilicity of the nucleophile. 2. stability of the leaving group. E R  G ‡
  • 55.
    Factors that affectthe rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. E R  G ‡
  • 56.
    Factors that affectthe rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. stronger bond  G ‡ E R  G ‡
  • 57.
    Relative reactivity ofalkyl substituted alkyl halides.
  • 58.
    Relative reactivity ofalkyl substituted alkyl halides.
  • 59.
    Factors that affectthe rate of S N 2 reactions 2. basicity of the leaving group. 1. basicity (nucleophilicity) of the nucleophile. structure of the substrate. alkyl group substitution. E R  G ‡
  • 60.
  • 61.
    S N 1 - SUBSTRAT DAN KARBOKATION R-X R + + X - lambat R + + Nu - R-Nu cepat The better ion will have the lower energy pathway. Energi intermediet karbokation faktor penting untuk reaksi S N 1 3 o < 2 o < 1 o
  • 62.
    SOLVOLYSIS tert-BUTILBROMIDA acetone S N 1
  • 63.
    1935: Hughes& Ingold SOLVOLYSIS t-BUTYL BROMIDA + H 3 O + + Br - tertiary
  • 64.
    kecepatan relatif1.0 1.7 45 RBr + H 2 O ROH + HBr 100% HCOOH kecepatan meningkat rel rate = rate CH 3 Br rate PENGARUH PENINGKATAN SUBSTITUSI - S N 1 methyl primary secondary tertiary Guess ? PENGARUH SUBSTRAT PADA KECEPATAN 10 8
  • 65.
  • 66.
    STABILITAS KARBOKATION HIPERKONYJUGASIC C H .. H H + R R elektron yang berdekatan ikatan C-H  membantu menstabilkan Muatan positif karbokation tertiary secondary primary << < Energi terendah Energi tertinggi REVIEW
  • 67.
  • 68.
    S N 2 - SUBSTRAT C R Br : H O : .. .. R R large groups introduce steric hindrance C H Br : H H easy access no steric hindrance H O : .. ..
  • 69.
    decreasing rate EFFECTOF DEGREE OF SUBSTITUTION - S N 2 methyl primary secondary tertiary EFFECT OF SUBSTRATE ON RATE 150 1 0.01 0.001 rel rate = rate EtBr rate
  • 70.
    decreasing rate EFFECTOF BULKY SUBSTITUENTS - S N 2 NEOPENTYL slower than t -butyl ALL ARE PRIMARY ! ( substitution on the  carbon ) 17 1 0.03 3 x 10 -6 rel rate = rate EtBr rate    
  • 71.
  • 72.
    isopropyl t -butylneopentyl COMPARATIVE STERIC HINDRANCE
  • 73.
    WILL NOT REACT - S N 2 backside attack is difficult Steric Hindrance
  • 74.
  • 75.
    S N 2increasing rate rel rate = rate EtBr rate
  • 76.
  • 77.
    S N 1S N 2 tertiary methyl ** benzyl benzyl allyl allyl secondary primary primary secondary tertiary neopentyl Notice that benzyl and allyl are good for both S N 1 and S N 2 BEST WORST (fastest) (slowest) bridgehead bridgehead (bicyclic) (bicyclic) APPROXIMATE RATE ORDERS BEST (fastest) WORST (slowest) SUMMARY ** In S N 2 reactions benzyl is actually better than methyl, but allyl is not. For illustration purposes benzyl and allyl were grouped in the yellow box.
  • 78.
    AND DON’T FORGET:S N 1 and S N 2 reactions occur only at sp 3 (tetrahedral) carbon atoms. yes no sp 3 sp 2 sp (attempted S N 2 reaction) (attempted S N 1 solvolysis) CH 3 CH 2 -C=CH-Br + H 2 O no reaction + NaCN no reaction acetone
  • 79.
    IS THE NUCLEOPHILEIMPORTANT IN BOTH S N 1 AND S N 2 REACTIONS ?
  • 80.
    Nucleophiles are unimportantin an S N 1 reaction; they are not involved in the rate-determining step. S N 1 rate = K 1 [RX] The nature of a nucleophile is only important to an S N 2 reaction. S N 2 rate = K 2 [RX][Nu] NUCLEOPHILES IMPORTANCE IN S N 1 AND S N 2 REACTIONS
  • 81.
    WHAT IS A GOOD NUCLEOPHILE ? S N 2 REACTIONS
  • 82.
    C R Br: R R WHAT IS THE IDEAL NUCLEOPHILE ? no way ! bad STERIC PROBLEMS Smaller is better ! LARGE SMALL S N 2 REACTIONS For an S N 2 reaction the nucleophile must find the back lobe of the sp 3 hybrid orbital that the leaving group is bonded to. good Y : : .. .. : .. .. X : -
  • 83.
    :C N:SMALL SPHERES ROD OR SPEAR SHAPED EXPECTED “IDEAL” NUCLEOPHILES :N N N: - - - - - + etc. These types should be able to find the target ! azide cyanide Generally this idea is correct. .. :F: .. :Cl: .. ..
  • 84.
    F Cl BrI 1.36 A 1.81 A 1.95 A 2.16 A - - - - smallest ion and we would expect the smallest one (fluoride) to be the best nucleophile, … .. however, that is not usually the case. OUR NAÏVE EXPECTATION We would expect the halides to be good nucleophiles: ionic radii:
  • 85.
    F - 5x 10 2 Cl - 2.3 x 10 4 Br - 6 x 10 5 I - 2 x 10 7 slowest fastest k CH 3 -I + NaX CH 3 -X + NaI Rate = k [CH 3 I] [X - ] RELATIVE RATES OF REACTION FOR THE HALIDES MeOH * MeOH solvates like water but dissolves everything better. EXPERIMENTAL RESULTS S N 2
  • 86.
    SOLVATION Solvation reversesour ideas of size.
  • 87.
    F - 120 Kcal / mole - gas phase F - H O H water solution H O H HEAT OF SOLVATION H O H H O H F - (g) F - (aq) HEAT OF SOLVATION SOLVATED ION ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER The interaction between the ion and the solvent is a type of weak bond. Energy is released when it occurs. Solvation lowers the potential energy of the nucleophile making it less reactive.
  • 88.
    F Cl BrI 1.36 A 1.81 A 1.95 A 2.16 A HALIDE IONS Heats of solvation in H 2 O - 120 - 90 Kcal / mole - 65 - - - - increasing solvation - 75 SMALL IONS SOLVATE MORE THAN LARGE IONS smallest ion larger n smaller n IONIC RADIUS X(H 2 O) n -
  • 89.
    WATER AS ASOLVENT polar OH bonds Water is a polar molecule. Negative on the oxygen end, and positive on the hydrogen end. It can solvate both cations and anions.
  • 90.
    SMALL IONS SOLVATEMORE HEAVILY THAN LARGE ONES solvent shell - - ...smaller solvent shell ...escapes easily … more potential energy BETTER NUCLEOPHILE I F - - “ Effective size” is larger. H O H H O H H O H H O H H O H H O H H O H H O H H O H H O H Heavy solvation lowers the potential energy of the nucleophile. It is difficult for the solvated nucleophile to escape the solvent shell. This ion is less reactive.
  • 91.
    PROTIC SOLVENTS water methanol ethanol amines Water is an example of a “protic” solvent. Protic solvents are those that have Protic solvents can form hydrogen bonds and can solvate both cations and anions. O-H, N-H or S-H bonds.
  • 92.
    In protic solventsthe larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potential energy. Since the solvent shell is smaller in a larger ion it can more easily “escape” from the surrounding solvent molecules during reaction. There is more potential energy. LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTS THREE FACTORS ARE INVOLVED : 1 2 3 The larger ions are thought ( by some ) to be more “polarizable”. see the next slide …..
  • 93.
    POLARIZABILITY Polarizability assumeslarger ions are able to easily distort the electons in their valence shell, and that smaller ions cannot. C Br The distortion of large ions is easier because the orbital clouds are more diffuse. The nucleophile “flows” into the reactive site. VERY HYPOTHETICAL
  • 94.
    If everything elseis equal, the stronger base is the better nucleophile . BASICITY This principle shows up in a period, where atoms do not vary appreciably in size, and solvate to similar extents. OH - is a better nucleophile than F -
  • 95.
    NUCLEOPHILICITY TRENDS IN PROTIC SOLVENTS
  • 96.
    OBSERVED NUCLEOPHILICITY TRENDS H 2 O OR OTHER “ PROTIC ” SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII basicity more solvation, larger effective size, lower potential energy basicity
  • 97.
    MeOH RELATIVE RATESOF SOME NUCLEOPHILES CH 3 -I + Nu: CH 3 -Nu + I - Rate = k [CH 3 I] [X - ] F- 5 x 10 2 CH 3 COO- 2 x 10 4 Cl- 2.3 x 10 2 C 6 H 5 O- 5.6 x 10 5 N 3 - 6 x 10 5 Br- 6 x 10 5 CH 3 O- 2 x 10 6 CN- 5 x 10 6 I- 2 x 10 7 C 6 H 5 S- 8 x 10 9 CH 3 OH 1.0 NH 3 3.2 x 10 5 (CH 3 ) 2 S 3.5 x 10 5 C 6 H 5 NH 2 5 x 10 5 C 6 H 5 SH 5 x 10 5 these are the good nucleophiles, but watch out, some are strong bases (solvolysis is faster) S N 2 CHARGED NEUTRAL
  • 98.
  • 99.
    APROTIC SOLVENTS dimethylsulfoxidedimethylformamide hexamethylphosphoramide acetone acetonitrile if scrupulously free of water + - - + APROTIC SOLVENTS DO NOT HAVE OH, NH, OR SH BONDS “ DMSO” “ DMF” “ HMPA” They do not form hydrogen bonds.
  • 100.
    APROTIC SOLVENTS SOLVATECATIONS, BUT NOT ANIONS (NUCLEOPHILES) The nucleophile is “ free” (unsolvated), and therefore is small and not hindered by a solvent shell. - - + + crowded
  • 101.
    S O HH DIMETHYLSUFOXIDE density - electrostatic potential plot space-filling
  • 102.
    X - DIMETHYLFORMAMIDEnucleophile is “free” (unsolvated)
  • 103.
    OBSERVED NUCLEOPHILICITY APROTIC SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII The direction of the red arrow ( COLUMNS ) represents a different order than in protic solvents. basicity decreasing ionic size
  • 104.
    WHY NOT ALWAYSUSE APROTIC SOLVENTS FOR S N 2 ? Mostly, it is a matter of expense. Water, ethanol, methanol and acetone are much cheaper, especially water. Water “free” Methanol $14.70 / L Ethanol $15.35 / L Acetone $16.60 / L DMSO $47.50 / L DMF $33.75 / L HMPA $163.40 / L Cheapest grades available, Aldrich Chemical Co., 2000.
  • 105.
    SOLVENTS WHAT AREGOOD SOLVENTS FOR S N 1 AND S N 2 ?
  • 106.
    S N 1reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. R-X R + + X - rate-determining step solvation of both ions speeds the ionization S N 1 SOLVENTS = POLAR Carbocation ions
  • 107.
    S N 2reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile. C R Br : : .. .. R R X : smaller is better ! SMALL, UNSOLVATED S N 2 SOLVENTS = NONPOLAR OR POLAR-APROTIC
  • 108.
    overall polarity NONPOLARPOLAR POLAR PROTIC SOLVENTS POLAR APROTIC SOLVENTS S N 2 NONPOLAR SOLVENTS S N 1
  • 109.
  • 110.
    SOLVENT MIXTURES AREVERY COMMON Alkyl halides don’t dissolve in water, but dissolve in most organic solvents. Nucleophile salts don’t dissolve in most organic solvents, but dissolve in water. RX NaX soluble in EtOH soluble in H 2 O miscible solvents Both dissolve in a mixed solvent.
  • 111.
    EXCEPTIONS NaX Dissolvein polar-aprotic organic solvents: DMF, DMSO, HMPA. NaI and NaCN dissolve in acetone, but NaCl and NaBr do not
  • 112.
    CARBOCATIONS REACT WITHALL NUCLEOPHILES EQUALLY S N 1 S N 2 BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT THE BOTTOM LINE The nucleophile is not involved in the rate-determining step. The nucleophile is involved in the rate-determining step.